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Schizophrenia Research

Blunted activation in right ventrolateral prefrontal cortex duringmotor response inhibition in schizophrenia

Arthur Kaladjian a,b,⁎, Régine Jeanningros a, Jean-Michel Azorin a,b,Stephan Grimault c,d, Jean-Luc Anton c, Pascale Mazzola-Pomietto a

a Equipe Imagerie Cérébrale en Psychiatrie, CNRS, IFR 131, Marseille, Franceb Service de Psychiatrie Adulte, CHU Sainte Marguerite, Marseille, France

c Centre d'Imagerie par Résonance Magnétique fonctionnelle, IFR 131, Marseille, Franced Centre de Recherche en Neuropsychologie et Cognition, Université de Montréal, Canada

Received 20 March 2007; received in revised form 27 June 2007; accepted 26 July 2007Available online 12 September 2007

Abstract

Objectives: Previous functional magnetic resonance imaging (fMRI) studies have reported abnormal brain activation in individualswith schizophrenia during performance of motor inhibition tasks. We aimed to clarify brain functional abnormalities related tomotor response inhibition in schizophrenia by using event-related fMRI in combination with a Go–NoGo task designed to controlfor non-inhibitory cognitive processes involved in task performance.Method:We studied 21 schizophrenic patients and 21 healthy subjects, group-matched for age, sex, and performance accuracy on aGo–NoGo task during event-related fMRI. The task was designed so that Go and NoGo events were equally probable. Between-group activation differences were assessed using ANCOVAs with response time and IQ as covariates of non-interest.Results: Compared to healthy subjects, schizophrenic patients exhibited a significant decrease in activation during motor responseinhibition in the right ventrolateral prefrontal cortex (VLPFC) only. There were no areas of increased brain activation in patientscompared to healthy subjects.Conclusions: Schizophrenic patients demonstrate a blunted activation in the right VLPFC, a region known to play a critical role inmotor response inhibition. Further research should ascertain the contribution of the VLPFC dysfunction to the impulsive behaviorobserved in schizophrenia.© 2007 Elsevier B.V. All rights reserved.

Keywords: fMRI; Inhibition; Schizophrenia; Ventrolateral prefrontal cortex

⁎ Corresponding author. Equipe Imagerie Cérébrale en Psychiatrie,CNRS, IFR 131, 5ème étage, Aile Rouge, Faculté de Médecine Timone,27 Bd Jean Moulin, 13385 Marseille Cedex 05, France. Tel.: +33 491299 808; fax: +33 491 789 914.

E-mail address: arthur.kaladjian@medecine.univ-mrs.fr(A. Kaladjian).

0920-9964/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.schres.2007.07.033

1. Introduction

Schizophrenia has been frequently associated withimpaired inhibitory control. Subjects with schizophreniaperform poorly on a variety of executive function taskswhich require the ability to suppress the effects ofinterference, to ignore distractor stimuli or to inhibitbehavior in a specific context (Henik et al., 2002; Javittet al., 2000; Thoma et al., 2007b; Wang et al., 2005). They

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also demonstrate deficits in motor response inhibition,which refers to the ability to withhold a simple motor act(Badcock et al., 2002; Bellgrove et al., 2006; Thoma et al.,2007a; Weisbrod et al., 2000).

Different regions of the prefrontal cortex have beenfound to play a critical role in the deficits of inhibitorycontrol observed in schizophrenic patients, dependingon the type of inhibitory process examined. Recentevent-related potential and functional magnetic reso-nance imaging (fMRI) studies have demonstrated thatsubjects with schizophrenia exhibit reduced activity inthe anterior cingulate cortex (ACC) during performanceof tasks which are sensitive to cognitive forms ofinhibition, such as the Stroop task (Kerns et al., 2005),the Multi-Source Interference Task (Heckers et al.,2004), the Anterior Network Test (Neuhaus et al., 2007)and the Continuous Performance Task (Fallgatter et al.,2003). In the motor domain, most of the studies aimingto explore the neural correlates of response inhibitionhave used fMRI in conjunction with the Go–NoGo task.These studies have provided evidence that the profiles ofbrain activation associated with motor response inhibitiondiffer between schizophrenic patients and healthy controlsubjects. However, the findings are rather discordant.Rubia et al. (2001) reported that, compared to healthysubjects, schizophrenic patients demonstrate a decrease inactivation in the rostral ACC, whereas Laurens et al.(2003) observed a decrease in the posterior cingulatecortex. Another study reported reduced activation inseveral regions of the frontal lobe, including both rostraland dorsal ACC, as well as dorsolateral prefrontal cortex(DLPFC) (Arce et al., 2006). Finally, Ford et al. (2004)observed that schizophrenic patients have abnormalactivation in discrete brain areas of the prefrontal,temporal and parietal cortices.

Additionally, it remains unclear whether the cerebralfunctional abnormalities that have been previously ob-served in the fMRI studies of the Go–NoGo task inschizophrenia are specific to motor response inhibition.Theses studies used versions of the Go–NoGo task thatincluded a higher ratio of Go to NoGo trials to establish aprepotent response. Thus, activations associatedwithmotorresponse inhibition were entailed by those of the oddballeffects of the relatively rare NoGo trials. This contamina-tion may be problematic when studying schizophrenicpatients, because these patients exhibit abnormal neuralresponse to novelty processing (Kiehl and Liddle, 2001;Laurens et al., 2005). Additional concern with two of thesestudies comes from the use of a block-design, in whichbrain activation related to motor response inhibition wasdetermined by contrasting blocks containingmixedGo andNoGo events with blocks consisting entirely of Go events

(Arce et al., 2006; Rubia et al., 2001). The problem withthese contrasts is that they do not allow to disentangle theneural correlates of motor response inhibition from thoseassociated to extraneous cognitive processes such as errormonitoring and overcoming conflict in action selection.This problem may be especially relevant in ACC becauseschizophrenic patients exhibit an abnormal neural responsewithin this areawhen committing errors (Carter et al., 2001;Laurens et al., 2003), and during conflict resolution(Dehaene et al., 2003; Kerns et al., 2005). It is thereforedifficult to conclude that the functional brain abnormalitiespreviously reported in schizophrenia, when using a block-design approach and/or infrequent NoGo events, arespecifically related to motor response inhibition.

The present study was designed to clarify the neuralbasis of motor response inhibition in schizophrenia bycontrolling for the potential confounds mentioned above.We used a Go–NoGo task with equally probable Go andNoGo events to control for the oddball effects, and weestablished a response bias by using cues to signal theimpending presentation of an event, irrespectively of itstype (Liddle et al., 2001). Furthermore, we used an event-related fMRI design which allows to identify brainactivation specifically associated with successful responseinhibition by removing error-based activation from thefunctional maps and by minimizing activation associatedwith conflict. Therefore, we hypothesized that no signif-icant difference in ACC activation would be observedbetween schizophrenic patients and healthy subjects. Weexpected that patients with schizophrenia would show anabnormal activationwithin the right ventrolateral prefrontalcortex (VLPFC), a region which has been shown to becritically implicated in motor response inhibition (Aronet al., 2004).

2. Methods

2.1. Participants

Thirty-six inpatients with schizophrenia and 30 healthycontrol subjects participated in this study. All participantsmet the following inclusion criteria: 1) age 18–65 years; 2)no history of alcohol or drug abuse or other medical orneurological disorder that might affect brain function; 3)right-handedness as assessed using the Edinburgh Hand-edness Inventory (Oldfield, 1971); 4) no contraindicationfor fMRI. Participants were interviewed using the Frenchversion of the Structured Clinical Interview for DSM-IVAxis I Disorders, Patient Edition (SCID-I/P) and Non-patient Edition (SCID-I/NP). This interview confirmed thatall patients met the DSM-IV criteria for schizophrenia withno comorbid Axis I condition, and that none of the healthy

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subjects had a history of or current major psychiatricdisorder. Data from 15 patients were excluded because ofexcessive head motion, incomplete fMRI exam, orinsufficient performance accuracy on the Go–NoGo task.The 21 patients, whose data were retained in the statisticalanalyses, were group-matched on sex, age and taskperformance accuracy to 21 healthy controls. Within thetwo days following the fMRI exam, all participantscompleted the French version of the National AdultReading Test (fNART) (Mackinnon et al., 1999) andsymptom severity was rated in schizophrenic patients usingthe Positive And Negative Syndrome Scale (PANSS) (Kayet al., 1987). Patients whose data were included in the studywere receiving antipsychotic medication (18 atypical and 3typical) with a mean daily dose in chlorpromazineequivalent of 433.3 mg (S.D.=223.8) (Woods, 2003).The study protocol was approved by the local ethicscommittee. After complete description of the study, writteninformed consent was obtained.

2.2. Task

The Go–NoGo task used was adapted from Liddleet al. (2001). In this task, Go and NoGo stimuli wereequally probable. A prepotent response was established

Fig. 1. Schematic representation of the Go–NoGo Task. After a series of cues w(letter ‘A’) was presented for 250 ms. Participants were asked to respond as qubutton, and to withhold response to each presentation of the NoGo stimulus. Du

by introducing a series of cues to signal the impendingpresentation of a stimulus, no matter its type (Go orNoGo), thereby facilitating speeded responses to Gostimuli and increasing the difficulty of withholdingresponses to NoGo stimuli. The Go and NoGo stimuliconsisted of the letter ‘X’ and ‘A’, respectively (Fig. 1).Subjects were instructed to respond as quickly aspossible by pressing a button upon each presentationof the Go stimulus, and to withhold response on theappearance of the NoGo stimulus. The task consisted oftwo runs lasting 11 min 08 s each. Each run contained 25NoGo and 25 Go trials, presented in a pseudo-randomorder. Each trial began with the series of cues (5 s) thatconsisted of five presentations of a circle centered on afixation cross (250 ms) alternating with that of the solefixation cross (750 ms). The circle was reduced indiameter at each presentation. After the cues, either theGo or NoGo stimulus was presented for 250 ms. Thepresentation of each of these stimuli was followed by aninter-trial interval demarcated by the central fixationcross. Intertrial intervals were jittered over the range3083 to 29,000 ms to optimize the sampling of fMRIsignal. Errors of omission (EO), errors of commission(EC) and response times to correct trials (RT) wererecorded, and perceptual sensitivity (d′) and response

hich lasted 5 s, either the Go stimulus (letter ‘X’) or the NoGo stimulusickly as possible to each presentation of the Go stimulus, by pressing aring the entire task, subjects were instructed to fixate on the fixation cross.

Table 1Demographic and clinical characteristics of schizophrenic patients and healthy subjects

Characteristic Schizophrenic patients (N=21) Healthy subjects (N=21) Statistic

N % N % χ2 p-value

Gender (Male/Female) 19/2 90.5/9.5 19/2 90.5/9.5 0 1.0DSM-IV Subtype

Paranoid 17 81.0Disorganized 1 4.8Undifferentiated 2 9.5Residual 1 4.8

Mean SD Mean SD t p-value

Age (years) 34.9 9.5 35.7 13.6 − .24 .814Edinburgh handedness score (%) 93.5 10.2 89.8 9.6 1.20 .238Estimated IQ a 106.1 4.3 111.6 4.1 −4.23 .000Illness duration (years) 12.8 9.4PANSS total score 69.2 12.6

Positive symptoms score 17.8 4.7Negative symptoms score 22.2 6.1General psychopathology score 29.2 8.8a Estimated from the French version of the National Adult Reading Test.

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bias (beta) were calculated for each subject. Beforescanning, a short practice session of the task wasperformed to ensure that the instructions had beencorrectly understood.

2.3. Data acquisition

Images were obtained using a 3 T whole body MRIscanner (Medspec 30/80 AVANCE, BRUKER, Ettlin-gen, Germany) with a circular polarized head coil. Avacuum-bag was used to limit head movements withinthe coil. An axial anatomical volume was acquired usinga 3D T1-weighted MPRAGE sequence (TI=800 ms,TR= 25 ms, TE= 5 ms, Trecov = 2300 ms, flipangle=15°, field of view=25.6×23.0×18.0 cm, voxelsize=1×1.2×1.73 mm). Blood-oxygen-level-depen-dent (BOLD) images were acquired using a T2⁎-weighted FID echoplanar sequence (36 contiguousinterleaved axial slices, TR=3000 ms, TE=35 ms, flipangle = 83°, field of view=19.2×19.2 cm, voxelsize=3×3×3 mm). Anatomical and BOLD imageswere collected during a single acquisition period.

2.4. Statistical analysis

The sociodemographic characteristics, clinical rat-ings, and behavioral task measures of the schizophrenicpatient and healthy subject groups were compared usingchi-square and two-sample Student's t tests, as appro-priate. The relationships between two variables wereexamined using Pearson's correlation analyses.

Image data were analyzed with SPM99 (WellcomeDepartment of Cognitive Neurology, London). Functionalimages of each subject were first corrected for slice timingandmotion. Themotion did not exceed 3mm in translationand 1.7° in rotation for any participant. In addition,whatever the direction considered in either translation orrotation, no significant difference for absolute andincremental mean displacement was observed betweenschizophrenic patients and healthy subjects (Wilks'lambda=.63, F(12, 29)=1.39, p=.225). The T1 imagewas then normalized to the standard SPM/MNI templateand the resulting transformation matrix was applied to allthe corresponding functional images for each subject.Finally, images were smoothed with a Gaussian filter (9-mm kernel). The data were high-pass-filtered (120 s cut-offperiod) to remove low-frequency signal drifts.

An event-related statistical analytical design, whichtook into account the trial outcomes and the preparationphase, was constructed for each individual subjectwithin the framework of the general linear model(Friston et al., 1995). Four types of trial outcomeswere distinguished: correct Go trial, incorrect Go trial,correct NoGo trial, incorrect NoGo trial. Each of themwas modeled with a canonical hemodynamic responsefunction. The preparation phase was modeled with adelayed box-car function convolved with a hemody-namic response function. In the first level of analysis,we assessed regional brain activation associated withsuccessful motor response inhibition by creating, foreach individual subject, one statistical contrast: correctNoGo minus correct Go trials. The contrast images of

Table 2Behavioral performance, response bias and perceptual sensitivity during the Go–NoGo task in schizophrenic patients and healthy subjects

Schizophrenic patients Healthy subjects Statistic

Mean SD Mean SD t p-value

AccuracyErrors of omission (%) .76 2.23 .19 .60 1.13 .264Errors of commission (%) 9.8 9.3 8.1 6.9 .66 .510

Response time in correct Go trials (ms) 398.9 61.0 343.7 40.3 3.46 .001Perceptual sensitivity (d′) 3.70 .67 3.82 .48 − .71 .483Response bias (beta) .38 .34 .29 .17 1.10 .282

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this first level of analysis were used for the second-levelgroup statistics. An initial examination of within-groupactivation was made up for each group separately bycomputing one-sample t tests. Between-group differ-ences in activation were assessed by using ANCOVAswith estimated IQ and RT as covariates of non-interest.Furthermore, to avoid confounding effects of relativedeactivation in one group, the between-group compar-isons were constrained with an inclusive mask in whichonly voxels surviving a height threshold of pb .05 forwithin-group analyses were retained. Activations werereported if they exceeded pb .001 uncorrected formultiple comparisons at the voxel level and pb .05

Table 3Brain areas showing significant activation during response inhibitiona in hea

Group and region Brodmann'area

Healthy subjectsLeft superior and bilateral medial frontal gyri 6/ 8/9/10Left middle and inferior frontal gyri 9/45/47Right inferior frontal gyrus 11/45/47Bilateral medial frontal gyri 10/32Left middle temporal gyrus 21Right middle temporal gyrus 21Left inferior parietal lobule and angular gyrus 39/40Right inferior parietal lobule and supramarginal gyrus 39/40Bilateral posterior cingulate and precuneus 7/31Left middle occipital gyrus and cuneus 18/19Right middle occipital gyrus and cuneus 18/19

Schizophrenic patientsLeft superior frontal gyrus 9Left middle and superior frontal gyri 6/8Right middle frontal gyrus 8Left superior parietal lobule and precuneus 7/19Right precuneus and angular gyrus 7/19/39Bilateral posterior cingulate and precuneus 7/31Left middle occipital gyrus 19

Healthy subjectsN schizophrenic patientsc

Right inferior frontal gyrus 45/47aAssessed by the contrast “correct NoGo trials versus correct Go trials” (pblevel).bFor peak area of activation.cAssessed by an ANCOVAwith IQ and RT as covariates of non-interest.

corrected at the cluster level. MNI coordinates weretransformed to Talairach coordinates (Talairach andTournoux, 1988) using a nonlinear transformation(Brett, 2000).

3. Results

3.1. Demographic, psychometric and behavioral data

Schizophrenic patients and healthy subjects wereclosely matched in terms of sex, age and handedness(Table 1). Patients had significantly lower estimated IQthan controls.

lthy subjects and schizophrenic patients

s Zscore

Talairach coordinatesb Number ofvoxels

x y z

5.45 −9 48 36 6874.94 −42 20 40 4355.09 45 29 −9 1334.41 0 52 −8 2274.08 −59 −29 −1 874.83 53 −9 −7 1124.73 −48 −56 50 2965.24 50 −57 28 1884.23 0 −57 30 1425.17 −39 −64 −2 2895.50 27 −81 18 316

4.18 −15 42 31 655.11 −36 11 44 1894.31 30 25 40 844.37 −33 −72 48 875.14 27 −74 42 3484.14 −3 −62 47 2073.99 −27 −69 26 46

4.61 45 23 −1 51

.001 uncorrected at the voxel level and pb .05 corrected at the cluster

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There were no significant between-group differencesregarding task performance accuracy (i.e., percentage ofEO and EC) (Table 2). A significant between-groupdifference for RT was found, with patients beingsignificantly slower than healthy subjects. Perceptualsensitivity (d′) and response bias (beta) did notsignificantly differ between the two groups, indicatingthat patients and control subjects distinguish withsimilar ease the Go and NoGo stimuli and developequivalent tendency toward responding.

There were no significant correlations between taskperformance measures (i.e., EC, EO, RT, d′ and beta)(all p valuesN .5) in the patient group nor in the controls.Moreover in the patient group, none of the taskperformance measures were significantly correlatedwith either symptom severity measures (i.e., PANSSscores) or antipsychotic dosages (all p values N .1).

3.2. fMRI data

Within-group analysis in healthy subjects demonstrat-ed significant activation during response inhibition in adistributed network of brain areas (Table 3 and Fig. 2A).The areas were localized in the left anterior dorsomedialprefrontal cortex (Brodmann's area [BA] 6, 8, 9, 10), left

Fig. 2. Statistical parametric maps depicting significant regional brain actischizophrenic patients (B). Motor response inhibition was assessed by the conare surface-rendered onto transaxial slices of a standard reference brain. Actiand pb .05 corrected at the cluster level.

DLPFC and VLPFC (BA 9, 45, 47), right VLPFC/lateralorbitofrontal cortex (BA 11, 45, 47), and bilateral anteriormedial prefrontal cortex and rostral ACC (BA 10, 32).Significant activations were also detected bilaterally in themiddle temporal gyri (BA 21), inferior parietal lobule andadjacent areas (BA 39, 40), posterior cingulate andprecuneus (BA 7, 31), and middle occipital gyri andcuneus (BA 18, 19). Within-group analysis in schizo-phrenic patients demonstrated significant activationduring response inhibition in a less widespread networkof brain areas than that observed in healthy subjects,particularly in inferior areas of both frontal and posteriorbrain regions (Table 3 and Fig. 2B). In the frontal lobe,activations were localized in the left anterior dorsalprefrontal cortex (BA 9) and bilateral dorsal prefrontalcortices (left BA 6, 8; right BA 8). In posterior brainregions, significant activations were observed in the leftsuperior parietal lobule and precuneus (BA 7, 19), rightprecuneus and angular gyrus (BA 7, 19, 39), bilateralposterior cingulate and precuneus (BA 7, 31), and leftmiddle occipital gyrus (BA 19). Between-group compar-isons revealed that the schizophrenia group had signifi-cantly less activation during response inhibition than thecontrol group in the right VLPFC only (BA 45, 47)(Table 3 and Fig. 3). In contrast, the schizophrenia group

vation during motor response inhibition in healthy subjects (A) andtrast “correct NoGo trials versus correct Go trials”. Regional activationsvation maps were thresholded at pb .001 uncorrected at the voxel level

Fig. 3. Statistical parametric maps depicting a significant decrease inactivation in the right VLPFC during motor response inhibition inschizophrenic patients as compared to healthy subjects, after covaryingfor IQ and RT. The right VLPFC cluster is surface-rendered onto acanonical image and a transaxial slice of a standard reference brain.Activation maps were thresholded at pb .001 uncorrected at the voxellevel and pb .05 corrected at the cluster level.

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did not show any significant areas of increased activationrelative to the control group.

4. Discussion

In the present study, we compared the neural correlatesof successful motor response inhibition in schizophrenicpatients and control subjects, by using a Go–NoGo taskwith equally probable Go and NoGo events and an event-related fMRI design. The main result is that a reducedactivation in the right VLPFCwas found in schizophrenicpatients during motor response inhibition.

Converging evidence coming from different experi-mental approaches suggest that the right VLPFC is a keyregion in mediating motor inhibitory processes. Neuro-imaging studies using either the Go–NoGo or Stop-

signal tasks have consistently reported the contributionof the right VLPFC in the neural circuitry subservingresponse inhibition in healthy subjects (Garavan et al.,1999; Horn et al., 2003; Menon et al., 2001). Additionalsupport for the critical role of this region in mediatingmotor response inhibition has been provided by a recentstudy using transcranial magnetic stimulation paradigmin conjunction with a Stop-signal task in healthy subjects(Chambers et al., 2006). In this study, it was observedthat temporary deactivation of the right VLPFCselectively impairs the ability to stop an ongoingresponse. Consistent evidence for the relation betweenright VLPFC integrity and motor response inhibitionalso comes from a clinical study showing that patientswith acquired lesions of the right VLPFC, but not otherregions of the right or left prefrontal cortex, demonstratedeficits in response inhibition during performance of aStop-signal task (Aron et al., 2003). The greater thedamage to this region, the worse was the responseinhibition. It is also interesting to note that reducedactivation in the right VLPFC during motor responseinhibition has been found in fMRI studies performed inimpulsive patients suffering from attention-deficit/hyper-activity disorder (Rubia et al., 2005) or mania (Altshuleret al., 2005). A decrease in brain perfusion in the rightVLPFC has also been demonstrated in a SPECT study inpersonality disorders characterized by impulsive behav-ior, including borderline and antisocial personalitydisorders (Goethals et al., 2005). Our findings inschizophrenic patients provide further neuro-functionalevidence to suggest that a right VLPFC dysfunction is akey feature in psychiatric disorders in which impulsivebehavior is frequently observed. This assertion isreinforced by the data of a diffusion tensor imagingstudy inwhich lower fractional anisotropy in right inferiorfrontal region was associated with higher motor impul-sivity in schizophrenic patients (Hoptman et al., 2002).

In the present study, we hypothesized that we wouldnot detect between-group difference in ACC activationbecause our experimental design would not allow toprobe the function of this area. Therefore, we wereintrigued to observe, in healthy subjects, a significantcluster of activation which extended from the medialfrontal gyrus (BA 10) to the rostral ACC (BA 32) duringsuccessful motor response inhibition. Furthermore, wenoticed that if we had used a slightly more liberalstatistical threshold for the between-group comparison(pb .005 uncorrected), a reduced activation would haveemerged within the rostral ACC in schizophrenicpatients (k=54; Z=4.03; x=−3, y=41, z=1). Twoprevious fMRI studies using a Go–NoGo task inschizophrenic patients have reported a decreased activation

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during response inhibition in a similar area of the rostralACC (Arce et al., 2006; Rubia et al., 2001). Rostral ACC isthought to subserve emotional rather than cognitiveprocessing (Bush et al., 2000). In particular, its activityhas been associated with the emotional response accom-panying errors during performance of cognitive interfer-ence andmotor response inhibition tasks in healthy subjects(Critchley et al., 2005; Matthews et al., 2005; Taylor et al.,2006). In the present study, given that we excluded errorsfrom the fMRI data analysis, it is likely that emotionalprocessing associated with motor response inhibition wassufficient to activate rostral ACC in healthy subjects, butnot to detect significant between-group difference inactivation within this area. We also speculate that ifprevious fMRI studies on motor response inhibition haveobserved significant decreased activation in rostral ACC inschizophrenic patients, it is because they used a block-design approach. This would engage greater emotionalprocessing in the mixed Go–NoGo blocks (e.g., thosearising from the processing of errors and conflict) than inthe pure Go blocks, leading to greater activation in healthysubjects than in patients. In line with this interpretation,Laurens et al. (2003) reported that schizophrenic patientshave a blunted activation in rostral ACC during errors in aGo–NoGo task, and suggested that aberrant recruitment ofthis area reflects disturbed emotional response to havingcommitted an error.

One of the important issues of the present study iswhy schizophrenic patients evidenced less neuralresponse than healthy subjects, despite similar perfor-mance accuracy on the task. Reduced brain activationdespite preserved accuracy on the Go–NoGo task hasbeen previously reported in schizophrenia (Arce et al.,2006; Rubia et al., 2001). One possible explanation forthis discrepancy is that, to compensate for the localizedfunctional deficit in the right VLPFC and maintain taskaccuracy, patients recruited additional neural resourceswhich may have been either too heterogeneous or toofunctionally discrete to be visualized. Alternatively, it ispossible that inhibitory performance as indexed in theGo–NoGo tasks by the rate of errors is not an enoughsensitive measure of the ability to inhibit (Aron et al.,2004). Therefore, we cannot formally exclude the notionthat the right VLPFC dysfunction reflects undetectedperformance abnormalities in schizophrenic patients.

The present study has several possible limitations. First,it is possible that medication may have contributed to thebetween-group difference in the right VLPFC response thatwe observed. Therefore, in the schizophrenia group, weperformed correlation analysis between antipsychoticdosage and the magnitude of activation within this region,as assessed by a ROI approach. No significant correlation

(r=.34, p=.126) was observed, suggesting minimalconfounding effect of medication. A second limitationcomes from the difference in IQ and RT that we observedbetween schizophrenic patients and healthy subjects.Although IQ and RT were covaried using ANCOVAs,this approach cannot entirely rule out the possibility that thebetween-group difference in activation might be related toslower response time or lower IQ. In an effort to assess RTeffects on the neural responses,we carried out a comparisonbased on subgroups matched on RT (t(30)=1.20, p=.241),in addition to age, sex, and performance accuracy. Weobserved that the schizophrenia subgroup continued todemonstrate significantly reduced activation in the rightVLPFC only, in a cluster which had similar characteristics(k=46; Z=4.09; x=42, y=29, z=1) than those of thecluster observed in the analysis based on all subjects,suggesting that between-group difference in RT cannotexplain the fMRI results. In the present study, we were notable to match subgroups on IQ. Finally, it should be notedthat most of the patients included in this study were of theparanoid subtype. It is likely, as suggested by Arce et al.(2006), that the overrepresentation of the paranoid subtypeis a sampling bias which results from the inclusion ofpatients showing the best accuracy task performances.Thus, it may be suggested that patients with paranoidschizophrenia have reduced VLPFC activation duringmotor response inhibition despite preserved performanceaccuracy on the task. Additional studies are needed togeneralize these findings to the other subtypes ofschizophrenia.

In summary, our data indicate that, in comparison tocontrol subjects, patients with schizophrenia have adeficit in their ability to engage right VLPFC duringsuccessful motor response inhibition. Further researchshould ascertain the role that such deficit may play in theimpulsive behavior observed in schizophrenia.

Role of the funding sourceFunding for this study was provided by the CNRS. The CNRS

had no further role in study design; in the collection, analysis andinterpretation of data; in the writing of the report; and in the decision tosubmit the paper for publication.

ContributorsKaladjian A. participated to the study and protocol design. He was

in charge of patients inclusion and diagnosis. He undertook, withMazzola-Pomietto P., the statistical analyses of the data and the writingof the first drafts of the manuscript.

Jeanningros R. had the idea of this study. She was involved in itsdesign, in the interpretation of the results, as well as in the writing ofthe protocol and of the different drafts of the manuscript.

Azorin J.M. overlook the clinical aspects of this study and participatedto patients recruitment.

Grimault S. contributed to this work by providing help for thefMRI data analysis.

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Anton J.L. provided MRI acquisition sequences and programmedthe behavioral task. He also participated to the fMRI data acquisitionand analyses.

Mazzola-Pomietto P. participated to the study and protocol designShe was in charge of healthy subjects recruitment and fMRI dataacquisition. She undertook, with Kaladjian A., the statistical analysesof the data and the writing of the first drafts of the manuscript.

All authors approved the final draft of the manuscript.

Conflicts of interestThe authors had no conflicts of interest.

AcknowledgementsThe authors thank Bruno Nazarian and Muriel Roth, who assisted

in the fMRI task design and data acquisition, and Hélène Rescignowho helped with the behavioral data analysis and literature search. Wealso thank Krista Hyde who provided helpful comments duringmanuscript preparation.

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