European Neuropsychopharmacology (]]]]) ], ]]]–]]]

0924-977X/$ - see frohttp://dx.doi.org/1

nCorrespondenceHuman Cognitive NPavilion, 6875 BouleTel.: +1 514 761 613

E-mail address: b

Please cite this artAn ERP.... Europea

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Effects of a small dose of olanzapine on healthysubjects according to their schizotypy: An ERP studyusing a semantic categorization and an oddball task

J. Bruno Debruillea,b,c,n, Mitchell Rodiera,b, Marie Pr �evosta,b, Claire Lionneta,Siamak Molavia

aResearch Center of the Douglas Mental Health University Institute, Montr �eal, Qu�ebec, CanadabDepartment of Neurology and Neurosurgery, McGill University, Montr �eal, Qu �ebec, CanadacDepartment of Psychiatry, McGill University, Montr �eal, Qu�ebec, Canada

Received 25 January 2012; received in revised form 23 May 2012; accepted 7 June 2012

KEYWORDSAntipsychotics;Schizotypal traits;Semantics;Event-related brainpotentials;N400

nt matter & 20120.1016/j.euroneur

to: Douglas Mentaeuroscience Labvard LaSalle, Mon1x3405; fax: +1 51

runo.debruille@m

icle as: Debruille,n Neuropsychopha

AbstractDelusions and hallucinations are often meaningful. They thus reveal abnormal semanticactivations. To start testing whether antipsychotics act by reducing abnormal semanticactivations we focused on the N400 event-related brain potential, which is elicited bymeaningful stimuli, such as words, and whose distribution on the scalp is known to dependon the semantic category of these stimuli. We used a semantic-categorization task speciallydesigned to reduce the impact of the variations of context processing across subjects’ groupsand a classical oddball task as a control. Healthy subjects were recruited rather than psychoticpatients to ensure that the medication effects could not be secondary to a reduction ofsymptoms. These participants (n=47) were tested in a double-blind cross-over paradigm wherethe ERP effects of 2.5 mg of olanzapine taken on the eve of the testing were compared to thoseof the placebo. The amplitudes of the N400s elicited by the target words were greater atanterior scalp sites in the half of the subjects having higher schizotypal scores. Olanzapinereduced these larger N400s and had no effect on the small anterior N400s of the half of thesubjects with lower scores. These results are discussed as consistent with the idea thatantipsychotics reduce abnormal activations of particular semantic representations. Furtherstudies should thus be done to see if this reduction correlates with and predicts the decrease ofpsychotic symptoms in patients.& 2012 Elsevier B.V. and ECNP. All rights reserved.

Elsevier B.V. and ECNP. All rightso.2012.06.005

l Health University Institute,oratory, Frank B. Commontr�eal, Canada QC H4H 1R3.4 8884099.

cgill.ca (J.B. Debruille).

J.B., et al., Effects of a small dosrmacology (2012), http://dx.doi.

1. Introduction

Most often, the so-called positive symptoms of schizophre-nia are meaningful. This is obvious for many delusions, suchas when the patient believes he is persecuted by a powerful

reserved.

e of olanzapine on healthy subjects according to their schizotypy:org/10.1016/j.euroneuro.2012.06.005

2Results were more complex when focusing on each of the threeparticular clinical dimensions and controlling for the two others.

J.B. Debruille et al.2

organization, and for many hallucinations, such as when thepatient hears voices that comment on his/her actions.These common psychotic symptoms reveal the activationof inappropriate semantic representations. Another symp-tom of schizophrenia, speech disorganization, may alsoreveal inappropriate semantic activations. These symptomsare reduced by antipsychotic medications and, in contrastto what was previously thought, these reductions startquickly, that is, a few hours after the intake of antipsycho-tics (Agid et al., 2008). The present work is aimed at testingwhether these fast decreases of symptoms are mediated bya direct reduction of abnormal semantic activations.

In cognitive neuroscience, the activation of semantic repre-sentations is usually studied by exploring the brain activitiestriggered by the presentation of a meaningful stimulus, such asa word, a face or an object. In the electrophysiologicaldomain, such presentations give rise to the N400, a negativegoing brain potential whose voltage is maximum around 400 msafter the onset of the stimulus. According to several authors,this N400 is an index of semantic activations (see Kutas et al.,2006 for a review).1 Recent studies have brought a new type ofsupport to this idea. These studies have shown that the N400 isof larger amplitude for words that activate more representa-tions, such as for concrete words (e.g., apple) than for abstractwords (e.g., idea), in accordance with the fact that the lattercould activate only verbal representations (Holcomb et al.,1999; Renoult et al., 2010). Most interestingly, the distributionof the N400 on the scalp depends on the nature of the semanticrepresentations activated by the stimulus. The voltages of theN400s elicited by isolated concrete words, for instance, aregreater over the anterior scalp area than those of the N400striggered by isolated abstract words (Holcomb et al., 1999).Within concrete words, the N400s elicited by names of animalshave a different distribution on the scalp than the N400selicited by names of objects (Sim and Kiefer, 2005; Renoult andDebruille, 2011). These distributions are thus used to study theparticular semantic representations activated by differenttypes of words (for concrete vs. abstract words, see Huanget al., 2010; Welcome et al., 2011; for action verbs, see Leeand Federmeier, 2008; for ambiguous vs. non ambiguous wordssee Lee and Federmeier, 2008; for animal vs. artifact namessee, Proverbio et al., 2007). The results of these studiesillustrate, among other things, the theory of grounded cogni-tion (Barsalou, 2008) according to which perceptual and actionrepresentations are also used to code for meanings.

This study of the scalp distributions of the N400 couldthus be used to explore the inappropriate activations ofsemantic representations revealed by the positive symp-toms of people suffering from schizophrenia. However,these explorations have not yet been done. In schizophreniapatients, the N400s have mainly been recorded to assess avery different effect. Namely, there were run to measurethe effect of the semantic activations induced by priorstimuli (Kiang et al., 2008; Kreher et al., 2009). When thisprior stimulus (e.g., nurse) is semantically related to atarget stimulus (e.g., doctor), the N400 elicited by thetarget word is of smaller amplitude, possibly because the

1According to another view (Debruille, 2007), the amplitude ofthe N400 is proportional to semantic activations because it reflectscompensatory processes that follow these activations and dependon them.

Please cite this article as: Debruille, J.B., et al., Effects of a small doAn ERP.... European Neuropsychopharmacology (2012), http://dx.doi.

semantic activation that remains to be performed by thetarget word is smaller when related primes already acti-vated part of the relevant representations. This, nowclassical phenomenon, called N400 semantic priming, hasbeen extensively studied in schizophrenia patients and inpeople with schizotypal traits. As mentioned, these studiesonly focused on the semantic relation between primes andtargets. They were run without controlling for the possiblevariations, across subjects’ groups, of the semantic activa-tions induced by the target words themselves. Two mainresults tended to be found according to the delay betweenthe onset of the prime word and the onset of the targetword (i.e., according to the SOA). With short SOAs (e.g.,300 ms), several studies reported an abnormal priming inpatients relative to normal controls, especially in thoughtdisordered patients. The N400s elicited by unrelated targetswere smaller in patients than in normals, suggesting thatthe prime activated inappropriate representations (Kreheret al., 2009), an idea supported by other studies (e.g.,Gouzoulis-Mayfrank et al., 2003). In contrast, with longSOAs (e.g., 2 s), N400s to related targets were found greaterin patients and people with schizotypal traits than in normalcontrols, suggesting a reduced priming. These latter resultshave been interpreted as illustrating a difficulty at main-taining and using the context defined by the prime toprocess upcoming stimuli (Kiang et al., 2007).

This latter difficulty could have a major importance whenstudying the scalp distribution of the N400s elicited byisolated target words. In the studies mentioned at first, theN400 scalp distribution differences reported between isolatedconcrete and abstract words or between isolated animal andobject names were obtained in tasks in which subjects wereinstructed before the experiment to categorize the namesalong these lines. These instructions constitute a semanticcontext whose maintenance in working memory may not beidentical in patients and normal controls. This inequality ofcontexts could be responsible for N400 differences acrosssubjects’ groups. To prevent this possibility, we designed asemantic categorization task in which the instruction isrepeated at the start of each trial so that it constantlyrefreshes the subject’s working memory (Debruille et al.,2010; Prevost et al., 2010). More precisely, it was thequestion word ‘‘animal?’’. In these conditions, we found thatthe anterior part of the N400s were of greater amplitudes insubjects with high- than in subjects with low-scores ofschizotypy (Prevost et al., 2010).2 This was particularly thecase for the category exemplars, that is, for names ofanimals, and somewhat less so for non-exemplars, that is,for names of objects. These results supported the idea thateven the mild equivalents of schizophrenia symptoms mea-sured by schizotypy scales go with abnormal activations ofparticular semantic representations.

Interestingly, N400s of schizophrenia patients currentlytreated with antipsychotics (i.e., haloperidol) have been

However, this complexity might derive from the number of parti-cipants that could have been unsufficient to allow this focus and thecontrol performed. Thus, here, we only use the global results of thisstudy, that is, the greater anterior N400s in participants with higherschizotypal scores.

se of olanzapine on healthy subjects according to their schizotypy:org/10.1016/j.euroneuro.2012.06.005

Table 1 Demographic and clinical characteristics ofthe participants with high scores at the schizotypalpersonality questionnaire (SPQ) and of those with lowscores.

High SPQN=23

Low SPQN=24

Mean(St. dev.)

Mean(St. dev.)

Mean age 28.7 (10.0) 31.8 (11.1)Numbers of years of study 14.1 (1.9) 14.5 (1.7)Mean global SPQ scores 29.9 (10.4) 7.4 (4.9)Mean scores for interpersonalfactor

11.3 (5.9) 2.8 (2.5)

Mean scores for disorga-nization

6.8 (3.4) 2.1 (2.1)

Mean scores for delusion 8.5 (3.5) 1.8 (1.8)

Olanzapine reverses schizotypy effect on anterior N400 3

compared to those of patients receiving a placebo in twoprevious studies (Condray et al., 1999, 2003). In these twostudies, for target words that matched their context words,anterior N400s appear smaller in patients with medicationthan in patients with placebo. Antipsychotics could thusnormalize anterior N400s. However, this reduction of theanterior N400 can be seen only in one of the two conditionsof these studies, the low-expectancy condition, in which thecontext words used rarely primed the target words. More-over, the reduction of the anterior N400s detected could beonly secondary to the alleviation of psychotic symptomsinduced by the medication, rather than reflecting a directeffect of the antipsychotic on semantic processes.

The present study is thus an attempt at replicating the largeranterior N400s found in healthy subjects with high scores ofschizotypy in Prevost et al. (2010) and at seeing whether theycan be reduced by an antipsychotic. To lower the odds that suchan effect could be secondary to a delayed cognitive changesecondary to the alleviation of symptoms, we again usedhealthy subjects having more or less schizotypal traits and wemeasured the effect immediately, that is, a few hours after asingle dose of the medication. To see whether the ERP effectswould be specific to semantic processing, we also recordedERPs in a classical oddball task with meaningless stimuli.

2. Experimental procedure

2.1. Participants

Forty-seven right-handed participants (34 women) aged between 18 and49 years were recruited by advertisements in an English and in a Frenchnewspaper. Participants who answered these ads were asked what theirmother tongue was. Only English and French were accepted. The rest ofthe procedure was carried in the language of the participants. They hadto have normal or corrected-to-normal vision and were screened bytelephone and systematically excluded for any history of DSM-IV Axis Ipsychiatric illnesses, except for depressive episodes that resolved atleast two years ago. The procedure to recruit the participants included,first, a short questionnaire made of the 16 items of the ‘odd belief andmagical thinking’ and ‘ideas of reference’ subscales of the schizotypalpersonality questionnaire (SPQ, Dumas et al., 2000; Raine, 1991). Theywere used to pre-assess delusional-like ideation over the phone. In thefirst phase of the recruitment, only those who scored 5 or more out of16 (the maximal score) were asked to participate in the study (n=23), inorder to have enough participants with high delusional-like ideationscores and, presumably, high SPQ total scores. No- or low-delusional-likeideation participants (n=24) were recruited in a second phase amongpeople with delusional-like ideation scores smaller than five and whosedemographic characteristics (age, gender and number of years ofeducation) matched those of the high-delusional-like ideation scoreparticipants. Participants with a history of head injury with loss ofconsciousness longer than 5 min were excluded, as well as participantswith neurological or medical conditions known to compromise brainfunction and participants abusing drugs. At their arrival in the lab, allparticipants gave written informed consent after the procedures weredescribed according to the criteria of the Research and Ethics Board ofthe Douglas Mental Health University Institute, which approved both thestudy and the consent form.

2.2. Procedure and tasks

Participants came three times into the laboratory. At the firstsession, they read and signed the informed consent and were given,in a double-blind way, either a capsule containing 2.5 mg of

Please cite this article as: Debruille, J.B., et al., Effects of a small dosAn ERP.... European Neuropsychopharmacology (2012), http://dx.doi.

olanzapine or a capsule having an identical appearance but contain-ing saccharose, the placebo. They were asked to take this capsuleon the eve of the second session. The second capsule was given tothem at the end of that second session and they were asked to takeit on the eve of the third session. Thus, for the 2nd and 3rd sessions,participants came in the lab at least 12 h after taking theircapsules. This long delay was found necessary to avoid anypossibility that the participants would fall asleep while driving tothe lab after taking olanzapine. Half of the subjects received theplacebo first and then, the olanzapine, the other half started witholanzapine and had the placebo for the third session. The minimumdelay between the 2nd and 3rd session was 48 h and the maximumdelay was 5 weeks.

During the 1st session, participants were also asked to fill theentire schizotypal personality questionnaire, the SPQ. This ques-tionnaire is based on the DSM-III-R criteria for schizotypal person-ality disorder and includes nine subscales that can be grouped intothree clusters or factors: (1) interpersonal, (2) disorganization, and(3) cognitive-perceptual (Raine et al., 1994). The validity of thewhole SPQ has been demonstrated (Raine, 1991). Its clusters havebeen defined by a factor analysis (Raine et al., 1994) and used inmany previous studies (e.g., Kiang and Kutas, 2005; Sommer et al.,2010). In addition to the total score, a score for delusional-likeideation was computed by adding the score for the ‘odd beliefs ormagical thinking’ subscale to that obtained for the ‘ideas ofreference’ subscale. The score for the ‘paranoid ideation’ subscalewas not entered into the delusional-like ideations computation as itwas part of the interpersonal factor. This interpersonal score wascomputed by adding the scores for the ‘social anxiety’, the ‘noclose friends’, the ‘constricted affect’ and the ‘paranoid ideation’subscale. The disorganization trait score was calculated by addingthe score for the ‘odd speech’ subscale to the score for the ‘odd oreccentric behavior’ subscale. Both subscales load on the samefactor (disorganization) in general and clinical populations(Reynolds et al., 2000). The sample was divided into a subgroupof High- and a subgroup of Low-SPQ scorers using a median split.Table 1 provides the characteristics of each subgroup.

The 2nd and 3rd sessions took place 12–18 h after the intake ofone of the two capsules. During each of these sessions, participantshad to fill two questionnaires and to perform the two ERP tasks. Thefirst questionnaire included nine items assessing the subjectivelevel of energy of the participant, mood and side-effects. Each itemhad to be rated on a 10 points Likert scale. The second ques-tionnaire was the state part of the state and trait anxiety inventory

e of olanzapine on healthy subjects according to their schizotypy:org/10.1016/j.euroneuro.2012.06.005

J.B. Debruille et al.4

(STAI-A, Spielberger, 1983). It was used to control for the reductionof anxiety the medication should induce.

The N400 task was the semantic-categorization task fullydescribed previously (Debruille et al., 2007, 2010; Prevost et al.,2010). For this task, subjects are seated comfortably in a dimly litroom and have to stare at a computer screen placed 1 m from theireyes. Black stimuli are presented on a white background at thecenter of this screen. Trials are made of two serially presentedwords. In two-third of the trials, the first word is the question word‘‘ANIMAL?’’. Having the same context word in the majority of thetrials is aimed at refreshing its representation in working memory inall subjects, and thus, at cancelling the variations of target N400sacross participants that can be due to variations of contextprocessing (Debruille et al., 2010). In one-third of the trials, thefirst word was the instruction ‘‘INACTION’’. It was introduced onlyto prevent habituation to the question word ‘‘ANIMAL?’’. Thesewords were then followed by the target word. The stimulus onsetasynchrony (SOA) was 2 s and each word was displayed for 1 s. Thislong SOA was chosen together with an explicit semantic categoriza-tion task because both have been shown to lead to larger N400potentials thus boosting the sensitivity of the test (Chwilla et al.,1995; Holcomb, 1988). The target word was either an exemplar ofthe animal category (e.g., dog) or a non-exemplar of this category(e.g., table). Subjects had to decide whether or not the target wordbelongs to the animal category as rapidly and as accurately aspossible by pressing one of two keys with their right index finger.The ‘‘INACTION’’ word signaled to the participants that they shouldnot respond to the target stimulus, which was also either anexemplar or a non-exemplar of the animal category. Exemplarand non-exemplars words were matched for number of letters andfrequency of usage using the Content et al. (1990) data base for theFrench words and the (Kucera and Francis, 1967) counts for theEnglish words. In the ‘‘ANIMAL?’’ condition, there were 60 trialswith the exemplar target word and 60 trials with the non-exemplartarget word. For the ‘‘INACTION’’ condition, there were 30 trials foreach of the two stimulus categories. The target word was followed2–2.5 s later by the word ‘‘Blink’’, giving the subjects the opportu-nity to blink without disrupting the electroencephalogram (EEG)signal during the trial. Target words were presented just once.There was thus no repetition across the 2nd and 3rd sessions oftesting. The particular stimulus sequences used for these sessionswere counterbalanced across subjects in each participant subgroup.

The classical auditory oddball task has also been fully describedelsewhere (Renoult et al., 2007; Debruille et al., 2005). In this task,the target is a 2000 Hz tone presented in 20% of the trials. The non-target is a 1000 Hz tone presented in 80% of the trials. Target andnon-target stimuli are delivered in a pseudo-random order andbinaurally at a 70 dB sound pressure level for 100 ms with a rise/falltime of 10 ms. Adjacent stimuli are separated by a 1440 ms inter-stimulus interval. The experiment includes four blocks containing150 stimuli each and separated by 5 min intervals. In each block,subjects have to mentally count the number of times the targettone is presented and to keep their eyes open. After each block,subjects are asked how many target stimuli they counted. Targetcount accuracy is computed as the difference between the correctnumber and the number given by the subject.

2.3. Data acquisition

In the N400 task, behavioral responses were recorded for eachaction trial. In both the N400 and the oddball task, the EEG wascaptured with tin electrodes from the ECI cap (Electro-Cap Inter-national), which were placed according to the modified expanded10–20 system (Electrode Position Nomenclature, 1991) with aninitial right ear lobe reference. Twenty-six electrodes were used.Sites were grouped into three subsets. The sagittal subset includedFz, FCz, Cz, and Pz; the parasagittal subset, F3/4, FC3/4, C3/4,

Please cite this article as: Debruille, J.B., et al., Effects of a small doAn ERP.... European Neuropsychopharmacology (2012), http://dx.doi.

CP3/4, P3/4, O1 and O2; and the lateral subset, F7/8, FT7/8, T3/4,TP7/8, T5 and T6. Eye movements and blinks were monitored withF7 and F8 for horizontal movements and with FP2 and an additionalelectrode placed on the right cheek for vertical movements. Theimpedance, which was measured before the beginning of theexperiment using a 30 Hz current, was kept below 5 kO. The gainof the Contact Precision Instruments amplifiers used was set at20,000. The half amplitude cut-offs of high- and low-pass frequencyfilters were set at 0.01 and 100 Hz, respectively. In addition, a 60 Hzelectronic notch filter was used. EEG signals were digitized at a512 Hz sampling frequency and stored along with the stimulus andresponse codes.

2.4. Data processing and measures

In the N400 task, EEG epochs corresponding to trials with incorrectresponses or with reaction times shorter than 200 ms or longer than2000 ms were rejected. For all tasks, we also rejected trials withexcessive eye movements, amplifier saturations or analog-to-digitalclippings lasting more than 100 ms. On average, 17% of the trialswere rejected. Averages for action trials were calculated over thetime period starting 200 ms before the onset of the target stimuliand up to 1200 ms later, re-referenced to the average of right andleft earlobe electrode signals. Our baseline was set between �200and 0 ms and measures were made relative to it. To compute N400amplitude, the mean voltages were calculated in the 300–500 mstime-window. The N400 effect, that is, the subtraction of the N400selicited by exemplars (i.e., names of animals) from the N400selicited by non-exemplars was not measured. Two reasons guidedthat unusual choice. First, this effect depends on both N400s.Second, our previous experiment in healthy subjects using thisrepeated-prime semantic-categorization task with concrete wordshas targets show that the effect of schizotypy on the N400 potentialhas an anterior distribution on the scalp. It thus differed from theparieto-central distribution of the classical N400 effect that wasfound in this task (Prevost et al., 2010). In the classical auditoryoddball task, a 400–900 ms time-window was used to test thesignificance of the small differences detected between the ERPsof the olanzapine and the placebo condition after the P300.

2.5. Analyses

In the N400 task, mean reaction times (RTs) and accuracies (As)were obtained in the action condition, that is, for all trials with thequestion word ‘‘ANIMAL?’’ as the prime word. RTs and As wereanalyzed with separate mixed-model repeated-measure ANOVAshaving SPQ subgroups as the between-subject factor and medica-tion (2.5 mg olanzapine vs. placebo) and category (animal vs.object names) as within-subject factors.

For the N400, Pearson’s correlations between the amplitude ofthe N400s at each electrode site and the scores at the SPQ were runin the placebo condition to see whether the results of our previousstudy (Prevost et al., 2010) could be replicated. Despite the largenumber of tests done, no correction of the alpha level was madesince the aim of these correlations was to localize the electrode siteat which they were maximal. In addition, as for behavioralmeasures, mixed-model repeated-measure ANOVAs were run, add-ing to SPQ subgroup, medication and category, the electrode site(Fz, FCz, Cz and Pz) for the sagittal subset of electrode as a thirdwithin-subject factor. For the parasagittal and the lateral subsets,two others ANOVAs were run with yet another within-subject factor:hemiscalp (right vs. left). Additional analyses were made to find thesource of the interactions found and to test the correlationsobserved between ERP measures and SPQ scores. We used theGreenhouse and Geisser (1959) procedure to compensate forheterogeneous variances for the factor having more than twolevels, that is, for electrode site. In each case, the original degrees

se of olanzapine on healthy subjects according to their schizotypy:org/10.1016/j.euroneuro.2012.06.005

Olanzapine reverses schizotypy effect on anterior N400 5

of freedom are reported together with the Epsilon (E) correctionfactor and the corrected probability level.

3. Results

3.1. State anxiety and ‘‘energy’’, mood and side-effects

The mean SPQ scores of the participants who had theplacebo before the medication did not differ from that ofSPQ scores of the participants who had the medicationbefore the placebo (t=�0.266, p=0.791). Surprisingly,participants were slightly but significantly more anxiousafter olanzapine (mean total state STAI-I score: 11.7) thanafter placebo (mean score: 8.8), F(1, 46)=10.6, p=0.002.This effect did not interact with SPQ subgroups (althoughanxiety levels correlated with SPQ scores, r=0.317,p=0.036). For the energy and mood scale, the repeatedmeasures ANOVA showed a main effect of medication, F(1,38)=4.9, po0.05, and a medication� items interaction,F(8, 304)=3.8, E=0.37, po0.05. Post-hoc analyses showedthat participants had a lower level of energy, F(1, 39)=13,po0.001, felt more sleepy, F(1, 39)=4.6, po0.05, reportedslowest thoughts, F(1, 39)=4.1, po0.05, less sharp think-ing, F(1, 39)=4.2, po0.05, and less intense mood, F(1,38)=4.3, po0.05 after 2.5 mg of olanzapine than after theplacebo. There was no interaction of these effects with SPQscores. None of the side-effects associated with olanzapine,such as, headache, abdominal pain, muscle stiffness, drymouth, increased appetite and agitation were found.

3.2. N400 task

3.2.1. Behavioral resultsParticipants were quicker to categorize the animal-namesexemplar-words (852 ms7128) than the object-names non-exemplar-words (933 ms7169), F(1, 46)=68.4, po0.001, andmade more errors for animal names (5.6%76.8) than forobject names (3.6%74.5), F(1, 46)=5.4, po0.05. There was asmall tendency for reaction times to be longer for the highthan for the low SPQ subgroup, F(1, 26)=1.8, po0.11, forboth animal names and object names. There was also a smalltendency for medication to delay reaction times relative tothe placebo in the exemplar (857 vs. 838 ms) and in the non-exemplar condition (940 vs. 920 ms), F(1, 26)=2.3, po0.15,which did not significantly interact with SPQ subgroup. Foraccuracies, there was no effect of medication and no effect ofSPQ subgroups or significant interaction involving this latterfactor.

3.2.2. Electrophysiological resultsThe Pearson’s correlations run in the placebo condition ateach electrode site replicated those obtained in our pre-vious study (Prevost et al., 2010). For names of animals,N400s were larger for higher SPQ scores, especially atanterior scalp sites Fz, r=�0.48, p=0.0008, F4, r=�0.46,p=0.001, F3, r=�0.50, p=0.0005, F8, r=�0.43 p=0.003,F7, r=�0.38, p=0.009, Ft8, r=�0.39, p=0.009, Ft7,r=�0.36, p=0.014, Fcz, r=�0.38, p=0.01, Fc4, r=�0.41,p=0.006, Fc3, r=�0.38, p=0.009, Cz, r=�0.29, p=0.05,C4, r=�0.35, p=0.018, and C3, r=�0.31, p=0.033. For

Please cite this article as: Debruille, J.B., et al., Effects of a small dosAn ERP.... European Neuropsychopharmacology (2012), http://dx.doi.

object names some of these correlations were significant,although weaker: Fz, r=�0.36, p=0.016, F4, r=�0.41,p=0.006, F3, r=�0.35, p=0.017, F8, r=�0.35, p=0.018,Ft8, r=�0.34, p=0.024, Fcz, r=�0.31, p=0.038, and Fc4,r=�0.34, p=0.022.

The ANOVAs revealed a main effect of category for eachelectrode subset (for the sagittal: F(1, 46)=55.1, po0.001,the parasagittal: F(1, 46)=48.5, po0.001 and the lateralsubset: F(1, 46)=49.3, po0.001). ERPs were more negativefor object names than for exemplar of animal names. Incontrast to the effect of schizotypal scores mentioned above(and to the medication effect, see below) this effect wasmaximal over centro-parietal sites and slightly greater overthe right than over the left hemiscalp, as in Prevost et al.(2010). However, this scalp distribution was not accompaniedby significant match� electrode or match� electrode�hemiscalp interaction.

Relative to placebo, N400s were smaller with the olanza-pine at the sagittal, F(1, 46)=6.2, p=0.017, and lateralsubset: F(1, 46)=5.2, p=0.028, and tend to be smaller atthe parasagittal subset: F(1, 46)=3.3, p=0.077. There was amedication� electrode� SPQ subgroup interaction at thesagittal, F(3, 129)=5.7, E=0.89, p=0.002 and the parasa-gittal subset, F(5, 215)=3.8, E=0.43, p=0.023. The posthocperformed at sagittal subset to find the source of the formerinteraction revealed a significant effect of medication onlyin the high SPQ subgroup. It was maximum at FCz, F(1,23)=12.1, p=0.002, and significant at Fz, F(1, 23)=6.5,p=0.018 and Cz, F(1, 23)=5.3, p=0.031. In contrast, in thelow SPQ subgroup, there was no effect of medication at Fcz,F(1, 23)=0.48, p=0.5, Fz, F(1, 23)=0.013, p=0.91 and Cz,F(1, 23)=1.9, p=0.186. The posthoc performed with at theparasagittal subset to find the source of the latter interac-tion revealed a significant effect of medication in the highSPQ subgroup at F4/3, F(1, 23)=6.03, p=0.022 and Fc4/3,F(1, 23)=6.33, p=0.019.

3.3. Auditory oddball task

There was no effect of medication on the accuracy ofbehavioral responses.

As observed in Fig. 2, the N1s, P2s, N2s and P3s forplacebo and olanzapine were almost superimposable. TargetERPs were slightly more positive with the medication thanwith the placebo after the peak of the P300, that is, in thetime-window of the slow-positive wave. This difference wasonly a tendency at Cz, F(1, 46)=3.5 p=0.069, and FCz, F(1,46)=2.3, p=0.13. It did not interact with SPQ scores.

4. Discussion

We investigated the effects of a single minimal dose (i.e.,2.5 mg) of olanzapine taken on the eve of the testing on theERPs evoked by target stimuli in two tasks: a semantic-categorization and an auditory oddball. Participants weresplit into a subgroup with high- and a subgroup with low-scores at the schizotypal personality questionnaire (SPQ,Raine, 1991). In placebo condition of the semantic task,anterior N400s were larger in the subjects with high- than inthe subjects with low-SPQ-scores, as in the previous study(Prevost et al., 2010). The medication was found to

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J.B. Debruille et al.6

decrease these larger fronto-central N400s only in the high-SPQ subgroup. This effect did not depend on the stateanxiety, energy and mood or side-effects. In contrast, in theoddball task, no significant effect of medication was foundon ERPs.

Before discussing the effects of the medication, it isworth mentioning the effects of schizotypy in the placebocondition. Differences were detected between high- andlow-SPQ scorers in the N400 time window, as in Prevostet al. (2010) and in Niznikiewicz et al. (2004). There, ERPswere more negative in subjects with high- than in subjectswith low-SPQ scores, especially at frontal and fronto-central electrodes and for names of animals and thus forwords that matched the ‘‘Animal?’’ context word. Onepossibility as to the functional significance of these greateranterior N400s may be discarded. They are unlikely to bedue to a smaller priming by the first word of each trial or toa deficit of the maintenance of the context defined by thisfirst word in working memory as could have been suggested(e.g., from Kiang et al. (2010)) for two reasons. First,

Figure 1 Effects of schizotypy. Grand average ERPs elicited by targthe placebo condition. Red lines correspond to the ERPs of participa(N=23). Black lines to those of participants with low scores (N=24).for the non-exemplar condition. (For interpretation of the referenceversion of this article.)

Please cite this article as: Debruille, J.B., et al., Effects of a small doAn ERP.... European Neuropsychopharmacology (2012), http://dx.doi.

priming and context are known to impact the centro-parietal N400s rather than the fronto-central N400s (for areview, see Kutas et al., 2006). This posterior distribution ofthe priming effect has been confirmed in the case of theprotocol used here (see Prevost et al., 2010). Second, theprotocol of the present study was precisely conceived forcircumventing the effect of a deficit of context processingby having almost always the same prime word (i.e.,ANIMAL?) in order to constantly refresh its representationin working memory. The activation of its memory represen-tation should thus be at ceiling in all subjects (even in thecase of schizophrenia patients, as supported by Debruilleet al. (2010)).

The component of the N400 potential that is modulatedby the degree of schizotypy here is an anterior andprolonged component, like the one differentiating theN400s elicited by concrete words from the N400s evokedby abstract words. This fact suggests that the faster andfarther spread of automatic activation in neural networksthat has been proposed in schizotypy and schizophrenia

et words in the repeated-prime semantic-categorization task innts with high scores at the schizotypal personality questionnaire(A) (top) is for the category exemplar condition, (B) (bottom),s to color in this figure legend, the reader is referred to the web

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Olanzapine reverses schizotypy effect on anterior N400 7

(Johnston et al., 2008; Kiang et al., 2008) could pertain toparticular subtypes of semantic representations.

Following Kutas and Hillyard (1984) idea that N400indexes semantic activations, this greater spread of auto-matic activation could be directly indexed by the greateranterior N400s themselves. However, it is also interesting toanalyze those results using an opposite idea of N400.Accordingly, N400 indexes semantic inhibition (Debruille,2007; Debruille et al., 2008). Within that latter framework,the larger N400s obtained for the non-exemplar targetwords than for those that were exemplars index theinhibition of the semantic representations activated by

Figure 2 Effects of medication in participants with higher scoreaverage ERPs in red correspond to olanzapine, in black to the pl(bottom), for the non-exemplar condition. (For interpretation of theto the web version of this article.)

Please cite this article as: Debruille, J.B., et al., Effects of a small dosAn ERP.... European Neuropsychopharmacology (2012), http://dx.doi.

the prime words in expectations that the target words willbe the name of an animal (and the inhibition of other typesof representations). Within the N400 inhibition framework,the N400 elicited by a word also indexes the inhibition ofrepresentations that have been inappropriately activated bythis word itself (Debruille, 1998; Debruille et al., 2008).Accordingly, the greater anterior N400s of high-SPQ subjectscould index the greater inhibition needed after the greaterspread, since this spread also leads to inappropriate activa-tions. Interestingly, this way of seeing things can be madecompatible with the fact that the effect of schizotypy onN400 appears larger for the target words that were category

s at the schizotypal personality questionnaire (N=23). Grandacebo condition. (A) (top) is for the exemplar condition, (B)references to color in this figure legend, the reader is referred

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J.B. Debruille et al.8

exemplars than for those that were not (Fig. 1). This largereffect of schizotypy for the matches than for mismatchesmay be due to the fact that, when both prime and targetare from the same category, they converge and providemore semantic constrain. This may lead to a greaterinhibition of the inappropriate activations of the abnormalspread. In contrast, when the target is from a categorydifferent from that of the prime, the two words provide lesssemantic constrain and relatively less inhibition of theseinappropriate activations could occur (Figs. 2–5).

Olanzapine did not modulate early ERPs, suggesting thatit has no impact on representations of the physical featuresof the words. In contrast, this medication reduced theamplitude of the larger anterior N400s of the participantswith high SPQ scores. This reduction appears reminiscent of

Figure 3 Effects of medication in participants with lower scores atFig. 2.

Please cite this article as: Debruille, J.B., et al., Effects of a small doAn ERP.... European Neuropsychopharmacology (2012), http://dx.doi.

the smaller anterior N400s that can be seen in schizophreniapatients treated with antipsychotic relative to patientsreceiving placebo in the low expectancy conditions ofCondray et al. (1999, 2003). This could simply mean thatthe medication makes some semantic representationsharder to activate, thereby limiting the spread of automaticactivation induced by target words. This limited spreadwould be directly indexed by the smaller N400s in the casethe N400 is a direct index of these automatic activations. Incontrast, the smaller N400s would reflect the smallerinhibition needed when less inappropriate activations haveoccurred if the N400 is an index of inhibition. In any case,the fact that the medication reduces anterior N400s only inparticipants with high SPQ scores suggests that olanzapinehad a greater impact in high- than in low-SPQ subjects. This

the schizotypal personality questionnaire (N=24). All else as in

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Figure 4 Subtractions for comparing the effects of schizoptypy to the effects of medication in high-SPQ scorers. Black is used forthe subtraction of the ERPs of the low-SPQ scorers from the ERPs of the high-SPQ scorers. Red is for the subtraction of the ERPs ofhigh-SPQ scorers with placebo from the ERPs of high-SPQ scorers with olanzapine. The exemplar condition is at the top (A), theobject-names condition at the bottom (B). (For interpretation of the references to color in this figure legend, the reader is referredto the web version of this article.)

Olanzapine reverses schizotypy effect on anterior N400 9

is not surprising since the former subjects are those in whomthe activation is likely to be too important and to reachmore inappropriate representations, as suggested by thegreater indirect semantic priming found in these subjects(Johnston et al., 2008; Kiang et al., 2008).

At first sight, the slight increase in reaction times inducedby the medication appears inconsistent with this interpreta-tion. If olanzapine made it harder for the stimulus toactivate some semantic representations, it seems thatreaction times should have been significantly longer thanwith the placebo. However, making it harder for thestimulus to activate some memory representations also

Please cite this article as: Debruille, J.B., et al., Effects of a small dosAn ERP.... European Neuropsychopharmacology (2012), http://dx.doi.

results in the activation of a lesser number of representa-tions and thus in a simplified stimulus processing. Also, theparticular representations at stake in the effect of olanza-pine might not be the main representations with which theanimal-yes/no decision is made. These two factors mighthave attenuated a RT effect, transforming it into a slighttendency.

ERPs obtained from 0 to 400 ms for placebo and medica-tion in the oddball task were superimposable. This confirmsthat olanzapine impacts mainly semantic representations. Italso suggests that the medication did not have any effect onthe various attentional processes indexed by the N1, the P2,

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Figure 5 Grand averages ERPs elicited by target stimuli of the auditory oddball task in all participants (N=47) with placebo (blacklines) and with olanzapine (red lines). (For interpretation of the references to color in this figure legend, the reader is referred tothe web version of this article.)

J.B. Debruille et al.10

the N2s, the P3a and the P3b. Nevertheless, it could still beargued that the observed effects of olanzapine on theanterior N400s reflect unspecific attentional influences thatwould have been more pronounced in the semantic cate-gorization task than in the oddball task. However, severalfacts go against this possibility. First, there is no effect ofmedication on N400 in the subjects with low SPQ scoreswhereas this should be the case if the effect was notspecific. Second, there was no interaction between SPQscores and medication on the subjective levels of energy,sleepiness, slowest thoughts, less sharp thinking and lessintense mood. Third, if the medication had an effect onattention, it should have significantly lengthened reactiontimes, which was not the case. The difference was just asmall tendency. Moreover, this difference did not interactwith groups, unlike the effect of medication on N400.Fourth, the oddball task may not be an easier task requiringless attention than the categorization task. Keeping track ofthe ever changing number of targets already presentedcould be more difficult than deciding whether or not a lionis an animal. Fifth, even if the oddball task had been easier,oddball ERPs have been shown in hundreds of studies to beextremely dependent on the amount of attention allocatedto the stimulus. Thus, if the effect was unspecific, it shouldhave had an impact on the N1, the N2, or the P300. Instead,these potentials were superimposable.

The absence of ERP effect in the oddball task that wasobserved for both SPQ subgroups is interesting for anotherreason. According to a recent theory, neuroleptics act bydecreasing motivational salience (Abler et al., 2007; Kapuret al., 2006). The fact that olanzapine affects the N400potential in the semantic task and that it does not affectthe ERPs of the oddball task (despite the well-knownsensitivity of these latter ERPs to the allocation of atten-tional resources) suggests that antipsychotics affect

Please cite this article as: Debruille, J.B., et al., Effects of a small doAn ERP.... European Neuropsychopharmacology (2012), http://dx.doi.

motivational salience for representations of semantic mem-ory and not for representations of the physical features ofmeaningless stimuli. Moreover, as mentioned, the fact thatboth schizotypy and medication appear to modulate theanterior part of the N400 suggests that only particularsemantic memory representations are at stake.

The decrease of the anterior N400s induced by olanzapinein participants with high SPQ scores is consistent with thesmaller anterior N400s that can be observed in schizophre-nia patients treated with anti-psychotics relative topatients with placebo in one of the conditions of Condrayet al. (1999, 2003). It suggests that the long term effect onpatients starts very early; at most a few hours after the firstdose. The fact that the effect in normals occurs only inparticipants with high SPQ scores suggests that it affects anabnormal mechanisms specific to schizophrenia symptoms,given the continuum that may exist between normality andschizophrenia via schizotypy (Claridge, 1997; Shevlin et al.,2007; Verdoux and van Os, 2002). This rapid action of onedose of olanzapine is consistent with the decrease ofpsychotic symptoms induced by a single dose of neurolepticin patients in just a few hours (Abler et al., 2007; Agidet al., 2008). The present results may thus be relevant forthe understanding of the mechanisms underlying the clinicaleffects of neuroleptics in schizophrenia patients. Thesemedications could make it harder for external stimuli toactivate some semantic memory representations. The pre-sent results would thus reciprocate the reduced semanticactivations observed in Parkinson, a disease with a deple-tion of dopamine, and their partial correction with levodopa(Angwin et al., 2006, 2007, 2009). Future directions ofresearch might focus on the particular semantic representa-tions at stake in the anterior N400s. A recent work(Debruille et al., in press) suggests that similar components,namely the anterior N300s obtained in conditions of massive

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Olanzapine reverses schizotypy effect on anterior N400 11

repetitions, might index the inhibition of affordances, thatis, the inhibition of the tendencies for actions that areautomatically activated by the presentation of concretestimuli (Ellis and Tucker, 2000; Tucker and Ellis, 2004)including names of concrete stimuli (Borghi et al., 2004).According to grounded cognition theories (e.g., Barsalou,2008), these affordances are part of the coding of themeaning of those stimuli. That antipsychotic would makethese action representations harder to activate appears inline with their major tranquilizing effect on motor behavior.

Role of funding source

The first author (JBD) was supported by the FRSQ 10084 SeniorClinician Researcher award. This work was accomplished with agrant from the National Alliance for Research on Schizophrenia andAffective Disorders (NARSAD) allocated to JBD. These two fundingsources had no role in study design; in the collection, analysis andinterpretation of data; in the writing of the report; and in thedecision to submit the paper for publication.

Contributors

J. Bruno Debruille, Mitchell Rodier and Marie Pr�evost designed thestudy and wrote the protocol together. Siamak Molavi managed theliterature searches and analyses. Claire Lionnet recorded the brainactivities, computed the ERPs and their measures and did part ofthe statistical analysis. JBD wrote the first draft of the manuscript.All authors contributed to and have approved the final manuscript.

Conflicts of interest

All authors declare that they have no conflicts of interest.

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