Schizophrenia Research 118 (2010) 189–200

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Schizophrenia Research

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Switching schizophrenia patients from typical neuroleptics to aripiprazole:Effects on working memory dependent functional activation

Florian Schlagenhauf a,⁎, Martin Dinges a, Anne Beck a, Torsten Wüstenberg a, Eva Friedel a,Theresa Dembler a, Rahul Sarkar a, Jana Wrase a, Jürgen Gallinat a, Georg Juckel b, Andreas Heinz a

a Department of Psychiatry, Charité-Universitaetsmedizin Berlin, Campus Mitte, Germanyb Department of Psychiatry, Ruhr-University Bochum, Germany

a r t i c l e i n f o

⁎ Corresponding author. Charité-UniversitaetsmeCampus Mitte, Charitéplatz 1, 10117 Berlin, Germ450517257; fax: +49 30 450517910.

E-mail address: florian.schlagenhauf@charite.de (F

0920-9964/$ – see front matter © 2010 Elsevier B.V.doi:10.1016/j.schres.2010.01.022

a b s t r a c t

Article history:Received 18 August 2009Received in revised form 4 January 2010Accepted 28 January 2010Available online 26 February 2010

Background: Deficits in working memory (WM) are a core symptom of schizophrenia patientsand have been linked to dysfunctional prefrontal activation, which might be caused by amesocortical hypodopaminergic state. Aripiprazole – a partial dopamine antagonist – is a novelantipsychotic, which increases frontal dopamine concentrations in preclinical studies. However,little is known about specific medication effects on the modulation of frontal activation duringWM performance.Methods:Wemeasured BOLD-response during aWMtask in a longitudinal fMRI-study in elevenschizophrenia patients first when they received conventional antipsychotics (T1) and a secondtime after they had been switched to aripiprazole (T2). A healthy control groupmatched for age,handedness and gender was investigated at two corresponding time points. Data was analyzedwith SPM5 in a 2×2×2 design (group×session×task).Results: Schizophrenia patients showed fewer correct responses compared to healthy controls atT1 and a trend-wise normalization at T2. The task activated the fronto-parietal network during thecontrast 2-backN0-back in all participants. At T1 patients revealed a hypoactivation in the dorsalanterior cingulate cortex (ACC), which normalized after switch to aripiprazole and correlatedwith improved taskperformance. Thiswas due to a significant increase in the patients groupwhilethe control group did not change, as corroborated by a significant group×time interaction in thisregion.Conclusions: This study showed for thefirst time that the partial dopamine antagonist aripiprazoleincreases BOLD-signal during aWMtask in the cognitive part of theACC in schizophrenia patients,which may reflect its beneficial effect on cognitive deficits.

© 2010 Elsevier B.V. All rights reserved.

Keywords:Working memoryFrontal cortexFunctional magnetic resonance imagingAntipsychotic agentsFirst generation antipsychoticsAripiprazoleSchizophrenia

1. Introduction

Deficits in working memory are a core neuropsychologicalsymptom of schizophrenia patients (Lee and Park, 2005;Aleman et al., 1999; Forbes et al., 2008; Nuechterlein et al.,2004) and a reduced activation of the prefrontal cortex duringworking memory tasks has been observed repeatedly in

dizin Berlin, Charitéany. Tel.: +49 30

. Schlagenhauf).

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schizophrenia patients (Kotrla and Weinberger, 1995; Heinzet al., 2003; Glahn et al., 2005). There have been some reportsof a beneficial influence of second generation antipsychotics(SGAs) on cognitive function in schizophrenia patients,although effect sizes are small (Woodward et al., 2005;Weiss et al., 2002; Weickert and Goldberg, 2005; Castneret al., 2000) and there also have been negative reports (Keefeet al., 2007). Given that the cognitive symptoms areimportant for the clinical outcome (Green, 1996), theunderstanding of the underlying neural mechanisms ofantipsychotic treatment on cognitive functions like WM areof crucial interest (e.g. Cognitive Neuroscience Treatment

190 F. Schlagenhauf et al. / Schizophrenia Research 118 (2010) 189–200

Research to Improve Cognition in Schizophrenia — CNTRICS,see Barch and Smith, 2008; Ranganath et al., 2008; Castneret al., 2000, 2004). Only few neuroimaging studies directlycompared first generation antipsychotics (FGAs) and SGAs onthe neural correlates of working memory: an increased BOLDresponse in supplementary motor cortex (SMA)/ACC and theright DLPFC (dorsal lateral prefrontal cortex) during a WMtask was found in schizophrenia patients switched fromhaloperidol to risperidone (Honey et al., 1999). Also,medicating previously drug-free patients with quetiapinerevealed a significant increase of the BOLD response in theventrolateral PFC (Meisenzahl et al., 2006). Differences in theBOLD response between FGAs and olanzapine were seenduring a simple attention task (Schlagenhauf et al., 2008).

The dopamine partial agonist aripiprazole has a uniquepharmacology among SGAs. Aripiprazole has a lower intrinsicactivity at D2-receptors than full agonists; it acts as afunctional antagonist in hyperdopaminergic states and as afunctional agonist in hypodopaminergic states, depending onthe surrounding levels of naturally occurring neurotransmit-ter (Lieberman, 2004). Animal studies demonstrated adopamine release in the medial prefrontal cortex (Li et al.,2004; Zocchi et al., 2005, but see Jordan et al., 2004). Clinicaltrials demonstrated that aripiprazole is effective in treatingpositive symptoms and, to some extent, negative andcognitive symptoms (Fleischhacker, 2005). One open-label,randomized study showed neurocognitive improvement (insecondary verbal memory) during aripiprazole treatment(Kern et al., 2006). So far, the influenceof the partial dopamineagonist aripiprazole on frontal cortex activation during

Table 1Group description.

Schizophrenia patient

Age (years) 34.1±8.3 (22–46)Gender 9 males, 2 femaleEdinburgh Handedness Inventory 98.3±5.3Verbal IQ (WST) 96.5±12.7 (n=8)Interval T2–T1 (days) 24.4±15.2Medication T1, dose (mg) 6 haloperidol,

4.7±1.24 flupenthixol,5.3±3.11 perazine (400)

CPZ equivalents T1 (mg) 260.0±99.4 (100–400Duration of treatment FGAs (days) 54.8±111.8 (medianMedication T2, dose (mg) Aripiprazole,

14.1±5.8CPZ equivalents T2 (mg) 187.7±78.0 (133–400Duration of treatment with aripiprazole (days) 22.9±18.1Duration of illness (years) 4.0±3.9Age of onset (years) 31.7±8.6Number of episodes 2.4±1.7CGI Severity T1 4.8±0.8CGI Severity T2 3.9±0.3PANSS total T1 86.7±36.4PANSS total T2 64.4±17.3PANSS positive T1 19.5±9.2PANSS positive T2 12.8±4.3PANSS negative T1 22.1±9.5PANSS negative T2 18.3±5.8PANSS general T1 43.3±19.4PANSS general T2 33.5±10.8

1t-test for independent samples; FGA: first generation antipsychotics; CPZ: chlorpr

working memory compared to conventional antipsychoticmedication has not been investigated.

We therefore tested the hypothesis that the BOLDresponse in the frontal cortex increases in schizophreniapatients when they are switched from conventional firstgeneration antipsychotics (FGAs or so-called typical) medi-cation (e.g. haloperidol) to aripiprazole.

2. Materials and methods

2.1. Subjects and instruments

Twenty-two subjects were included (eleven schizophre-nia patients and eleven healthy volunteers matched for age,gender and handedness). The schizophrenia patients (ninemales and two females; mean age: 34.1±8.3 years) fulfilledDSM-IV and ICD-10 criteria for schizophrenia, had no otherpsychiatric axis I disorder (SCID interview, diagnosis made byF.S. and R.S.) (First et al., 2001) and no current drug abuse orpast history of drug dependence (SCID interview and randomurine drug testing). Patients were recruited at the Depart-ment of Psychiatry and Psychotherapy (Campus CharitéMitte) of the Charité — Universitaetsmedizin Berlin.

Eleven healthy volunteers (nine males and two females;mean age: 37.9±13.5 years) were included; they had no axisI or II psychiatric disorder (SCID interviews) (First et al.,1997, 2001), no family history of psychiatric disorders in firstdegree relatives, current drug abuse or a past history of drugdependence other thannicotine consumption (SCID interviewand random urine drug testing). Matching was performed

s Healthy controls Sig.

37.9±13.5 (22–59) t=0.087, pN0.21

9 males, 2 female98.6±3.4 t=0.721, pN0.41

110.0±13.1 (n=10) t=2.195, p=0.04332.5±14.9 t=1.270, p=0.2191

)12 days)

)

omazine equivalents.

Fig. 1. Working memory paradigm. (A) Upper row: displays the stimulussequence and the target stimulus in the 2-back (left side) and the 0-backcondition (right side). (B) Lower row: shows the task design with alternatingblocks of 2-back and 0-back conditions separated by fixation cross baseline.Each condition is preceded by an instruction cue indicating the upcomingcondition.

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for age, sex and handedness across the groups. In all subjects,handedness was assessed with the Edinburgh HandednessInventory (Oldfield, 1971), and verbal IQ with a Germanvocabulary test (WST, (Schmidt and Metzler, 1992) (Table 1).The local ethics committee approved the study, and aftercomplete description of the study to the subjects, written fullyinformed consent was obtained.

Patients and healthy controls were investigated withfunctional magnetic resonance imaging at two time points(T1 and T2). Schizophrenia patients were scanned for the firsttime (T1) after having received conventional antipsychoticmedication (i.e., flupenthixol, haloperidol, or perazine;Table 1) for approximately two weeks with a medianduration of twelve days (54.8±111.8 days; range: 9–365;n=11). The second scan (T2) was performed approximatelythree weeks (22.9±18.1; range: 11–60 days; n=11) afterthey were switched to aripiprazole (14.1±5.8 mg). Forclinical reasons the switching was performed at an individ-ually adapted scheme with an overlap of conventional andatypical treatment. There were no significant differencesbetween duration of treatment with FGAs vs. aripiprazole(paired t-test: t=0.977, p=0.354), nor between chlorprom-azine equivalents according to Woods (2003) at T1 and T2(see Table 1, paired t-test: t=1.792, p=0.107). Psychopath-ological symptomswere assessed at both time pointswith thePositive and Negative Syndrome Scale (PANSS) (Kay et al.,1987), global clinical impression scale (CGI) and subjectivesleepiness levels with the Stanford Sleepiness Scale (Hoddeset al., 1973). Healthy volunteers were also scanned twice,with the second scan (T2) being performed approximatelythree to four weeks after the first one (32.5±14.9; range: 11–56 days). There were no differences between the schizophre-nia and the control group in age, handedness or intervalbetween scan one (T1) and scan two (T2) (Table 1; t-values:between 0.115 and 1.270; all pN0.2).

2.2. Working memory task

Subjects were scanned using functional magnetic reso-nance imaging (fMRI) while performing a numeric n-backworking memory task with two conditions: 1) in the ‘2-back’condition, subjects were required to press a button when thenumber they saw equaled the number seen two numbersbefore, and 2) in a control condition, subjects had to respondwith a button press each time they saw the number zero(Fig. 1). Numbers between 0 and 9 where displayed for500 ms with an inter trial interval of 900 ms between eachother. Each block consisted of 22 stimuli containing threetargets. The kind of condition for the current block wasdefined by an instruction cue displayed for 2 s. Stimulationblocks and resting periods alternated within the experiment.During resting periods volunteers were instructed to focus ona cross in the center of the screen.

2.3. Functional magnetic resonance imaging

FMRI was performed on a 1.5 Tesla scanner (MagnetomVISIONSiemens®)equippedwitha standardcircularlypolarizedhead coil (CP-Headcoil) using gradient-echo echo-planar imag-ing (GE-EPI, TR=2600ms, TE=40 ms, flip angle=90°, ma-trix=64×64, voxel size=4mm×4mm×5.5 mm). Twenty-

four slices approximately parallel to the bicommissural plane(ac-pc-plane)were collected, covering thewholebrain. TwentyfMRI volumes were acquired per block: twelve duringstimulation (2-back or 0-back) and eight during the restingperiod. Blockswerepresented alternating three times in each ofthe two runs (A B A B A B). During the paradigm a total of 252volumes were collected. For anatomical reference, a 3DMPRAGE (Magnetization Prepared Rapid Gradient Echo,TR=9.7 ms; TE =4 ms; flip angle 12°; matrix=256×256,voxel size 1 mm×1 mm×1 mm) image data set was acquired.Head movement was minimized by using a vacuum pad.

2.4. FMRI data analysis

Functional MRI data were analyzed with SPM5 (http//www.fil.ion.ucl.ac.uk/spm). The first three volumes of eachfunctional time series were discarded to remove non-steady-state effects caused by T1 saturation. To correct for between-scanmovements, in afirst step all imageswere coregistered tothefirst image and amean EPI imagewas computed and in thesecond step all volumes were realigned to the mean volume.The mean EPI image was spatially normalized to the standardEPI template provided by the Montreal Neurological Institute(MNI template) and the normalization parameters wereapplied to all EPI images. Finally, the normalized images,with a voxel size of 4 mm×4 mm×4 mm, were smoothedwith a Gaussian kernel (full width at half maximum=8 mm)to create a locallyweighted average of the surrounding voxels.

After artifact reduction and stereo-tactical normalizationwe analyzed the fMRI data in the context of the GeneralLinear Model (GLM) approach as implemented in SPM5(Friston et al., 1995). The hypothetical voxel time series foreach task condition (2-back and 0-back) and the instructioncue were modeled, using the canonical hemodynamicresponse function (HRF) as provided by SPM5. The realign-ment parameters were integrated into the first level designmatrix. Finally, to remove low frequency signal drifts andhigh frequency physiological artifacts caused by respiration

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and cardiologic effects, the voxel time series were filteredwith a high pass filter (cut off frequency=1/128 Hz). Serialcorrelations from aliased cardiological and respiratory effectswere accounted for using a 1st order autoregressive model.After this procedure the GLMwas fitted into the preprocesseddata set. Using the resulting parameter estimates voxel-wisestatistics were performed at two levels.

At a first single subject level, the changes in the BOLDresponse for each subject were assessed using linear contrastsof the estimated GLM parameters. The contrasts for ‘2-back N

0-back’ and the baseline contrast (‘0-back versus fixationcross’ and ‘2-back versus fixation cross’) were calculated aslinear combinations of the estimated beta values, stored incontrast images and taken to the second level group analysis.

On the group level (second level) the contrast ‘2-back N

0-back’was subjected to a repeatedmeasurement, two-wayANOVA designwith subjects as a random factor and the fixedfactors group (between-subject factor, control group/schizo-phrenic patients) and session (within-subject factor, T1/T2)respectively. Using the appropriate contrasts activationdifferences between schizophrenia patients and controls atT1 and T2, differences within each group between T1 andT2, and the interaction group×session were assessed.Furthermore, activations for each group at each time pointwere calculated.

Given our a priori hypotheses of group differences andwithin group activation changes in the frontal cortex, afunctional volume of interest (VOI) was used as a correctionfor multiple comparisons. The VOI was constructed using theleft and right frontal lobe from the WFU Pick Atlas toolbox(Lancaster et al., 2000; Maldjian et al., 2003) and combing itwith amask from themain effect of condition (2-backN0-back)for all subjects (combining patients and controls) at pb0.05FWE-corrected on the voxel level to restrict the search volumeto voxel activated by the task. Significant level was set topb0.05 FWE-corrected on the voxel level for the functionalfrontal VOI.

To monitor whether changes in BOLD signal in the frontalcortex between the two time points are confounded byvasomotor properties of the medication, we performed a VOI-analysis in the primary visual cortex (BA 17). We modeled theoverall visual stimulation (combining 2-back and 0-backconditions and the instruction cue) against baseline andextracted the mean effect size of this contrast for the BA 17VOI (4928 mm3, 77 voxel) for each subject and session andconducted an ANOVA with repeated measures in SPSS™ withsession as within-subject factor and group as between-subjectfactor.

Behavioral data (reaction time, correct responses/hits andfalse alarms, sensitivity d′, criterion) was analyzed withSPSS™ Version 16 using an ANOVA design with repeatedmeasures with task and session as within-subject factors andgroup as between-subjects factor. Differences in othermeasures (age, IQ etc.) between schizophrenia patients andhealthy controls were assessed with 2-sample t-tests,differences in psychopathological symptoms (PANSS scalesand CGI, CGI) between the first and second scans with pairedt-tests in the patient group.

Correlations between alterations in brain activation andbehavioral performance were explored using Pearson'scorrelation coefficients with peak activation of brain areas

showing a group difference using SPSS™; for this exploratorypart of the study p values are only given for descriptivereasons.

3. Results

3.1. Clinical assessments

Schizophrenia patients displayed a significant decrease inthe total PANSS score from the first to the second scan(t=3.300, p=0.008), in the positive symptoms subscale(t=3.187, p=0.010) and the general psychopathologysubscale (t=3.075, p=0.012), but not the negative symp-toms subscale (t=1.799, p=0.102). A significant improve-ment was also seen on the global clinical impression scale CGI(t=3.873, p=0.004).

Sedation measured with the Stanford Sleepiness Scalebefore and after the first and the second scan showed nodifferences in the patient group (F-values between 0.066 and0.095, all pN0.4).

3.2. Behavioral performance

A three-way ANOVA with repeated measures (group, taskand session) for accuracy (correct responses) revealed asignificant main effect for task (F=61.141, pb0.001), andgroup (F=8.199, p=0.010) and a trend-wise session effect(F=3.218, p=0.088) and session×group interaction (F=3.765, p=0.067). Therewere no significant other interactions(F-values between 0.004 and 0.349, all pN0.5). This reflected abetter performance in the 0-back condition compared to the2-back condition in both groups (post-hoc paired t-test atsession T1: t=4.523, p=0.001 and session T2: t=5.469,pb0.001) and a worse performance of the schizophreniapatients compared to the healthy controls especially at T1which showed a tendency to normalize at T2 (post-hoc t-testsfor 2-back at T1: t=2.589, p=0.018 and at T2: t=0.842,p=0.410; and for 0-back at T1: t=1.928, p=0.083 and at T2:t=1.606, p=0.124) (Fig. 2).

In a similar analysis for thenumber of false alarms,we founda significant main effect for task (F=40.872, pb0.001) andgroup (F=5.554, p=0.029) and a trend wise three-wayinteraction group×task×session (F=3.073, p=0.095), butno significant other main effects or interactions (F-valuesbetween 0.613 and 2.440, all pN0.1). This showed that therewere more false alarms during the 2-back condition comparedto the0-back condition inbothgroups taken together (post-hocpaired t-test 2-back vs. 0-back at session T1: t=6.580, pb0.001and session T2: t=9.585, pb0.001) and more false alarms inthe patient group (post-hoc t-tests for 2-back at T1: t=1.902,p=0.072 and at T2: t=1.909, p=0.080; and for 0-back at T1:t=1.969, p=0.077 and at T2: t=1.275, p=0.217). There wasa significant decrease in false alarms in the healthy controls forthe 2-back condition (post-hoc paired t-test t=4.236,p=0.002), but not for the schizophrenia patients (Fig. 2).

A three-way ANOVA with repeated measures (group, taskand session) for d′ revealed a significant main effect for task(F=130.664, pb0.001), group (F=11.523, p=0.003), ses-sion (F=10.895, p=0.004) and session×group interaction(F=5.515, p=0.029). There were no significant otherinteractions (F-values between 0.294 and 1.619, all pN0.3).

Fig. 2. Behavioral performance. The number of correct responses and false alarms for schizophrenia patients (‘Pat’ in red) and healthy controls (‘Con’ in blue) atboth time points for the 2-back and the 0-back condition are shown. The boxes have lines at the lower, median, and upper quartile values. Whiskers extend fromeach end of the box to the adjacent values within 1.5 times the interquartile range from the ends of the box. Notches display the variability of the median betweensamples. The width of a notch is computed so that box plots whose notches do not overlap have different medians at the 5% significance level. In addition, singlesubject data are displayed as dots.

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This reflected a better performance in the 0-back conditioncompared to the 2-back condition in both groups (post-hocpaired t-test at session T1: t=8.256, pb0.001 and session T2:t=9.878, pb0.001) and a worse performance of the schizo-phrenia patients compared to the healthy controls (post-hoct-tests for 2-back at T1: t=3.350, p=0.003 and at T2: t=2.162, p=0.043; and for 0-back at T1: t=2.623, p=0.025and at T2: t=1.608, p=0.124). Schizophrenia patients

Fig. 3. Reaction times. Displayed are the mean reaction times for schizophrenia patiand T2) for 2-back and 0-back condition in ms. The boxes have lines at the lower, methe adjacent values within 1.5 times the interquartile range from the ends of the box.notch is computed so that box plots whose notches do not overlap have different meas dots.

displayed a significant increase of d′ (post-hoc paired t-testbetween T1 and T2 for 0-back: t=2.328, p=0.042 and for 2-back: t=2.959, p=0.014) while healthy controls did notchange significantly (post-hoc paired t-test between T1 andT2 for 0-back: t=1.000, p=0.341 and for 2-back: t=1.250,p=0.240) (see Supplementary Table 1).

In a similar analysis for the criterion (c) only a significantmain effect for task was found (F=6.100, p=0.023), but no

ents (‘Pat’ in red) and healthy controls (‘Con’ in blue) at both time points (T1dian, and upper quartile values. Whiskers extend from each end of the box toNotches display the variability of themedian between samples. Thewidth of adians at the 5% significance level. In addition, single subject data are displayed

Table 2Activation during working memory task for the contrast ‘2-back N0-back’ in all participants. Reported are all clusters at pb0.05 family wise error (FWE) correctedfor the whole brain with the Brodmann area (BA), corrected p-value (p (FWE)) and MNI-coordinates.

BA Cluster size p (FWE) t-value x y z

Frontal lobe Middle frontal gyrus 6 105 0.000 8.773 −28 8 64Middle frontal gyrus 9 0.002 6.252 −52 16 36

Frontal lobe Medial frontal gyrus 8 40 0.000 7.146 0 20 52Anterior cingulate cortex 32 0.040 5.130 −8 12 48

Frontal lobe Middle frontal gyrus 6 35 0.000 7.029 36 12 60Frontal lobe Middle frontal gyrus 46 5 0.004 5.991 −48 36 28Frontal lobe Middle frontal gyrus 10 7 0.010 5.675 32 60 16Parietal lobe Superior parietal lobule 7 65 0.000 9.156 −12 −76 56Parietal lobe Superior parietal lobule 7 13 0.004 6.028 36 −64 60Parietal lobe Precuneus 7 1 0.039 5.171 8 −64 64Parietal lobe Inferior parietal lobule 40 1 0.039 5.163 40 −44 44Parietal lobe Inferior parietal lobule 40 8 0.002 6.244 48 −44 56Parietal lobe Inferior parietal lobule 40 24 0.004 6.058 −44 −48 60Temporal lobe Fusiform gyrus 37 1 0.018 5.464 −52 −60 −20Cerebellum Declive 35 0.001 6.710 36 −64 −28Cerebellum Declive 9 0.007 5.828 −32 −68 −28Cerebellum Declive 23 0.002 6.186 −8 −80 −24

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other main effect or interaction (F-values between 0.031 and2.453, all pN0.1) (see Supplementary material).

Reaction times displayed a significant main effect of task(F=51.737, pb0.001) and a main effect of group (F=15.848,p=0.001), but no significant session main effect nor interac-

Fig. 4. Activation during working memory task. Main effect of task for the contrastrendering; lower row: three coronal slices at the indicated MNI coordinates.

tions (F-value between 0.003-2.018, all pN0.2) (Fig. 3),indicating slower response in both groups during the 2-backcondition (post-hoc paired t-test 2-back vs. 0-back at T1:t=5.617, pb0.001 and at T2: t=6.590, pb0.001) and a slowerresponse of the schizophrenia patients (post-hoc t-tests for

‘2-back N0-back’ in all participants at both time points. Upper row: surface

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patients vs. controls at T1: t=3.146, p=0.005 and at T2:t=3.875, p=0.001).

3.3. fMRI

3.3.1. Main effect of task: the working memory networkThe main effect of task for the contrast ‘2-backN0-back’

in all subjects together revealed a significant BOLD-effect inthe working memory network including the medial frontalgyrus (including BA 8 and anterior cingulate cortex BA 32),bilateral middle frontal gyrus (BA 9, BA 6, BA 46 and leftBA 10), the bilateral parietal cortex (BA 7 and 40) and thecerebellum (Table 2 and Fig. 4).

3.3.2. Main effects of group and session and group×sessioninteraction

Given our a priori hypothesis of an increase in activationduring working memory performance in the frontal cortex,the analysis for within and between group differences andgroup x session interaction was restricted to those voxeldisplaying a significant condition effect in the frontal cortex.

There was a main effect of group in the left middle frontalgyrus (BA 6, [x y z]=[−28 8 64], F=17.81, p=0.006 FWE-corrected for functional frontal VOI) and a tendency in themiddle frontal gyrus (BA 46, [x y z]=[−48 32 28], F=9.98,p=0.090 FWE-corrected for functional frontal VOI). A

Table 3Activation in the frontal cortex during working memory performance (‘2-back N0-bacontrols (HC) at both time points (T1 and T2) and for schizophrenia patients whiaripiprazole (Arip) at T2. Given are the family wise error corrected p-value (p FWE)are displayed in italic letters.

t x y z p (FWE)

HC T1Left frontal 6.06 −28 8 64 0.000Right frontal 5.16 32 8 52 0.000

HC T2Left frontal 7.48 −28 8 64 0.000Right frontal 4.84 4 24 44 0.000

Group differences at T1 and T2HC T1NFGAsLeft frontal 3.39 −8 12 52 0.027

3.38 −28 8 64 0.027Right frontal 3.45 40 8 52 0.012

HC T2NaripiprazoleLeft frontal 2.82 −28 8 64 0.097Right frontal –

Session effects within each groupHC T1NHC T2Left frontal –

Right frontal –

HC T2NHC T1Left frontal –

Right frontal –

Interaction group×timeInteraction AripN FGAs vs HC T1NT2Left frontal 3.72 −8 12 48 0.024Right frontal 2.76 8 16 52 0.084

significant group by session interaction was found in theanterior cingulate cortex (ACC) (medial frontal gyrus, BA 32,[x y z]=[−8 12 48], F=13.87, p=0.048 FWE-corrected forfunctional frontal VOI). There was no significant main effectof session.

3.3.3. Normalization in ACC activation after switch of medicationPost-hoc t-tests revealed that the group by time interac-

tion in the anterior cingulate cortex (BA 32) was due to asignificant increase in the patients group after switch fromtypical antipsychotics to aripiprazole ([x y z]=[−8 12 48],t=4.08, p=0.012 FWE-corrected for functional frontal VOI),while the controls did not change significantly. Whilemedicated with FGAs at T1 there was a significant groupdifference in the same region ([x y z]=[−8 12 52], t=3.39,p=0.027 FWE-corrected for functional frontal VOI), whichwas not present after switch to aripiprazole at T2 (Table 3and Fig. 5).

Exploratory analysis showed that at T1, when patientsshowed lower dorsal ACC activation compared to controls,lower task performance (number of false alarms) correlatednegatively with ACC activation (BA 32 peak activation for thecontrast ‘2-backN0-back’ at [x y z]=[−8 12 48]) in all subjects(false alarm during 2-back condition: r=−0.444, p=0.038and false alarm during 0-back condition: r=−0.456, p=0.033). Furthermore, the increase in BA 32 activation was

ck’). Results are corrected for functional frontal VOI and reported for healthyle receiving first generation antipsychotics (FGAs) at T1 and after switch to, the t-value (t), and the MNI-coordinate for the peak voxel. Statistical trends

t x y z p (FWE)

FGAsLeft frontal –

Right frontal –

AripiprazoleLeft frontal 5.32 −4 8 56 0.000Right frontal 4.79 4 12 52 0.000

FGAsNHC T1Left frontal –

Right frontal –

AripiprazoleNHC T2Left frontal –

Right frontal –

FGAsNaripiprazoleLeft frontal –

Right frontal –

AripiprazoleNFGAsLeft frontal 4.08 −8 12 48 0.012Right frontal 2.75 4 12 52 0.085

Interaction FGAsNArip vs. HC T1NT2Left frontal –

Right frontal –

Fig. 5. Increase in dorsal ACC activation (contrast ‘2-backN0-back’) in schizophrenia patients compared to healthy controls from 1st (T1) to 2nd (T2) scan.(A) Upper row: group by session interaction: image displayed at MNI coordinates x=−8 and y=12. (B) Lower row: parameter estimates for the 2-back and0-back condition for healthy controls (‘Con’ in blue) and schizophrenia patients (‘Pat’ in red) at both time points (T1 and T2) extracted from a 10 mm sphere at thiscoordinate. The boxes have lines at the lower, median, and upper quartile values. Whiskers extend from each end of the box to the adjacent values within 1.5 timesthe interquartile range from the ends of the box. Notches display the variability of the median between samples. The width of a notch is computed so that box plotswhose notches do not overlap have different medians at the 5% significance level. In addition, single subject data are displayed as dots.

196 F. Schlagenhauf et al. / Schizophrenia Research 118 (2010) 189–200

associated with an increase in task performance (decrease ofthe number of false alarms from T1 to T2) for the 0-backcondition (r=−0.531, p=0.011, but not for the 2-backcondition: r=−0.231, p=0.300).

3.3.4. VOI analysis of primary visual activationVOI analysis of the primary visual cortex (BA 17)

confirmed that there were no significant differences betweenthe two groups in the BOLD signal in this primary sensoryarea in response to simple visual stimulation (effect of group:F=2.904, pN0.1; session: F=3.525, p=0.075; group×ses-sion: F=0.026, pN0.8).

4. Discussion

In this study, we show for the first time that anteriorcingulate cortex (ACC) activation elicited during a working

memory (WM) task increased when patients suffering fromschizophrenia were switched from typical neuroleptic med-ication to aripiprazole. Furthermore, we observed a signifi-cant reduction in prefrontal BA 46 and BA 6 brain activationduringWM task performance among patients compared withcontrols, confirming previous reports of prefrontal dysfunc-tion in patients suffering from schizophrenia (Kotrla andWeinberger, 1995; Heinz et al., 2003; Glahn et al., 2005).

The significant increase of the BOLD-signal after switch toaripiprazole was observed in the dorsal part of the ACC (Bushet al., 2000), which is involved in the executive control ofbehaviour (Carter and van Veen, 2007). This region is part ofthe working memory encoding network in healthy subjects(Woodward et al., 2006; Owen et al., 2005). A first meta-analysis reported a hyperactive anterior cingulate duringWMin schizophrenia patients compared to controls, althoughmedication was not controlled for in these analyses (Glahn

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et al., 2005). One the other hand, a recent study found ahypoactive ACC in a group of schizophrenia patients withdifferent antipsychotics during the encoding phase in amodified Sternberg task (Schlosser et al., 2008) and a recentquantitative meta-analysis also described reduced activity inthe dorsal ACC for schizophrenia patients compared tocontrols during different executive functions (Minzenberget al., 2009), which was interpreted as indicating deficits inmonitoring performance and conflict. Therefore, the increasedACC activity found in our studymay affect attention allocation,which may help to explain the trendwise improvementin accuracy (correct responses) and the significant increasein d′ for the 0-back and 2-back condition in the patient groupas an indicator for the ratio of hits to false alarms (Wickens,2002).

Compared with typical neuroleptic blockade of dopamineD2 receptors, aripiprazole can interact with prefrontaldopaminergic neurotransmission in a more complex way.First, aripiprazole is a partial dopamineD2 receptor antagonistwith a lower intrinsic activity at D2 receptors compared withfull agonists (Lieberman, 2004), which can directly modulatethe cortical BOLD response (Dixon et al., 2005). Stimulation ofdopamine D2 receptors may specifically interact with theBOLD response during encoding of a working memory task(Gibbs and D'Esposito, 2005), however, the block design usedin our study does not allow for separate analysis of theencoding, delay and response period of the working memorytask. Secondly, aripiprazole releases dopamine in the medialprefrontal cortex according to animal experiments (Li et al.,2004; Zocchi et al., 2005, but see Jordan et al., 2004). Othersecond generation neuroleptics have also been reported toincrease PFC dopamine release (Rowley et al., 2000; Ichikawaet al., 2001) and may thus influence PFC informationprocessing (Durstewitz and Seamans, 2002). Studies in non-human primates revealed that prefrontal dopamine interactswith working memory performance in an “inverted-U”shaped form, with optimal performance associated withintermediate dopaminergic neurotransmission (Williamsand Goldman-Rakic, 1995). In our study, switching patientsfrom typical neuroleptics to aripiprazolewas associatedwith atrend wise improvement in correct responses among patientssuffering from schizophrenia, who no longer differed signif-icantly from control subjects when medicated with aripipra-zole at T2.

The observed effect in the ACCmight be related to direct D2receptor-mediated mechanisms due to the partial D2 antago-nism of aripiprazole. The ACC receives dopaminergic projec-tions (Williams and Goldman-Rakic, 1998) and is among thebrain regions with the highest extrastriatal D2 receptorsdensity (only second to medial temporal structures) (Suharaet al., 1999). In schizophrenia, an altered DAmodulation of theACC was suggested by several lines of evidence: an increasedbloodflow in the ACCwas found in unmedicated schizophreniapatients after application of the DA agonist apomorphineduring a cognitive task (verbal fluency) (Dolan et al., 1995).Moreover, a reduced D2 receptor binding in the ACCwas foundin drug-naive schizophrenia patients compared to healthycontrols (Suhara et al., 2002), whichmight indicate a lower D2receptordensity in this region (Takahashi et al., 2006), althoughthere have been also negative findings (Kessler et al., 2009).Postmortem studies reported altered intrinsic circuitry of DA

innervations in the ACC of schizophrenia patients, particularlyin layer II (Benes, 2000), which is the primary cortico-corticaloutput layer. In healthy controls, administration of the D2agonist bromocriptine was associated with reduced workingmemory accuracy and associated with a decreased BOLD signalduring encoding in parietal regions and an increased BOLDsignal in parietal and frontal regions including the right anteriorcingulate gyrus during response period (Gibbs and D'Esposito,2005). Healthy controls showed reduced WM performanceafter application of the selectiveD2antagonist sulpiride (Mehtaet al., 2008).

Optimal working memory performance has been foundwith an intermediate dopamine D1 receptor stimulation,suggesting an ‘inverted-U’ dose–response curve (Vijayragha-van et al., 2007; Williams and Castner, 2006). The abovequoted findings in healthy controls and schizophreniapatients also suggest that overstimulation of D2 receptors(in healthy controls) worsens WM performance and impairsthe underlying neuronal activation, while in schizophreniapatients with putatively lower prefrontal dopamine levels(Meyer-Lindenberg et al., 2002; Abi-Dargham et al., 2002),dopaminergic stimulation of D2 receptors may help toimprove WM performance.

It has been suggested that the extend and distribution ofbrain activation reflects the efficiency of the neuronal networkthat executes the working memory task (Callicott et al., 1999,2000; Manoach et al., 2000; Daniel et al., 1991; Mattay et al.,1996, 2003). Studieswithpharmacologically different atypicalneuroleptics such as olanzapine and risperidone extend thesefindings and suggest that the effects of these drugs on WM-associated brain activation differ from each other: switchingschizophrenia patients from typicals to olanzapine wasmainly associated with alterations in brain activation duringthe 0-back condition (Schlagenhauf et al., 2008), whileswitching from typicals to risperidone and quetiapine wasassociated with increased brain activation in the dorsolateralor ventrolateral PFC, respectively (Honey et al., 1999;Meisenzahl et al., 2006). In accordance with our study, asimple attentional task was associated with an increase in theACC response with clozapine but not with haloperidol (Lahtiet al., 2004).

Our own finding is not easily explained by sedative effectsof aripiprazole: we observed no significant difference inreaction times or sedation (Stanford Sleepiness Scale) inpatients switched to aripiprazole from conventional neurolep-tics. Since switching patients from first to second generationneuroleptics can alter baseline glucose utilization and regionalcerebral blood flow (Lahti et al., 2003; Molina et al., 2005),we monitored task unspecific effects on the BOLD responsein the primary visual area BA 17 during visual stimulation andobserved no relevant alteration of the BOLD signal in this area.Nevertheless, we have to caution that dopamine D2 receptordensities are lower in the occipital cortex than in the ACC(Suhara et al., 1999) and that our analysis of visual V1 BOLDresponse cannot rule out differential vasoactive propertiesof FGAs vs. aripiprazole in other cortical areas.

It has been suggested that dopamine dysfunction inschizophrenia is the result of a primary dysfunction ofglutamatergic neurotransmission (Carlsson et al., 1999;Krystal et al., 1999; Pilowsky et al., 2006; Heinz et al., 2003)and a recent study demonstrated that first generation

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neuroleptics such as haloperidol reduce glutamate receptortrafficking in the rat frontal cortex, which was not observedwith some second generation neuroleptic drugs (Fumagalliet al., 2008). However, to date aripiprazole's effects onglutamatergic neurotransmission have not been explored indepth.

Our pilot study is limited by the rather small sample size,although a power analysis revealed that our sample wassufficient (see Supplementary material for power analysis);however, switching the same patients from first to secondgeneration neuroleptic medication reduced inter-individualdifferences. Further limitations include possible order effects.Furthermore, the duration of exposure to the antipsychoticmedication was short. Differences of the antipsychotic dosesat T1 and T2 are unlikely to explain the observed BOLDincrease in the ACC, because chlorpromazine equivalentswere not significantly different, although comparabilitybetween antipsychotic doses with chlorpromazine equiva-lents is limited.

Our sample size was also too small to assess genotypeeffects on task-associated BOLD response; while there are nospecific findings of genotype×apripiprazole interactions onworking memory function, such interactions have beendescribed for olanzapine and the catechol-O-methyltransfer-ase (COMT) genotype (Bertolino et al., 2004).

Altogether, our study suggests that switching patientsfrom first generation neuroleptics to aripiprazole results inincreased activation of the anterior cingulate cortex (ACC),which after switchno longer differs significantly fromfindingsin healthy control subjects. It is tempting to speculate butremains to be explored whether such changes in ACCactivation interact with neurocognitive improvement ob-served during aripiprazole treatment (Kern et al., 2006). Ourstudy confirms that medication type has to be considered amajor factor that influences executive task performance inschizophrenia.

Role of funding sourceThis studywas supported by the German Research Foundation (Deutsche

Forschungsgemeinschaft DFG; HE 2597/4-3) and by investigator-initiatedtrials funded by Bristol-Myers Squibb Germany; the German ResearchFoundation and Bristol-Myers Squibb Germany had no further role in studydesign; in the collection, analysis and interpretation of data; in the writing ofthe report; and in the decision to submit the paper for publication.

ContributorsF. Schlagenhauf, M. Dinges, T. Wüstenberg, and A. Heinz designed the

study. A. Beck and E. Friedel helped analyze the data, T. Dembler and R. Sarkarassisted in the collection of data. J. Wrase, J. Gallinat and G. Juckel contributedto the manuscript. All authors contributed to and have approved the finalmanuscript.

Conflict of interestDr. Schlagenhauf, Mr. Dinges, Mrs. Beck, Mr. Wüstenberg, Mrs. Dembler,

Dr. Sarkar, and Dr. Wrase reported no biomedical financial interests orpotential conflicts of interest. Dr. Juckel reports having received researchfunding from Lilly (IIT) and consultant fees from Janssen-Cilag, AstraZenics,Lilly, GSK and Bristol-Myers Squibb. Dr. Gallinat disclosed research supportfrom AstraZeneca and fees as consultant from Bristol-Myers Squibb. Dr.Heinz has received research funding from the German Research Foundationand the Bernstein Center for Computational Neuroscience Berlin (GermanFederal Ministry of Education and Research), Eli Lilly and Company, Janssen-Cilag, and Bristol-Myers Squibb. Dr. Heinz has received Speaker Honorariafrom Janssen-Cilag, Johnson and Johnson, Lilly, Pfizer and Servier.

AcknowledgmentsWe thank Michael Koslowski, Dimitri Filonov, and Meline Stoy for

assistance during scanning procedures.

Appendix A. Supplementary data

Supplementarydata associatedwith this article canbe found,in the online version, at doi:10.1016/j.schres.2010.01.022.

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