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Article history:Received 22 July 2010Revised 23 November 2010Accepted 6 December 2010Available online 13 December 2010

Keywords:

NeuroImage 55 (2011) 329337

Contents lists available at ScienceDirect

NeuroIm

j ourna l homepage: www.e lIntroduction

Several studies have convincingly shown that individuals whodevelop schizophrenia display subclinical symptoms already yearsbefore the rst hospitalization (Klosterktter et al., 2001; Miller et al.,1999; Yung et al., 2004), and that programs to detect subjects at high-risk of developing schizophrenia before full-blown psychosis man-ifests have proven highly effective (McGlashan et al., 2007; McGorryet al., 2008). Structured interviews developed to explore the presenceor absence of attenuated psychotic symptoms and brief limited andintermittent psychotic symptoms (BLIPS) have also taken into

critical for arriving at a diagnosis of an at-risk state of schizophrenia(McGlashan et al., 2001). Recent research in patients with manifestschizophrenia suggests that impaired theory of mind (ToM) thecognitive ability to reect upon own and others' mental states(Premack and Woodruff, 1978) has greater predictive power forpoor social functioning than other cognitive domains such as generalintelligence or executive functioning (e.g., Brne et al., 2007; Boraet al., 2006; Lysaker et al., 2004). This nding is entirely in line withwhat was predicted over a decade ago (Penn et al., 1997), indicatingthat impaired ToM or other relevant aspects within the domain ofsocial cognition such as emotion recognition, and social perceptionaccount the observation that deterioration

Corresponding author. Research Department of CPsychiatric Preventive Medicine, Ruhr-University BochAlexandrinenstr 1, 44791 Bochum, Germany. Fax: +49

E-mail address: martin.bruene@rub.de (M. Brne).1 The rst author and the last author contributed equ

paper.

1053-8119/$ see front matter 2010 Elsevier Inc. Aldoi:10.1016/j.neuroimage.2010.12.018 2010 Elsevier Inc. All rights reserved.Theory of mindAt-risk of psychosisSchizophreniaEmotional involvement

controls were recruited. During fMRI scanning, participants were shown a series of cartoons. The task was toinfer the mental states of the cartoon characters in terms of beliefs, states of knowledge and intentions.Results: Subjects at risk of psychosis activated the ToM neural network comprising the prefrontal cortex, theposterior cingulate cortex, and the temporoparietal cortex more strongly than patients with manifestschizophrenia, and, in part, also more strongly than healthy controls. Manifest schizophrenia patients andcontrols activated the ToM neural network differently with little overlap of activated regions, where overall,controls showed stronger activations than schizophrenia patients.Conclusions: Individuals with at-risk states of schizophrenia activate the ToM neural network differently, andin part, more strongly compared to patients with schizophrenia and controls. This could suggest acompensatory overactivation of brain regions critical for empathic responses during mental state attributionin at-risk subjects for schizophrenia.a b s t r a c t

Objective: Poor social functioning is a hallmark of schizophrenia and may precede the onset of illness. One ofthe most robust predictors of social impairment is a decit in the ability to appreciate the mental states ofothers (theory of mind; ToM). We therefore examined ToM in subjects at risk of developing psychosis usingan fMRI paradigm and compared brain activations with those of patients with manifest schizophrenia andhealthy controls.Method: Ten subjects with at-risk (prodromal) states of psychosis, 22 schizophrenia patients and 26 healthya r t i c l e i n f oAn fMRI study of theory of mind in at-rmanifest schizophrenia and healthy contr

Martin Brne a,b,,1, Seza zgrdal b, Nina Ansorge b,Volkmar Nicolas d, Martin Tegenthoff c, Georg Juckela Research Department of Cognitive Neuropsychiatry and Psychiatric Preventive Medicine,b Department of Psychiatry, Ruhr-University Bochum, LWL University Hospital, Germanyc Department of Neurology, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, Germand Department of Radiology, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, Germanof social functioning is

ognitive Neuropsychiatry andum, LWL University Hospital,234 5077 234.

ally to the nal version of the

l rights reserved.k states of psychosis: Comparison withls

einrich Graf von Reventlow b, Sren Peters d,Silke Lissek c,1

r-University Bochum, LWL University Hospital, Germany

age

sev ie r.com/ locate /yn img(Penn et al., 2008) may also be present in at-risk states ofschizophrenia. As regards ToM, a few studies have addressed thisquestion behaviourally in the recent past. While Couture et al. (2008)found that subjects at high risk for psychosis as determined usingthe Structured Interview for Prodromal Symptoms (SIPS; Miller et al.,1999) performed comparably well compared to healthy controls ona task that requires inference of complex mental states from viewingthe eye region of a person in still photographs (Reading the Mind in

330 M. Brne et al. / NeuroImage 55 (2011) 329337the Eyes Task (RMET); Baron-Cohen et al., 2001), a nding that wasrecently replicated (Gibson et al., 2010). Chung et al. (2008) showedthat subjects at high risk for psychosis as determined using theComprehensive Assessment of At-Risk Mental States (CAARMS; Yunget al., 2005) performed more poorly on a second-order ToM task(that is, a representation of another person's state of mind about athird person'smental processes) and an advanced ToM task comparedto healthy controls, but not on a rst-order ToM task (that is, arepresentation of another person's state of mind) or a simpler cartoontask. These ndings indicate that subjects at risk of developingschizophrenia may have subtle ToM decits, depending on whetherthe task involves mental state decoding (as is the case for the RMET)or mental state reasoning, i.e. independent of observable facial cues(Bora et al., 2006).

With regard to neuroanatomical correlates of ToM performance,only one study has examined this issue in subjects at risk of psychosis(Marjoram et al., 2006) using cartoon stories depicting jokes thateither invoked the understanding of false belief, ignorance, ordeception (i.e. ToM), or physical joke conditions that did not requireToM abilities (Gallagher et al., 2000).

ToM involves activation of a neural network comprising themedialprefrontal cortex (mPFC), the anterior part of the cingulate cortex(ACC), the posterior cingulate cortex (PCC)/precuneus region (PC), aswell as the middle temporal lobes (MT), superior temporal sulcus(STS), and the temporo-parietal junction (TPJ) (reviewed in Saxe etal., 2004; Amodio and Frith, 2006; Saxe, 2006). Within this neuralnetwork the mPFC and the ACC are engaged in distinguishing selffrom other, in error monitoring and prediction, and in decouplinghypothetical states from reality (Carter et al., 2001; Siegal and Varley,2002; Frith and Frith, 2003; Heatherton et al., 2006). The PCC and PCseem to be important for the experience of agency and self-consciousness (Cavanna & Trimble, 2006; Schilbach et al., 2006).The temporal regions contain mirror neurons that play a decisive rolefor imitation and learning as well as for the recognition of intentionalmovements (Gallagher and Frith, 2003). The TPJ contributes toreasoning about the contents of another person's mind (Saxe andWexler, 2005), attribution of a character's true and false beliefs (Saxe,2006; Sommer et al., 2007), recognition of cooperation versusdeception (Lissek et al., 2008) as well as self-other discrimination(Gallagher et al., 2000).

Functional brain imaging studies have revealed that the ToMneural network is profoundly altered in schizophrenia. Morespecically, reduced activation has been found in several areas ofthe prefrontal cortex, i.e. the left middle/inferior frontal gyrus andinsula (Russell et al., 2000), and the medial prefrontal cortex (Brunetet al., 2003; Lee et al., 2006; Brne et al., 2008;Walter et al., 2009), andright insula (Brne et al., 2008). Moreover, these studies demonstrat-ed that some schizophrenia patients also show greater activationwithin the ToM network, as was the case for patients with passivitysymptoms such as thought insertion or voice-commenting hallucina-tions, who activated the TPJ more strongly than controls (Brne et al.,2008), and greater activation of the mPFC and TPJ when observingphysically caused movements, suggest an overattribution of inten-tionality to inanimate objects (Walter et al., 2009).

In the fMRI study of subjects at ultra-high risk (UHR) of psychosis dened as having two or more rst or second degree relatives withschizophrenia UHR subjects activated the right inferior parietallobule and parts of the prefrontal cortex less if they had experiencedpsychotic symptoms in the past compared with healthy controls(Marjoram et al., 2006). Moreover, the high-risk group of subjectswho at the day of scanning had psychotic symptoms displayedactivations more similar to patients with manifest schizophrenia thanhigh-risk relatives who had psychotic symptoms in the past, but nocurrent symptoms (Marjoram et al., 2006). In contrast, subjects athigh risk who had never experienced psychotic symptoms showed

signicantly greater activation in the middle frontal gyrus comparedto high risk subjects who did experience psychotic symptoms in thepast, and to controls. This suggests that subjects at risk of developingschizophrenia display patterns of activation during the execution ofToM tasks that differ from patterns found in healthy subjects andmanifest schizophrenia patients, including compensatory overactiva-tions in regions that are normally not activated (Marjoram et al.,2006).

Accordingly, we sought to examine ToM activation duringfunctional brain imaging in subjects with at-risk states dened bythe presence of schizophrenia diagnosed according to structuredquestionnaires for prodromal symptoms, a procedure that does notnecessarily involve biological relatedness to schizophrenia patients.We used an fMRI paradigm that was previously established (Brneet al., 2008; Lissek et al., 2008), and compared activation patterns ofat-risk subjects with a group of manifest schizophrenia patients andhealthy controls. Specically, we expected based on the observa-tions in Marjoram et al.'s study (2006) that subjects with at-riskstates would deviate from both manifest schizophrenia patients andhealthy controls in activation of the ToM network.

Methods

Participants

Fifty-eight subjects were enrolled in the study after giving writteninformed consent. The study was approved by the Ethics Committeeof the Medical Faculty of the Ruhr-University of Bochum. Participantswith a history of substance dependence, traumatic brain injury ormental retardation were excluded from the study.

Ten subjects (3 women) fullled the criteria for an at-risk stage ofschizophrenia, for which we henceforth use the shorthand PROD(for prodromal) in the Methods and Results sections, as well as inTables and Figures, to illustrate that they fullled the followinginclusion criteria: Presence of at least two basic symptoms accordingto Klosterktter et al. (2001) in the category cognitive disturbancesof the Bonn Scale for the Assessment of Basic Symptoms (BSABS), or atleast one attenuated positive symptom (APS) on the Scale ofProdromal Symptoms (SOPS; McFarlane et al., 2003), and/or subjectshad a brief limited intermittent psychotic symptom (BLIPS) such ashallucinations or delusions (McGlashan et al., 2001). At-risk subjectswere recruited from the Early Recognition Centre at the Departmentof Psychiatry, Ruhr-University Bochum, and clinical interviews for thepresence of prodromal symptoms were conducted by S.. and H.G.R.At 1-year follow-up, one of the PROD subjects had made transitioninto psychosis, 2 were lost to follow-up, and the remaining 6PRODsubjects had no signs of transition into psychosis. For compar-isons, twenty-two patients (8 women) with a manifest diagnosis ofschizophrenia (SCHIZ) according to DSM-IV criteria (AmericanPsychiatric Association, 1994) were included, as well as a group oftwenty-six healthy control subjects (CONTR) (9 women). None of thecontrol subjects had a history of any psychiatric diagnosis or rst- orsecond degree relatives with a psychiatric disorder, as determined in asemi-structured interview performed by N.A. All schizophreniapatients received second-generation antipsychotic medication (SGA)with a mean chlorpromazine equivalent dose (CPZ; Woods, 2003) of475 mg (sd429 mg) per day, whereas in the PROD group only 3subjects received SGA, the other 6 PROD subjects were medication-free. No differences emerged between the three groups regarding age(F=1.386, df=2, p=0.260) or sex distribution (chi square=0.82,df=2, p=0.960). Mean positive and negative syndrome scores on thePositive and Negative Syndrome Scale (PANSS; Kay et al., 1989) were12.1 and 14.5 (sd2.9 and4.1, respectively) for PROD subjects; and18.2 and 21.2 (sd4.8 and7.1 respectively) for SCHIZ patients. AnANOVA revealed signicant group differences for both positive (F(1)=6.322 p=0.018) and negative (F(1)=11.504 p=0.002) symptoms,

indicating that PROD subjects exhibited signicantly less negative and

positive symptoms than schizophrenia patients. As expected, PRODsubjects received on average fewer antipsychotic medication(p=0.006). The demographic and clinical characteristics of the threegroups are summarized in Table 1.

Theory of mind task

The ability to infer somebody else's mental state was assessedusing a computerized Theory of Mind (ToM) test consisting of apicture sequencing task and a questionnaire (Brne, 2005). This testcomprises six cartoon picture stories. Two cartoon sequences deal

331M. Brne et al. / NeuroImage 55 (2011) 329337with the cooperation of two characters, two scenarios depict how onecharacter deceives another, and two stories portray two characterscooperating in order to deceive a third one (for examples, see Fig. 1).Subjects' behavioural performance on the ToM task was examinedafter scanning, following the procedure used in previous studies (e.g.,Brne, 2005; Brne et al., 2007; for details, see paragraph onbehavioural measures further down).

fMRI imaging

For the purpose of acquiring fMRI data during task performance,the cartoon stories were presented on a screen during the MRscanning session. All four pictures of a given story were shownsimultaneously on the screen, arranged in two rows in left to rightorder. In order to compare activation elicited by demands on ToMwith activation elicited by neutral questions not requiring ToM, weapplied two different conditions in presenting the cartoon stories: inthe ToM condition, the pictures of the stories were presented in thecorrect order, in the non-ToM condition, pictures of the same storieswere presented in jumbled order (examples see Fig. 1). We chose thisdesign to ensure greatest similarity of stimuli in both conditions, andbecause we believed that a jumbled order of the cartoon pictures inthe non-ToM condition, where questions regarding physical char-acteristics of the surrounding were asked, would produce sufcientlydistinct activation without creating an expectation bias inparticipants.

Accordingly, in each condition, at rst the cartoon story waspresented for 15 s, then two questions were successively super-imposed upon the screen between the rst and the second row ofpictures for 12 s each. In the ToM condition, the questions referred tointentions and expectations of the protagonists (e.g., what does theboy with the red pullover have in mind?), in the non-ToM condition,the questions referred to properties of objects appearing in the scene(e.g., is the background blue or yellow?). Prior to scanning,participants had been instructed to contemplate the story duringthe rst phase and then to think about the answer to each question aslong as the question was displayed on the screen.

The cartoon stories for the ToM and non-ToM conditions werepresented alternatingly in a blocked design with a total of 12 phases(6 ToM phases and 6 non-ToM (baseline) phases) of 39 s durationeach, always beginning with a non-ToM phase. Each of these phasesconsisted of the three parts as described above. We chose a block-

Table 1Demographic and clinical data of study participants.

PROD(N=10)

SCHIZ(N=22)

CONTR(N=26)

Statistics

Mean age (years) 25.55.3 26.85.5 28.84.1 n.s.Male to female ratio 7:3 15:7 16:9 n.s.Mean age at onset 24.16.8 23.45.0 n.s.Mean duration of illness (years) 0.60.2 3.33.7 p=0.002PANSS positive 12.12.9 18.24.8 p=0.018PANSS negative 14.54.1 21.27.1 p=0.02Mean CPZ equivalents (mg) 112230 475429 0.006design in order to capture the complete period of participants'thinking about the cartoon contents and the more specic questionspertaining to the cartoon characters' mental states, because weassumed that both aspects involved activation of the ToM network.Each experimental scanning session had a duration of approx. 7 min48 s. Using the software Presentation (Neurobehavioral Systems, Inc.,USA), the cartoon stories were projected via a Laptop Computer ontoMRI-compatible LCD goggles (Resonance Technology Inc., USA) wornby the participant. Prior to scanning, a test imagewas displayed on thescreen to ensure that the imageswere in focus and that the participantcould comfortably see the pictures and read the questions.

fMRI data acquisition

Data were acquired using a whole body 1.5 T scanner (MagnetomSymphony, Siemens, Germany) equipped with a high power gradientsystem (30 mT/m/s; SR 125 T/m/s), using a standard imaging headcoil. 157 Blood-oxygen level dependent (BOLD) contrast images wereobtained with a single-shot SpinEcho-EPI sequence (TR 3000 ms, TE60 ms, matrix 6464, ip angle 90, eld of view 224 mm, slicethickness 3.0 mm, 0.3 mm gap between slices, voxel size3.53.53.0 mm). We acquired 30 transaxial slices parallel to theanterior commissure posterior commissure (AC-PC) line whichcovered the whole brain. In total 157 images were acquired over7 min. 48 s. Additionally, anatomical images of each subject wereacquired using an isotropic T1-3dGE (MPRAGE) sequence (TR1800 ms, TE 3.87 ms, matrix 256256, eld of view 256 mm, slicethickness 1 mm, no gap, voxel size 111 mm) with 160 sagittallyoriented slices covering the whole brain.

fMRI data analysis

For preprocessing and statistical analysis of the fMRI data, we usedthe Statistical Parametric Mapping (SPM) Software, Version 5 (Well-come Department of Cognitive Neurology, London, UK) implementedin Matlab (Mathworks, Sherbon, MA). The rst 5 images of each fMRIsession (total 157 images), during which the BOLD signal reachessteady state, were discarded from further analysis. Single subjectpreprocessing consisted of the following steps: realignment of allimages to the rst volume, correction for head movement artifacts,normalization into standard stereotaxic space at 222 mm usingan EPI template provided by the Montreal Neurological Institute,smoothing at 6 mm voxels, and single subject data analysis. In a rst-level single-subject analysis, contrast images were calculated foractivation in the ToM condition compared to the non-ToM conditionin order to nd the areas activated by mentally answering questionsrequiring theory of mind. In order to determine those brain regionsinvolved in the ToM task across all subjects, we performed anexploratory second-level random effects analysis containing theindividual contrast images (one-sample t-test), with a threshold ofp=0.05 uncorrected and aminimum cluster size of k=10 voxels. Theresulting regions corresponded to our a priori hypothesis, derivedfrom previous ndings from brain activation patterns in theory ofmind tasks in schizophrenia (Russell et al., 2000; Brunet et al., 2003;Lee et al., 2006; Brne et al., 2008; Walter et al., 2009), in showingactivation of temporoparietal junction (TPJ), posterior cingulatecortex/precuneus, superior temporal gyrus, anterior cingulate cortexand medial prefrontal regions.

We restricted our further analysis to these ToM-relevant areas ifsignicantly activated in the rst exploratory analysis, fromwhich wederived regions of interest (ROIs) by using the MARSBAR toolbox(Brett et al., 2002). These ROI clusters encompassed signicantlyactivated regions in bilateral TPJ, posterior cingulate gyrus, precuneus,left superior temporal gyrus, anterior cingulate gyrus, inferior frontal

gyrus, medial frontal gyrus, and superior/middle frontal gyrus.

332 M. Brne et al. / NeuroImage 55 (2011) 329337To compare the groups with regard to their ToM activation,random effects contrasts were calculated between the groups (two-sample t-tests; height threshold pb0.05 uncorrected, extent thresholdk=10), resulting in six contrasts (CONTRNPROD, CONTRNSCHIZ,SCHIZNPROD, SCHIZNCONTR, PRODNCONTR, PRODNSCHIZ).

Behavioural measures

After the scanning procedure, all participants completed a paperand pencil version of the ToM task. For each cartoon story sequencedcorrectly, subjects received 6 points. In addition, 23 questionspertaining to the mental states of the cartoon characters were given,such that the total score for sequencing and questionnaire was 59 pts.maximum (for details, see Brne, 2005).

Statistical analyses were carried out using SPSS 11.5 for Windows.

Results

Behavioural data

Performance of the groups in the ToM task did not differsignicantly the scores for the ToM tasks were 58.4 (sd1.2) forPROD subjects, 57.3 (sd2.2) for SCHIZ patients, and 59.0 (sd0.0)

Fig. 1. Examples of the ToM cartoon stories: A) cooperation, B) deception, C) cooperation/decondition.

Fig. 2. Two-sample random effects analyses (pb0.05 k=10 uncorrected) contrasting brain a(B), and SCHIZ versus CONTR and PROD.for CONTR. For the ToMquestionnaire alone scoreswere 23.0 (sd0.0)for PROD patients, 21.96 (sd1.9) for SCHIZ, and 23.0 (sd0.0) forCONTR. For ToM sequencing the scores for all three groups were 36.00each (sd0.0). Thus, behaviourally all groups performed at ceilinglevel on the ToM task.

Imaging data

We analyzed results by directly contrasting all three groups:CONTR, PROD and SCHIZ with each other, using a height threshold ofpb0.05 uncorrected and an extent threshold of k=10.

CONTR compared to PROD and SCHIZ

CONTR showed higher activation than both PROD and SCHIZ inmedial frontal gryus (BA 9). CONTR also activated the posteriorcingulate gyrus (left BA 23) more strongly than PROD, and also morestrongly compared to SCHIZ yet in a different location (bilateral BA 29,30, 31). Furthermore, CONTR exhibited considerably higher activationthan SCHIZ patients, but not than PROD, in the TPJ, and in temporaland parietal cortex areas (left TPJ, BA 21, 22, 39), predominantly in theright precuneus (BA 31). (Fig. 2 and Table 2)

ception. D) Shows an example of the jumbled cartoon stories presented in the non-ToM

ctivation in CONTR versus PROD and SCHIZ patients (A), PROD versus CONTR and SCHIZ

333M. Brne et al. / NeuroImage 55 (2011) 329337

Table 2Contrasts of the groups CONTR, PROD and SCHIZ (n=58, height threshold pb0.05 extent threshold k=10). Xyz=MNI coordinates, BA=Brodmann area. Table denotes the coordinates of local peak activation for the listed brain regions.

CONTRNPROD CONTRNSCHIZ PRODNCONTR PRODNSCHIZ SCHIZNCONTR SCHIZNPROD

Anatomicalregion

BA x y z Cluster T-score x y z Cluster T-score x y z Cluster T-score x y z Cluster T-score x y z Cluster T-score x y z Cluster T-score

Prefrontal cortexSuperior frontalgyrus

10 L 8 68 22 48 1.948 L 40 14 54 18 2.31

Inferior frontalgyrus

45 L 52 24 14 126 3.25 62 24 4 11 2.2746 L 48 26 18 20 2.42 54 28 12 20 2.17

Medial frontalgyrus

9 L 6 52 24 48 1.71R 10 48 24 44 2.38

Limbic areasCingulate gyrus 31 L 12 46 40 31 2.42

R 4 46 50 28 2.46 8 46 46 53 2.2014 46 24 11 2.30

Posteriorcingulate

31 L 10 58 22 2.4029 L 14 50 12 25 3.15

R 4 40 16 2.5723 L 4 60 20 48 2.68 0 64 14 3.15

R 10 58 12 766 3.6230 L 20 64 2 35 2.21

Parahippocampalgyrus

R 16 62 4 275 3.15 6 64 8 1929 5.5030 L 18 46 2 35 2.73

Temporoparietal junctionSuperiortemporal g.

39 L 50 54 4 17 2.69 44 56 26 2.10 58 64 26 22 2.46 46 60 30 46 2.09R 40 56 26 493 3.53 42 54 28 72 2.53

52 58 24 1.7822 L 38 54 8 104 3.29 62 50 14 61 2.10 38 54 8 220 3.18

60 60 14 18 2.21R 36 56 10 42 2.34 62 58 18 2.48 64 54 20 84 3.10

Middle temporalgyrus

60 40 12 22 2.3239 L 48 74 20 68 2.15 40 48 8 52 3.65

R 44 66 26 2.0319 L 44 62 10 2.96

R 44 62 10 3.02Inferior parietallobule

40 L 52 46 28 36 2.76

Supramarginalgyrus

40 L 48 54 34 101 3.10 46 50 34 46 2.58

Temporal cortexSuperiortemporal g.

21 L 58 22 2 14 2.65 70 34 2 48 2.3941 L 44 38 10 27 2.19 46 42 8 2.8022 L 58 26 2 2.19

R 36 54 8 141 3.76Middle temporalgyrus

21 L 70 32 2 25 3.5764 56 0 18 2.30

41 R 42 44 8 2.57

Parietal cortexPrecuneus 7 R 2 54 58 18 2.58 16 50 48 21 3.48

10 70 36 22 2.13 16 54 38 11 2.004 52 54 53 2.31

7 L 8 64 36 17 2.22 6 66 48 31 2.0331 R 2 72 22 223 2.65 16 54 30 2.03 16 56 34 27 2.7

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PROD compared to CONTR and SCHIZ

PROD subjects showed more activation than both CONTR andSCHIZ in the left inferior frontal gyrus (BA 45/46); in several regions ofthe TPJ, in the superior/middle temporal gyrus bilaterally (BA 22 and39), as well as in some regions of left superior and middle temporalgyrus anterior to temporoparietal junction (BA 21, 22, 41). In addition,higher activation as compared to CONTR was found in the posteriorcingulate gyrus (bilateral BA 31), and in a right-hemispheric portionof the posterior cingulate (BA 23), as well as in the right precuneus(BA 7) (Fig. 3 and Table 2).

SCHIZ compared to CONTR and PROD

SCHIZ patients showed scattered patches of higher activation thanCONTR in the left superior and inferior frontal gyrus (BA 45, 46), in thebilateral TPJ (BA 22, 39), as well as in the right hemispheric posteriorcingulate gyrus/precuneus (BA 31). In comparison to PROD, SCHIZonly showed greater activation in some clusters in the right precuneus(BA 7). (Fig. 3 and Table 2).

Discussion

Recent studies have highlighted the possibility that socialcognitive abilities such as theory of mind (ToM) may be compro-

335M. Brne et al. / NeuroImage 55 (2011) 329337Fig. 3. Two-sample random effects analyses (pb0.05 k=10 uncorrected) contrastingbrain activation in CONTR versus PROD and SCHIZ patients (A), PROD versus CONTR

and SCHIZ (B), and SCHIZ versus CONTR and PROD (medial surface view).mised in at-risk states of psychosis (Chung et al. 2008). The soleexisting functional brain imaging study in subjects at ultra-high risk ofpsychosis during performance of a mental state attribution taskdetected complex deviations of activation patterns in ultra-high risksubjects compared to manifest patients with schizophrenia andcontrols, suggesting both state- and trait dependent changes inbrain activation during ToM task performance (Marjoram et al., 2006).To the best of our knowledge, no functional brain imaging study onToM performance has been carried out in subjects with an increasedrisk for developing psychosis as determined using the criteria forprodromal symptoms according to the SOPS (McFarlane et al., 2003),BSABS (Klosterktter et al., 2001), or CAARMS (Yung et al., 2005). Inline with Marjoram et al. (2006), we found that at-risk subjectsdiffered markedly in their activation patterns from manifest schizo-phrenia patients in that they showed greater activation in prefrontal,limbic and temporo-parietal areas during ToM task performancecompared to patients with schizophrenia. At-risk subjects alsodeviated from healthy controls in their activation patterns in thatthey displayed greater activation in posterior cingulate regions,temporal areas and precuneus. In addition, healthy controls activatedthe ToM neural network more strongly than schizophrenia patients,which is in accordance with previous studies (Russell et al. 2000;Brunet et al. 2003; Lee et al. 2006; Brne et al. 2008; Walter et al.2009). This seems to be a particularly robust nding, as the samplesizes of both schizophrenia patients and controls were fairly large. Incontrast, greater activation of manifest schizophrenia patientscompared to controls was observable only in small clusters. Thisresult differed from our own previous study, where schizophreniapatients with passivity symptoms showed greater activation of the TPJthan controls (Brne et al., 2008). We believe that the divergingnding of the present study mainly resides in the fact that theschizophrenia group exhibited more negative symptoms than thepassivity symptom group of our previous study (21.2 versus 15.7points on the PANSS negative syndrome). Another importantobservation was that greater activation in schizophrenia patientsrelative to at-risk subjects was almost absent in this study.

The pronounced activation of the right posterior cingulate regionin at-risk subjects relative to controls, and more so, compared tomanifest schizophrenia patients, warrants further discussion. In moststudies using ToM paradigms in healthy subjects, this region has notshown outstanding activation (e.g., Vllm et al., 2006; Sommer et al.,2007). Interestingly, however, in more complex social interactiontasks using economic games, the posterior cingulate cortex (PCC) hasrevealed strong activation, possibly, because game theoretical para-digms are more similar to actual social interaction (Rilling et al.,2004). Moreover, the PCC is believed to be involved in the evaluationof emotionally salient stimuli (Maddock, 1999), which could suggest in line with clinical observation that at-risk subjects wereemotionally more aroused during task performance, perhaps, becauseour ToM task is more similar to real-life scenarios than other ToMparadigms used in fMRI studies into ToM. An alternative explanationcould be that subjects at-risk of psychosis who experience thoughtdisorder, perceptual anomalies, and who have functionally deterio-rated, is still capable of recruiting additional resources whenperforming a mental state attribution task. In line with the latterassumption, subjects at risk of psychosis also activated the temporo-parietal junction (TPJ) and the inferior frontal gyrus (IFG) morestrongly than controls. These areas are particularly interesting,because they are believed to contain mirror neurons, which areknown to be part of the ToM network in that they are active duringaction prediction tasks and possibly malfunctioning in psychiatricconditions (Gallese, 2003). Unfortunately, our design was not suitableto test the hypothesis whether or not patients with schizophreniawould fail to deactivate the ToM network relative to controls andsubjects at-risk of psychosis during the non-ToM condition. Such

failure of deactivation was shown by Walter et al. (2009) in a sample

hyper-mentalising.In any event, our ndings support the previous interpretations

336 M. Brne et al. / NeuroImage 55 (2011) 329337(Marjoram et al., 2006) according to which subjects at high risk ofdeveloping schizophrenia may compensatorily overactivate brainregions that overlap only to some degree with the neural networkactivated by healthy subjects. The results of our study can beinterpreted in a way that suggests a graded activation pattern,with at-risk subjects showing the most extended activation, andmanifest schizophrenia patients the least activation during ToM taskperformance.

The results of our study, though, have to be considered in view ofthe fact that the sample size of the at-risk group was lower than thoseof the manifest schizophrenia group and the control group. Thus, wecannot rule out that these differences in group size inuenced ourndings regarding activation of the ToM network. Moreover, in the at-risk sample, only one subject made transition into psychosis at follow-up, 2 subjects were lost to follow-up, and the remaining 6 individualswere stable or even clinically improved. Thus, we are unable to rmlydraw the conclusion that greater activation of the ToM network in at-risk states of psychosis is in any specic way linked to a diseaseprocess associated with schizophrenia. To answer this question, alonger follow-up period would be necessary, or a direct post-hoccomparison between at-risk subjects with and without progressioninto psychosis. Furthermore, it would be interesting to explore infuture studies whether the differences in brain activation foundbetween at-risk subjects, manifest schizophrenia patients and con-trols are specic to the presented ToM task or express a more generalcognitive mechanism a question our present study cannot answer.Also, it needs to be emphasized that the group of manifestschizophrenia patients was exceptional in that they performednormally on both the sequencing and the questionnaire parts of theToM task, suggesting a selection bias towards better functionaloutcome (Brne et al., 2011). Previous behavioural studies of largersamples from our own group have shown that patients withschizophrenia score, on average, much lower (in the range of 47 outof 59 points) on the ToM task (Brne, 2005; Brne et al., 2007, 2011).The superior performance of the patients included in the fMRI studydoes not rule out, however, that in the present study schizophreniapatients still had a ToM decit that remained undetected by the ToMtask used. Nor can we entirely rule out that subjects activated the ToMneural network in the control condition to some degree, given that thevisual presentation of the picture stories though in jumbled order elicited some attribution of mental states to the cartoon characters.Finally, we did not examine general intelligence in all three groups,which could have inuenced performance.

In any event, our study is the rst to demonstrate brain activationpatterns during ToM task performance in at-risk states of schizo-phrenia as determined using psychopathological criteria. Subjectsat-risk of psychosis activate the neural network involved in ToMdifferently, and in part, more strongly, than manifest schizophreniapatients and healthy controls. However, future studies need toexplore whether these overactivations can be observed longitudinallyand whether or not there is a point of no return at which ToMactivation deteriorates during transition into psychosis. Finally, itwould be interesting to examine if alterations in activation patternsduring ToM task performance are associated with changes at thefunctional level.

Acknowledgments

The studywas supported by a grant from theMedical Faculty of theof patients with paranoid schizophrenia, which suggested thatparanoid patients tended to ascribe intentions to physically causedmovements (for example, a door slammed by a gust of air) as a sign ofRuhr-University Bochum (FoRUM F519-2006).References

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337M. Brne et al. / NeuroImage 55 (2011) 329337

An fMRI study of theory of mind in at-risk states of psychosis: Comparison with manifest schizophrenia and healthy controlsIntroductionMethodsParticipantsTheory of mind taskfMRI imagingfMRI data acquisitionfMRI data analysisBehavioural measures

ResultsBehavioural dataImaging dataCONTR compared to PROD and SCHIZPROD compared to CONTR and SCHIZSCHIZ compared to CONTR and PROD

DiscussionAcknowledgmentsReferences