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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: [email protected] (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
334M.Brne
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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
American Psychiatric Association, 1994. Diagnostic and
statistical manual of mentaldisorders, 4th ed. American Psychiatric
Association, Washington DC.
Amodio, D.M., Frith, C.D., 2006. Meeting of minds: the medial
frontal cortex and socialcognition. Nat. Rev. Neurosci. 7 (4),
268277.
Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Y., Plumb,
I., 2001. The Reading theMind in the Eyes test revised version: a
study with normal adults, and adults withAsperger syndrome or
high-functioning autism. J. Child Psychol. Psychiatry 42
(2),241251.
Bora, E., Eryavuz, A., Kayahan, B., Sungu, G., Veznedaroglu, B.,
2006. Social functioning,theory of mind and neurocognition in
outpatients with schizophrenia; mental statedecoding may be a
better predictor of social functioning than mental statereasoning.
Psychiatry Res. 145 (23), 95103.
Brett, M., Anton, J.L., Valabregue, R., Poline, J.P., 2002.
abstract. Presented at the 8thInternational Conference on
Functional Mapping of the Human Brain, June 26,2002, Sendai, Japan.
Available on CD-ROM in Neuroimage 16 (2).
Brne, M., 2005. Emotion recognition, theory of mind and social
behavior inschizophrenia. Psychiatry Res. 133 (23), 135147.
Brne, M., Abdel-Hamid, M., Lehmkmper, C., Sonntag, C., 2007.
Mental stateattribution, neurocognitive functioning, and
psychopathology: what predictspoor social competence in
schizophrenia best? Schizophr. Res. 92 (13), 151159.
Brne, M., Lissek, S., Fuchs, N., Witthaus, H., Peters, S.,
Nicolas, V., Juckel, G., Tegenthoff,M., 2008. An fMRI study of
theory of mind in schizophrenic patients withpassivity symptoms.
Neuropsychologia 46 (7), 19922001.
Brne, M., Schaub, D., Juckel, G., Langdon, R., 2011. Social
skills and behavioral problemsin schizophrenia: the role of mental
state attribution, neurocognition and clinicalsymptomatology.
Psychiatry Res. [Epub ahead of print].
Brunet, E., Sarfati, Y., Hardy-Bayl, M.C., Decety, J., 2003.
Abnormalities of brain functionduring a nonverbal theory of mind
task in schizophrenia. Neuropsychologia 41(12), 15741582.
Carter, C.S., MacDonald III, A.W., Ross, L.L., Stenger, V.A.,
2001. Anterior cingulate cortexactivity and impaired
self-monitoring of performance in patients with schizophre-nia: an
event-related fMRI study. Am. J. Psychiatry 158 (9), 14231428.
Cavanna, A.E., Trimble, M.R., 2006. The precuneus: a review of
its functional anatomyand behavioural correlates. Brain 129,
564583.
Chung, Y.S., Kang, D.H., Shin, N.Y., Yoo, S.Y., Kwon, J.S.,
2008. Decit of theory of mind inindividuals at ultra-high-risk for
schizophrenia. Schizophr. Res. 99 (13), 111118.
Couture, S.M., Penn, D.L., Addington, J., Woods, S.W., Perkins,
D.O., 2008. Assessment ofsocial judgments and complex mental states
in the early phases of psychosis.Schizophr. Res. 100 (13),
237241.
Frith, U., Frith, C.D., 2003. Development and neurophysiology of
mentalizing. Philos.Trans. R. Soc. Lond. B 358, 459473.
Gallagher, H.L., Frith, C.D., 2003. Functional imaging of theory
of mind. Trends Cogn.Sci. 7, 7783.
Gallagher, H.L., Happe, F., Brunswick, N., Fletcher, P.C.,
Frith, U., Frith, C.D., 2000.Reading the mind in cartoons and
stories: an fMRI study of theory of mind inverbal and nonverbal
tasks. Neuropsychologia 38 (1), 1121.
Gallese, V., 2003. The roots of empathy: the shared manifold
hypothesis and the neuralbasis of intersubjectivity.
Psychopathology 36 (4), 171180.
Gibson, C.M., Penn, D.L., Prinstein, M.J., Perkins, D.O.,
Belger, A., 2010. Social skilland social cognition in adolescents
at genetic risk for psychosis. Schizophr. Res.122 (13), 179184.
Heatherton, T.F., Wyland, C.L., Macrae, C.N., Demos, K.E.,
Denny, B.T., Kelley,W.M., 2006.Medial prefrontal activity
differentiates self from close others. Soc. Cogn. Affect.Neurosci.
1, 1825.
Kay, S.R., Opler, L.A., Lindenmayer, J.P., 1989. The positive
and negative syndrome scale(PANSS): rationale and standardisation.
Br. J. Psychiatry 7 (7), 5967.
Klosterktter, J., Hellmich, M., Steinmeyer, E.M.,
Schultze-Lutter, F., 2001. Diagnosingschizophrenia in the initial
prodromal phase. Arch. Gen. Psychiatry 58 (2),158164.
Lee, K.H., Brown,W.H., Egleston, P.N., Green, R.D.J., Farrow,
T.F.D., Hunter,M.D., Parks, R.W.,Wilkinson, I.D., Spence, S.A.,
Woodruff, P.W.R., 2006. A functional magnetic resonanceimaging
study of social cognition in schizophrenia during an acute episode
and afterrecovery. Am. J. Psychiatry 163 (11), 19261933.
Lissek, S., Peters, S., Fuchs, N., Witthaus, H., Nicolas, V.,
Tegenthoff, M., Juckel, G., Brne,M., 2008. Cooperation and
Deception Recruit Different Subsets of the Theory-of-Mind Network:
PLoS One, 3, p. e2023.
Lysaker, P.H., Lancaster, R.S., Nees, M.A., Davis, L.W., 2004.
Attributional style andsymptoms as predictors of social function in
schizophrenia. J. Rehab. Res. Dev. 41(2), 225232.
Maddock, R.J., 1999. The retrosplenial cortex and emotion: new
insights fromfunctional neuroimaging of the human brain. Trends
Neurosci. 22 (7), 310316.
Marjoram, D., Job, D.E., Whalley, H.C., Gountouna, V.E.,
McIntosh, A.M., Simonotto, E.,Cunningham-Owens, D., Johnstone,
E.C., Lawrie, S., 2006. A visual joke fMRIinvestigation into theory
of mind and enhanced risk of schizophrenia. Neuroimage31 (4),
18501858.
McFarlane, W., Perkins, D.O., Pearlson, G.D., Woods, S.W., 2003.
Prodromal assessmentwith the structured interview for prodromal
syndromes and the scale of prodromalsymptoms: predictive validity,
interrater reliability, and training to reliability.Schizophr.
Bull. 29 (4), 703-15. Erratum in: Schizophr. Bull. 2004, 30 (2),
following217.
McGlashan, T.H., Miller, T.J., Woods, S.W., 2001. In: Miller,
T.J., Mednick, S.A.,McGlashan, T.H., Libiger, J., Johannessen, J.O.
(Eds.), A scale for the assessment ofprodromal symptoms and states.
: Early Intervention in Psychotic Disorders.
Kluwer Academic, Dordrecht, the Netherlands, pp. 135150.
-
McGlashan, T.H., Addington, J., Cannon, T., Heinimaa, M.,
McGorry, P., O'Brien, M., Penn,D., Perkins, D., Salokangas, R.K.,
Walsh, B., Woods, S.W., Yung, A., 2007. Recruitmentand treatment
practices for help-seeking prodromal patients. Schizophr. Bull.
33(3), 715726.
McGorry, P.D., Killackey, E., Yung, A., 2008. Early intervention
in psychosis: concepts,evidence and future directions. World
Psychiat. 7 (3), 148156.
Miller, T.J., McGlashan, T.H., Rosen, J.L., Cadenhead, K.,
Cannon, T., Ventura, J., Miller, T.J.,McGlashan, T.H., Woods, S.W.,
Stein, K., Driesen, N., Corcoran, C.M., Hoffman, R.,Davidson, L.,
1999. Symptom assessment in schizophrenic prodromal
states.Psychiat. Quart. 70 (4), 273287.
Penn, D.L., Corrigan, P.W., Bentall, R.P., Racenstein, J.M.,
Newman, L., 1997. Socialcognition in schizophrenia. Psychol. Bull.
121 (1), 114132.
Penn, D.L., Sanna, L.J., Roberts, D.L., 2008. Social cognition
in schizophrenia: an overview.Schizophr. Bull. 34, 408411.
Premack, D., Woodruff, G., 1978. Does the chimpanzee have a
theory of mind? Behav.Brain Sci. 4, 515526.
Rilling, J.K., Sanfey, A.G., Aronson, J.A., Nystrom, L.E.,
Cohen, J.D., 2004. Theneural correlatesof theory of mind within
interpersonal interactions. Neuroimage 22 (4), 16941703.
Russell, T.A., Rubia, K., Bullmore, E.T., Soni, W., Suckling,
J., Brammer, M.J., Simmons, A.,Williams, S.C., Sharma, T., 2000.
Exploring the social brain in schizophrenia: leftprefrontal
underactivation during mental state attribution. Am. J. Psychiatry
157(12), 20402042.
Saxe, R., 2006. Uniquely human social cognition. Curr. Opin.
Neurobiol. 16 (12), 235239.Saxe, R., Wexler, A., 2005. Making sense
of another mind: the role of the right temporo-
parietal junction. Neuropsychologia 43 (10), 13911399.
Saxe, R., Carey, S., Kanwisher, N., 2004. Understanding other
minds: linkingdevelopmental psychology and functional neuroimaging.
Ann. Rev. Psychol. 55,87124.
Schilbach, L., Wohlschlaeger, A.M., Kraemer, N.C., Newen, A.,
Shah, N.J., Fink, G.R.,Vogeley, K., 2006. Being with virtual
others: neural correlates of social interaction.Neuropsychologia 44
(5), 718730.
Siegal, M., Varley, R., 2002. Neural systems involved in theory
of mind. Nat. Rev.Neurosci. 3 (6), 463471.
Sommer, M., Dhnel, K., Sodian, B., Meinhardt, J., Thoermer, C.,
Hajak, G., 2007. Neuralcorrelates of true and false belief
reasoning. Neuroimage 35 (3), 13781384.
Vllm, B.A., Taylor, A.N., Richardson, P., Corcoran, R.,
Stirling, J., McKie, S., Deakin, J.F.,Elliott, R., 2006. Neuronal
correlates of theory of mind and empathy: a functionalmagnetic
resonance imaging study in a nonverbal task. Neuroimage 29 (1),
9098.
Walter, H., Ciaramidaro, A., Adenzato, M., Vasic, N., Ardito,
R.B., Erk, S., Bara, B.G., 2009.Dysfunction of the social brain in
schizophrnia is modulated by intention type: anfMRI study. Soc.
Cogn. Affect. Neurosci. 4 (2), 166176.
Woods, S.W., 2003. Chlorpromazine equivalent doses for the newer
atypicalantipsychotics. J. Clin. Psychiatry 64 (6), 663667.
Yung, A.R., Phillips, L.J., Yuen, H.P.,McGorry, P.D., 2004. Risk
factors for psychosis in anultrahigh-risk group: psychopathology
and clinical features. Schizophr. Res. 67 (23),131142.
Yung, A.R., Yuen, H.P., McGorry, P.D., Phillips, L.J., Kelly,
D., Dell'Olio, M., Francey, S.M.,Cosgrave, E.M., Killackey, E.,
Stanford, C., Godfrey, K., Buckby, J., 2005. Mapping theonset of
psychosis: the comprehensive assessment of at-risk mental states.
Aust. N.Z. J. Psychiatry 39 (1112), 964971.
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