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Childhood trauma-related alterations in brain

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DOI: 10.1016/j.schres.2017.02.012

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SCHRES-07175; No of Pages 7
Schizophrenia Research xxx (2017) xxxxxx

Contents lists available at ScienceDirect

Schizophrenia Research

journal homepage: www.elsevier.com/locate/schres

Childhood trauma-related alterations in brain function during a

Theory-of-Mind task in schizophrenia
Yann Quid a,b,, Xin H. Ong c, Sebastian Mohnke d, Knut Schnell e, Henrik Walter d,
Vaughan J. Carr a,b,f, Melissa J. Green a,b,g,h
a
School of Psychiatry, University of New South Wales Research Unit for Schizophrenia Epidemiology Randwick, NSW Australia
b
Neuroscience Research Australia, Randwick, NSW, Australia
c
Faculty of Medicine, University of New South Wales, Randwick, NSW, Australia
d
Department of Psychiatry and Psychotherapy, Charit Universittsmedizin Berlin, Berlin, Germany
e
Department of Psychiatry, University of Heidelberg, Heidelberg, Germany
f
Department of Psychiatry, School of Clinical Sciences, Monash University, Clayton, VIC, Australia
g
Black Dog Institute, Prince of Wales Hospital, Randwick, NSW, Australia
h
ARC Centre for Cognition and its Disorders (CCD), Macquarie University, Sydney, NSW, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Childhood trauma is a risk factor for schizophrenia that affects brain functions associated with higher cognitive
Received 27 September 2016 processes, including social cognition. Alterations in Theory-of-Mind (ToM), or mentalizing skills, are a hallmark
Received in revised form 6 February 2017 feature of schizophrenia, and are also evident in individuals exposed to childhood trauma. However, the impact
Accepted 9 February 2017
of childhood trauma exposure on brain function during social cognition in schizophrenia remains unclear. We
Available online xxxx
thus examined the association between childhood trauma and brain function during the performance of a ToM
Keywords:
task in 47 patients diagnosed with schizophrenia or schizoaffective disorder. All participants completed the
Childhood adversity Childhood Trauma Questionnaire (CTQ) and underwent functional magnetic resonance imaging while
Maltreatment performing an established visual-cartoon affective ToM task. Whole-brain multiple regression analysis was per-
Schizophrenia formed on ToM-related brain activation, with CTQ total score as regressor of interest, while accounting for the ef-
Mentalizing fects of age, sex, diagnosis, symptom severity, behavioural performance, intelligence and medications levels. First,
Social cognition using a small-volume correction approach within a mask made of key regions for ToM [including bilateral
Functional magnetic resonance imaging temporo-parietal junctions (TPJ), medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC)/
precuneus], total CTQ scores were positively associated with activation of the PCC/precuneus. Second, explorato-
ry analyses for the rest of the brain (i.e., ROIs masked-out), revealed a positive association between trauma expo-
sure and activation of the dorsomedial prefrontal cortex (dmPFC), and a negative association with activation of
the anterior section of the TPJ. These results suggest that childhood trauma exposure may, at least partially, con-
tribute to functional alterations of brain regions essential for effective mental state inference in schizophrenia.
2017 Elsevier B.V. All rights reserved.

1. Introduction integrity of affective ToM and cognitive ToM networks (Abu-Akel

Theory-of-Mind (ToM), or mentalizing, involves higher-order so-
cial cognitive processes to facilitate accurate understanding of others'
thoughts, emotions and intentions (i.e., mental states), which in turn fa-
cilitates adaptive social behaviour (Wimmer and Perner, 1983). Decits
in ToM are pervasive features of schizophrenia (Bora et al., 2009) that
are known to impact social functioning (Couture et al., 2006) in both
acute (Bora et al., 2009) and remitted patients (Sprong et al., 2007).
Effective ToM processes are critically dependent on the functional
Corresponding author at: School of Psychiatry, University of New South Wales
Research Unit for Schizophrenia Epidemiology Randwick, NSW Australia.
E-mail addresses: y.quide@unsw.edu.au, yannquide@gmail.com (Y. Quid).
and Shamay-Tsoory, 2011). The temporo-parietal junction (TPJ), the
posterior cingulate cortex (PCC)/precuneus and the superior temporal
sulcus (STS) are common to both networks; however, the affective
ToM network also involves the ventromedial prefrontal cortex
(vmPFC)/orbitofrontal cortex (OFC), ventrolateral prefrontal cortex
(vlPFC), ventral anterior cingulate cortex (vACC), ventral striatum,
amygdala, temporal poles, while the cognitive ToM network involves
the dorsomedial prefrontal cortex (dmPFC), dorsolateral prefrontal cor-
tex (dlPFC), dorsal ACC (dACC) and the dorsal striatum (Abu-Akel and
Shamay-Tsoory, 2011). A recent meta-analysis of neural activation in
schizophrenia during ToM tasks (including 9 studies comparing 133
schizophrenia patients to 140 healthy controls) revealed increased acti-
vation of the PCC, the STS and somatosensory cortices, and decreased

http://dx.doi.org/10.1016/j.schres.2017.02.012
0920-9964/ 2017 Elsevier B.V. All rights reserved.

Please cite this article as: Quid, Y., et al., Childhood trauma-related alterations in brain function during a Theory-of-Mind task in schizophrenia,
Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.02.012
2 Y. Quid et al. / Schizophrenia Research xxx (2017) xxxxxx
activation of the mPFC (Sugranyes et al., 2011). Similarly increased acti-
vation in the PCC and the TPJ and decreased activation in the mPFC have
been reported in unaffected rst-degree relatives of patients with
schizophrenia (Mohnke et al., 2016).
In non-psychotic populations, exposure to childhood trauma is com-
monly associated with decits on higher cognitive processes (executive
functions, working memory or emotional processes) and associated
brain regions (Hart and Rubia, 2012). Importantly, alterations of social
cognitive skills are evident in maltreated youths (Benarous et al.,
2015; Luke and Banerjee, 2013) and ostensibly healthy adults
(Germine et al., 2015), and adults with posttraumatic stress disorder
(Nazarov et al., 2014). Childhood maltreatment is associated with in-
creased centrality (i.e., the importance of a node in a network) of the
right precuneus and the right anterior insula, and reduced importance
of the left ACC, in brain networks sustaining social cognitive skills
(such as emotion regulation, mental state inference, ascribing inten-
tions or beliefs to others; Teicher et al., 2014). Consistently, increased
amygdala activation has been found in trauma-exposed patients with
chronic depression performing an affective ToM task (Hentze et al.,
2016), consistent with similar patterns of amygdala hyper-activation
reported in trauma-exposed (healthy) individuals performing a face-
matching task (Dannlowski et al., 2012).
Exposure to childhood trauma is also a signicant risk factor for psy-
chosis (Green et al., 2014; Read et al., 2014) that impacts morphology
and function of key brain regions for cognition in these populations. In
mixed samples of psychotic disorders (i.e., comprising schizophrenia,
schizoaffective disorder, and psychotic bipolar cases), exposure to sexual
abuse has been associated with decreased grey matter in the left dlPFC
and the ACC (Shefeld et al., 2013), while exposure to any type of child-
hood trauma has been associated with increased activation of the left infe-
rior parietal lobule when performing a working memory task (Quid et
al., 2016). In schizophrenia, exposure to emotional neglect has been asso-
ciated with reduced grey matter volume of the right dlPFC (Cancel et al.,
2015), while exposure to sexual abuse and physical neglect were associ-
ated with aberrant amygdala-PCC/precuneus functional connectivity dur-
ing an emotion-processing task (Cancel et al., 2016). These regions show
considerable overlap with brain regions implicated in ToM performance,
suggesting that trauma-exposure may contribute to brain functional al-
terations associated with social cognitive impairments, as previously de-
scribed in schizophrenia (Mrizak et al., 2016). Despite the high
prevalence of trauma exposure in schizophrenia (Larsson et al., 2013;
Matheson et al., 2013) and evidence for trauma-related ToM decits,
the effects of childhood trauma on ToM brain function in schizophrenia
have not yet been investigated.
We thus set out to investigate the effects of childhood trauma expo-
sure on brain function associated with ToM processes in a sample of pa-
tients with schizophrenia and schizoaffective disorder. Specically, we
investigated the associations between exposure to childhood trauma
(Bernstein et al., 2003) and brain activation (blood oxygenation level de-
pendent signal changes) occurring during the performance of a well-
characterized and robust ToM task. Unlike its extended version (Schnell
et al., 2011), the two conditions version of the ToM task used here, does
not distinguish between affective and cognitive ToM processes
(Mohnke et al., 2014; Walter et al., 2011). We expected that childhood
trauma would be associated with increased activation within a mask of
ToM-related key regions derived from van Overwalle's meta-analysis
(Van Overwalle, 2009), including bilateral TPJ, the PCC/precuneus and
the mPFC. We also explored the potential associations between childhood
trauma exposure and activation of brain regions outside these regions.
2. Materials and methods
2.1. Participants
All participants provided informed consent according to procedures
approved by the UNSW Human Research Ethics committees
Please cite this article as: Quid, Y., et al., Childhood trauma-related alterations in brain function during a Theory-of-Mind task in schizophrenia,
Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.02.012
(HC12384), the South East Sydney and Illawarra Area Health Service
(HREC 09/081) and St Vincent's Hospital (HREC/10/SVH/9). Participants
were 47 clinical cases meeting ICD-10 criteria (W.H.O., 2008) for schizo-
phrenia (n = 29) or schizoaffective disorder (n = 18), recruited from
local area health services, the Australian Schizophrenia Research Bank
(ASRB; Loughland et al., 2010) and by advertisement in the local com-
munity. Exclusion criteria included inability to communicate sufcient-
ly in English, current neurological disorder, any history of head injuries
with loss of consciousness, a diagnosis of substance abuse/dependence
in the past six months, and having received electroconvulsive therapy
in the previous six months.
2.2. Materials
Clinical diagnoses according to ICD-10 criteria were derived using
the OPCRIT algorithm (McGufn and Farmer, 1991) applied to inter-
viewer ratings on the Diagnostic Interview for Psychosis (Castle et al.,
2006). Current symptom severity was determined using the Positive
and Negative Syndrome Scale (PANSS; Kay et al., 1989), current Intellec-
tual Quotient (IQ) levels were measured by the Wechsler Abbreviated
Scale of Intelligence (WASI; Wechsler, 1999), and handedness was de-
termined using the Edinburgh Handedness Inventory (Oldeld, 1971).
Exposure to childhood trauma was measured using the short form
(25 items) of the Childhood Trauma Questionnaire (CTQ; Bernstein et
al., 2003). The CTQ is a self-report questionnaire that measures child-
hood (before age 12 years) trauma exposure on domains of emotional
(EA), physical (PA) and sexual (SA) abuse, as well as physical (PN)
and emotional (EN) neglect. For each domain, a score is calculated
from 5 items, each rated with a 5-point Likert scale ranging from 1
(never true) to 5 (very often true); responses within each domain
were summed, and scores within the Moderate to Extreme range (i.e.,
EA N 12; PA N 9; SA N 7; EN N 14; PN N 9) on any one of these domains
indicates signicant trauma severity (Mrkved et al., 2016; Quid et
al., 2016; Shannon et al., 2011). Due to high correlation among CTQ do-
mains (Table 1) and because 38% of the present sample reported expo-
sure to signicant trauma severity on multiple CTQ domains (Table 2),
we used the CTQ total score for focal functional brain imaging analyses.
2.3. Theory-of-Mind (ToM) task
The ToM task was developed for use in functional neuroimaging
studies (Schnell et al., 2011) and demonstrates excellent reliability
(0.76 b ICC b 0.82) of ToM-related brain activity (Mohnke et al., 2014).
In its shortened version with two conditions, that is, a control condition
and an affective ToM condition (Mohnke et al., 2014; Walter et al.,
2011), it does not distinguish between affective and cognitive ToM pro-
cesses and is not particularly sensitive to behavioural performance
(Mohnke et al., 2014). The task employed a block-design that alternates
between 8 blocks of ToM and 8 blocks of Control conditions (total par-
adigm time: 480 s). Each block comprised 4 frames: an instruction
frame (6.53 s), followed by a cartoon story in three consecutive frames
(22.58 s; 7.53 s per image). For the control conditions, participants
counted the number of living characters in the cartoon frames and de-
termined if there was a change (same, more or less) between frames.
For the ToM condition, participants were required to report whether
the protagonist's affect would be expected to have changed according
to the circumstances, by specically indicating whether the affective
state of the protagonist would be expected to be the same as, better, or
worse than, the previous picture in the cartoon sequence. Pictures
were free of direct emotional cues such as characters' facial expressions
to avoid simple activation of emotion perception networks.
Stimuli were displayed on a Philips LCD monitor at the rear of the
magnet, viewed by the participant via a standard head coil mirror. A
Cedrus Lumina response box was used to measure behavioural re-
sponses. All participants underwent an ofine task training session
before the fMRI data acquisition. Accuracy in the different conditions
 Y. Quid et al. / Schizophrenia Research xxx (2017) xxxxxx 3

Table 1
Correlational analyses between the different CTQ domains within the schizophrenia sample. Signicant correlations are in bold.

CTQ emotional abuse CTQ physical abuse CTQ sexual abuse CTQ emotional neglect

CTQ emotional abuse

CTQ physical abuse r = 0.559
CTQ sexual abuse r = 0.145 r = 0.108
CTQ emotional neglect r = 0.530 r = 0.354 r = 0.109
CTQ physical neglect r = 0.682 r = 0.547 r = 0.052 r = 0.487

CTQ: childhood trauma questionnaire.

p b 0.05.
p b 0.001.
p b 0.001.

was estimated as the percentage of correct answers relative to the total identies images that are outliers for movement (translation and rota-
number of possible answers (correct, incorrect or missed). tion) and global BOLD signal, and then allows the integration of
dummy variables as new regressors to a new rst-level model for
2.4. Images acquisition and processing each bad time point. Only participants showing 10% or less outlier for
each task condition separately, as well as for the whole run, were con-
We acquired 240 whole-brain T2* weighted echo-planar images served for further analyses.
(EPI); slice thickness 4 mm, 0.3 mm gap, 32 axial slices in ascending Finally, the data were high-pass ltered using a cut-off of 128 s and
order, TR 2000 ms, TE 30 ms, ip angle 80, matrix 96 96, eld of the autoregressive (AR1) function was applied. To help account for
view 240 mm, on a Philips Achieva 3 T scanner, housed at Neuroscience movement and image intensity-related variance, the regressors obtain-
Research Australia (Randwick, NSW, Australia). A high-resolution T1- ed after ART inspection were added to the design matrix at the rst-
weighted anatomical scan (MPRAGE) was also obtained for each partic- level; this includes regressors for movement (n = 6) and global signal
ipant for registration and screening; TR 8.9 ms, TE 4.1 ms, eld of view intensity (n = 1) across all subjects, as well as individual potential out-
240 mm, matrix 268 268, 200 sagittal slices, slice thickness 0.9 mm liers. Also, variance accounted for the instructions and the button
(no gap). presses were modelled as separate conditions and were added as re-
Image processing and all analyses were performed using SPM8 gressors of no-interest to the design matrix. A rst-level (individual)
(Wellcome Trust Centre for Neuroimaging, London, UK; http://www. step modelled contrasts for the different conditions (ToM, Control,
l.ion.ucl.ac.uk/spm) in Matlab r2011b (Mathworks Inc., Sherborn, ToM N Control). Individual (ToM N Control) contrasts were used in
MA, USA). The rst ve volumes were automatically discarded to second-level steps.
allow for magnetic stabilization. Following manual re-orientation to
the AC-PC line, images for each participant were slice-timing corrected,
2.5. Analyses
realigned to the rst image in the sequence to help correct for head mo-
tion, and anatomical images were co-registered to the mean functional
Whole-brain multiple regression analyses were performed on brain
image. Scans were screened for stability (b2 mm head movement; b2
function during mentalizing (ToM N Control), with CTQ total score as
rotation), image artifact, and structural abnormalities and were then
regressor of interest, and age, sex, diagnosis (schizophrenia or
spatially normalised into the Montreal Neurological Institute (MNI)
schizoaffective disorder), behavioural performance (ToM accuracy and
space using a non-linear 12-parameter afne transformation, re-sliced
reaction time), PANSS total score, medication (imipramine and chlor-
to 2 2 2 mm voxels and nally smoothed with an isotropic Gaussian
promazine equivalent dosages for antidepressant and antipsychotic
kernel set at 8 mm full-width half-maximum. After rst-level modeling,
medications, respectively, and mood stabilizer use) and IQ levels as co-
scans for all participants were additionally inspected for movements
variates of no-interest. First, a family-wise error correction within an
and intensity artifacts using the Artifact Detection Toolbox for SPM8
unique mask (small volume correction [p(SVC-FWE) = 0.05]) made of
(ART; https://www.nitrc.org/projects/artifact_detect/). This toolbox
large functional regions-of-interest (ROIs; 545692 voxels) generated
for the bilateral TPJ, dmPFC and PCC/precuneus [see (Mohnke et al.,
Table 2 2016) for details] was applied to an initial voxel-level threshold of
Number and type of CTQ domains within the Moderate to Extreme range endorsed by the p b 0.001 (uncorrected). Briey, the ROIs were created literature-
schizophrenia patients (n = 47). based on coordinates reported by van Overwalle's meta-analysis (Van
CTQ emotional abuse, n (%) 15 (32%) Overwalle, 2009) using the TWURoi toolbox (Schubert et al., 2008). Sec-
CTQ physical abuse, n (%) 10 (21%) ond, to identify ToM-related brain function associated with trauma ex-
CTQ sexual abuse, n (%) 15 (26%) posure in regions located outside these ROIs, a cluster-level family-
CTQ emotional neglect, n (%) 12 (26%)
wise error (FWE)-correction [p(FWEc) b 0.05] was applied to an initial
CTQ physical neglect, n (%) 14 (30%)
voxel-level threshold of p b 0.001 (uncorrected), masked-out for the
CTQ domains within Moderate to Extreme range ROIs mask. Finally, potential associations between childhood trauma
At least 1 CTQ domain, n (%) 31 (66%) exposure (CTQ total score) and behavioural performance (ToM accura-
1 CTQ domain, n (%) 13 (28%)
2 CTQ domains, n (%) 6 (13%)
cy and reaction-time) and IQ levels as previously found associated
3 CTQ domains, n (%) 8 (17%) with ToM in schizophrenia (Bora et al., 2009) and following childhood
4 CTQ domains, n (%) 3 (6%) trauma exposure (Hart and Rubia, 2012) were evaluated using addi-
5 CTQ domains, n (%) 1 (2%) tional Pearson's correlation.
Number of cases reporting each domain of CTQ uniquely
CTQ emotional abuse, n (%) 2 (4%)
CTQ physical abuse, n (%) 1 (2%) 3. Results
CTQ sexual abuse, n (%) 5 (11%)
CTQ emotional neglect, n (%) 4 (9%) Sociodemographic, clinical and behavioural data are presented in
CTQ physical neglect, n (%) 1 (2%) Table 3. For the full sample, the ToM task engendered signicant activa-
Note: CTQ = childhood trauma questionnaire tion of the bilateral dmPFC, dlPFC, vlPFC, TPJ, ACC, PCC, STS and

Please cite this article as: Quid, Y., et al., Childhood trauma-related alterations in brain function during a Theory-of-Mind task in schizophrenia,
Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.02.012
4 Y. Quid et al. / Schizophrenia Research xxx (2017) xxxxxx

thalamus, when contrasted with activation engendered by the control Effective ToM is critically dependent on the integrity of key brain re-
condition (i.e., ToM N Control; see Fig. 1). gions including the PCC/precuneus, dmPFC and TPJ (Abu-Akel and
The SVC analysis indicated a signicant positive association between Shamay-Tsoory, 2011). Consistent with our hypothesis, ToM-related ac-
CTQ total scores and activation within the PCC/precuneus [R2 = 0.156; tivation of both the PCC/precuneus and the dmPFC were positively asso-
peak MNI coordinates (6, 54,30), k = 165, t35 = 4.86, z = 4.22, ciated with childhood trauma exposure independently of any effect of
p(SVC-FWE) = 0.031] (see Fig. 2). The exploratory whole-brain analysis trauma on task performance. During ToM, the PCC/precuneus is
(excluding voxels from the ROIs), indicated a signicant positive associ- implicated in processing self-related information (Abu-Akel and
ation between CTQ total score and BOLD signal (R2 = 0.107) in a cluster Shamay-Tsoory, 2011; Spreng and Grady, 2010; Spreng et al., 2009),
including the right medial superior frontal gyrus, the superior frontal as well as in contributing to mental state understanding using mental
gyrus and the supplementary motor area [dmPFC; peak MNI coordi- imagery skills (Cavanna and Trimble, 2006; Schurz et al., 2014), while
nates (14,16,50), k = 140, t35 = 4.33, z = 3.84, p(FWEc) = 0.038] the dmPFC is involved in processing social and/or emotional content
that was located posterior to the dmPFC ROI. In addition, a signicant about others (Saxe and Powell, 2006). Whereas the dmPFC cluster re-
negative association between BOLD signal and CTQ total score (R2 = ported here was posterior to the dmPFC ROI from a meta-analysis of
0.380) was revealed in a cluster encompassing the right Rolandic Oper- brain regions involved in social cognition (Van Overwalle, 2009), it o-
culum, superior temporal gyrus, supramarginal gyrus and posterior verlapped with the dmPFC/supplementary motor area (cluster 2;
insula [TPJ; peak MNI coordinates (54,-28,20), k = 154, t35 = 4.11, ROI#3) ROI from a more recent meta-analysis (Schurz et al., 2014),
z = 3.69, p(FWEc) = 0.026]; this cluster was located anterior to the which suggests this region is involved in trait judgements, especially
right TPJ ROI. Changes in BOLD signal in these regions were not associ- about unfamiliar others (Schurz et al., 2014; Van Overwalle, 2009). Un-
ated with any of the other covariates. expectedly, trauma exposure was associated with decreased activation
Additional Pearson correlation revealed no signicant associations in the TPJ, a region representing the nexus between mental inference
between CTQ total score and task performance (ToM accuracy: and salience detection (Carter et al., 2012) in order to establish a social
r = 0.013, p = 0.930; ToM reaction-time: r = 0.176, p = 0.238) context (Carter and Huettel, 2013). The interpretation of these ndings
or IQ levels (r = 0.014, p = 0.926). should also consider that the TPJ cluster identied in the present study
is anterior to the TPJ ROI in van Overwalle's meta-analysis (Van
Overwalle, 2009), but overlaps with the anterior TPJ (TPJa; ROI#7) ROI
4. Discussion from the Schurz et al. meta-analysis (Schurz et al., 2014), of which the
latter is associated with social animation and rational action to under-
This is the rst study to investigate the long-term effects of child- stand human action or behaviour (Mars et al., 2012; Schurz et al., 2014).
hood trauma exposure on social brain function in adults diagnosed Together, these results indicate that trauma-exposure may, at least
with schizophrenia or schizoaffective disorder during the performance partially, account for the development of functional brain alterations
of a Theory-of-Mind (ToM) task. Results indicate that greater levels of contributing to abnormally self-oriented mental imagery (through in-
childhood trauma exposure are associated with increased activation of creased PCC/precuneus activation), misrepresentation of others inten-
the PCC/precuneus and dmPFC, and reduced activation of the right TPJ, tions (through increased dmPFC activation), and/or misunderstanding
regardless of diagnosis. of the social context of an action/behaviour (through decreased TPJa ac-
tivation) during ToM. These trauma-related functional brain alterations
may thus contribute to abnormal mental state inference in individuals
Table 3 who later develop schizophrenia or schizoaffective disorder. Interest-
Sociodemographic, clinical and behavioural results of the schizophrenia sample. ingly, the TPJ, PCC and mPFC have been recently implicated as part of
Age (SD) 38.78 (10.56)
an extended default-mode network (eDMN), engaged in perspective-
Gender (F/M) 17/30 taking and empathizing when social-emotional stimuli, in particular
Education (SD) 14.40 (2.33) negative emotions, are displayed (Gottlich et al., 2017). Future use of a
Handedness (L/A/R) 1/7/39 network analysis will be required to conrm this interpretation, since
WASI (SD) 107.45 (14.24)
trauma exposure is likely to impact an extended network of brain re-
Age of onset, years (SD) 22.42 (7.29)
Length of illness, years (SD) 16.23 (9.13) gions that includes, but is not limited to, ToM regions (Teicher et al.,
PANSS positive (SD) 13.83 (5.97) 2014; Teicher et al., 2016).
PANSS negative (SD) 14.72 (6.36) The present ndings should be considered in light of the following
PANSS general (SD) 27.62 (10.34) limitations. Given the adult age of this sample, and the use of retrospec-
PANSS Total (SD) 56.17 (20.26)
CTQ emotional abuse (SD) 11.21 (4.99)
tive reports of childhood trauma, it remains unclear as to whether these
CTQ physical abuse (SD) 7.70 (3.87) functional brain alterations began to form during early child develop-
CTQ sexual abuse (SD) 7.23 (3.56) ment, potentially underlying decits in social and emotional function-
CTQ emotional neglect (SD) 11.79 (4.57) ing that are antecedent to schizophrenia; longitudinal studies are
CTQ physical neglect (SD) 8.00 (2.92)
required to clarify the extent to which childhood trauma can be
CTQ Total score (SD) 45.94 (13.82)
Antidepressant IMI, mg (SD) 56.83 (125.39) regarded as a primary cause of these brain disturbances. In addition,
Antipsychotic CPZ, mg (SD) 636.45 (1225.06) we were unable to identify the effects of domain-specic trauma with-
Mood Stabilizers (Y/N) 11/36 out contamination from other domains due to the strong correlations
Accuracy control, % (SD) 89.10 (11.83) between each other. This was, however, not the case for sexual abuse,
RT correct control, s (SD) 2.522 (0.676)
but as only 5 cases reported signicant exposure to sexual abuse
Errors control, n (SD) 1.30 (1.69)
Missed control, n (SD) 0.45 (0.72) uniquely (see Table 2), we did not investigate the specic effects of
Accuracy ToM, % (SD) 60.77 (12.62) this traumatic domain on ToM brain function. Other limitations of this
RT correct ToM, s (SD) 2.853 (0.720) study include the relatively small sample size, the high levels of medica-
Errors ToM, n (SD) 5.32 (1.89)
tion among schizophrenia participants; although the dosage equiva-
Missed ToM, n (SD) 0.96 (1.72)
lents of the major classes were accounted for in focal analyses.
SD: standard deviation; F/M: female/male; L/A/R: left handed, ambidextrous or Although we attempted to account for diagnosis in the analyses, we ac-
right handed; WASI: Weschler abbreviated scale of intelligence; PANSS: positive
and negative syndrome scale; CTQ: childhood trauma questionnaire; IMI: mean
knowledge that the inclusion of cases with schizoaffective disorder may
imipramine dosage equivalent in milligrams; CPZ: mean chlorpromazine dosage have inuenced the patterns of affective processing and/or symptoms
equivalent in milligrams; RT: reaction time in seconds. within the sample. Finally, the ToM imaging paradigm used in this

Please cite this article as: Quid, Y., et al., Childhood trauma-related alterations in brain function during a Theory-of-Mind task in schizophrenia,
Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.02.012
 Y. Quid et al. / Schizophrenia Research xxx (2017) xxxxxx 5

Fig. 1. Main effect of task (ToM N Control) within the schizophrenia sample. The main effect of task included signicant activation of the bilateral dmPFC, dlPFC, vlPFC, TPJ, ACC, PCC, STS
and thalamus. Color bar represents t-values; statistical signicance was set at a voxel-wise threshold of p = 0.001 uncorrected, to which a family-wise error (FWE)-correction was applied
on cluster statistics [p(FWEc) b 0.05];

Fig. 2. Association of childhood trauma severity with brain function during mentalizing in patients with schizophrenia or schizoaffective disorder. (A) Within a unique mask including our
four regions-of-interest [ROIs; bilateral temporo-parietal junctions (TPJ), posterior cingulate cortex (PCC)/precuneus, and medial prefrontal cortex (mPFC)], a small volume correction
(SVC) was applied to an initial uncorrected voxel-wise threshold of p = 0.001, and revealed that severity of childhood trauma exposure (CTQ total score) was positively associated
with activation in the posterior cingulate cortex (PCC)/precuneus (in red). (B) An explorative whole-brain analysis, masked-out for the ROIs, revealed a positive association between
CTQ total score and activation of the dorsomedial prefrontal cortex (dmPFC, in green, posterior to the mPFC ROI) and a negative association in the right anterior TPJ (in blue, anterior
to the TPJ ROI). Statistical signicance was set at a voxel-wise threshold of p = 0.001 uncorrected, to which a family-wise error (FWE)-correction was applied on cluster statistics
[p(FWEc) b 0.05]. a.u.: arbitrary unit. (For interpretation of the references to color in this gure legend, the reader is referred to the web version of this article.)

Please cite this article as: Quid, Y., et al., Childhood trauma-related alterations in brain function during a Theory-of-Mind task in schizophrenia,
Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.02.012
6 Y. Quid et al. / Schizophrenia Research xxx (2017) xxxxxx
study was specically designed to measure robust affective ToM-related
brain activation and does not demonstrate particular sensitivity for be-
havioural ToM performance (Mohnke et al., 2014). This may, at least in
part, explain the lack of association between behavioural variables and
trauma exposure.
In conclusion, we show here that signicant trauma experienced in
childhood is associated with functional variations in key brain regions
for effective ToM (TPJ, PCC, dmPFC) in adult patients with schizophrenia
or schizoaffective disorder. Future studies of effective connectivity with-
in ToM networks using graph theory or dynamic causal modelling, in
longitudinal studies beginning in childhood, would assist in under-
standing the impact of childhood trauma on the functional circuitry as-
sociated with social cognition dysfunction in schizophrenia.
Contributors
Drs Green and Quid designed the study and wrote the protocol. Dr. Quid managed
the literature searches and wrote the rst draft of the manuscript. Dr. Quid and Ms. Ong
undertook the statistical analyses. Dr. Mohnke, Dr. Schnell and Dr. Walter provided exper-
tise on data processing and interpretation. Dr. Carr assisted with recruitment of partici-
pants, and contributed to the interpretation of the analyses and preparation of the
manuscript. All authors have contributed to, and have approved the nal version of this
manuscript.
Role of the funding source
This study was funded by Project Grants from the Australian Nation-
al Health and Medical Research Council (NHMRC; APP630471 and
APP1081603), the Schizophrenia Research Institute Grant-in-Aid pro-
gram, and the Macquarie University's ARC Centre of Excellence in Cog-
nition and its Disorders. Green was supported by the NMHRC's R.D.
Wright Biomedical Career Development Fellowship (APP1061875;
2014-17). The funding bodies had no role in the decision to publish
these results.
Conict of interest
All of the authors declare that they have no conicts of interest.
Acknowledgments
We would like to acknowledge Meelah Hamilton (now deceased),
Jesseca E. Rowland, Nicholas Vella, Inika Gillis and Nicole OReilly for as-
sistance with data collection and entry. We would also like to thank the
volunteers who participated in this study. We acknowledge recruitment
assistance from the Australian Schizophrenia Research Bank (ASRB),
which was supported by the National Health and Medical Research
Council of Australia (NHMRC) Enabling Grant (No. 386500), the Pratt
Foundation, Ramsay Health Care, the Viertel Charitable Foundation
and the Schizophrenia Research Institute.
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