The World Journal of Biological Psychiatry, 2011; 12: 349–363
ORIGINAL INVESTIGATION
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Enhanced brain responsiveness during active emotional face
processing in obsessive compulsive disorder
NARCÍS CARDONER1,2,3,5, BEN J. HARRISON3,6, JESÚS PUJOL3,7,
CARLES SORIANO-MAS1,3,4, ROSA HERNÁNDEZ-RIBAS1,2,3, MARINA LÓPEZ-SOLÀ3,5,
EVA REAL1, JOAN DEUS3,8, HECTOR ORTIZ3,9, PINO ALONSO1,2 &
JOSÉ M. MENCHÓN1,2,5
1Department
of Psychiatry, Bellvitge University Hospital-IDIBELL, Barcelona, Spain, 2Centro de Investigación Biomédica en
Red de Salud Mental (CIBERSAM), Barcelona, Spain, 3Institut d’Alta Tecnologia–Parc de Recerca Biomèdica de Barcelona,
Barcelona, Spain, 4Carlos III Health Institute, Madrid, Spain, 5Department of Clinical Sciences, Faculty of Medicine, University
of Barcelona, Spain, 6Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne
Health, Australia, 7Centro de Investigación Biomédica en Red en Bioenginiería, Biomaterials y Nanomedicina, Barcelona, Spain,
8Department of Clinical and Health Psychology, Autonomous University of Barcelona, Barcelona, Spain, and 9Department of
Electronic Engineering, Technical University of Catalonia, Barcelona, Spain
Abstract
Objectives. The abnormal processing of emotional stimuli is common to a variety of psychiatric disorders. Specifically, patients
with prominent anxiety symptoms generally overreact to emotional cues, which has been linked to increased amygdala
activation. However, in OCD, enhanced responses are predominantly obtained using disease-specific stimuli and preferentially involve frontostriatal systems. Methods. We assessed 21 OCD patients and 21 healthy controls with fMRI during an
emotional face-processing paradigm involving active response generation to test for alterations in both brain activation and
task-induced functional connectivity of the frontal cortex, the amygdala and the fusiform face area. Results. OCD patients
showed significantly greater activation of “face-processing” regions including the amygdala, fusiform gyrus and dorsolateral
prefrontal cortex. The reciprocal connectivity between face-processing regions was enhanced in OCD. Importantly, we detected
significant correlations between patients’ clinical symptom severity and both task-related region activation and network functional connectivity. Conclusions. The results suggest that OCD patients may show enhanced brain responsiveness during emotional
face-processing when tasks involve active response generation. Our findings diverge from previously described alterations in
anxiety disorders, as patients showed enhanced amygdala-prefrontal connectivity as opposed to negative reciprocal interaction.
This pattern would appear to be disorder-specific and was significantly related to obsessive-compulsive symptom severity.
Key words: Functional imaging, obsessive-compulsive disorder, emotion, amygdala, prefrontal cortex
Objectives
Accurate recognition of facial expressions of emotion
is critical to adaptive behaviour and is supported by
distributed brain areas including the visual cortex and
fusiform gyrus, amygdala and hippocampus, and subregions of prefrontal cortex (Haxby et al. 2000; Ishai
et al. 2005). The functionally defined “fusiform face
area” appears to be a common feedforward modulator
of amygdala activity particularly when faces express
emotion (Fairhall and Ishai 2007). Visual sensory
processing can also be modified via feedback modulation from emotion-related regions and via interaction
with attentional mechanisms assigned to dorsal
prefrontal cortical regions (Phillips et al. 2003b;
Bishop 2007; Vuilleumier and Driver 2007).
Alterations in the normal response and interaction
of components of this brain network, as studied with
functional neuroimaging, have been linked to disturbances of emotion perception and behaviour in a variety of psychiatric disorders, including mood disorders,
schizophrenia and autism spectrum disorders, among
others (Williams et al. 2004; Dalton et al. 2005; Surguladze et al. 2005, Chen et al. 2006; Holsen et al.
2008). Arguably, however, the most solid evidence of
Correspondence: Dr Narcís Cardoner, Department of Psychiatry, Bellvitge University Hospital-IDIBELL, Feixa Llarga s/n, Barcelona, 08907,
Spain. Tel: ⫹34 932 602839. Fax: ⫹34 932 605878. E-mail: ncardoner@bellvitgehospital.cat
(Received 29 June 2010 ; accepted 20 January 2011)
ISSN 1562-2975 print/ISSN 1814-1412 online © 2011 Informa Healthcare
DOI: 10.3109/15622975.2011.559268
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350 N. Cardoner et al.
abnormal emotional face-processing in a psychiatric
context has been with respect to anxiety-related symptoms or to individual differences in anxiety traits. In
particular, patients with anxiety disorders and of individuals with high trait anxiety have consistently shown
a heightened response of the amygdala and other key
elements of the network when compared to healthy
and low trait anxious subjects (Fredrikson and Furmark 2003; Rauch et al. 2003, Etkin and Wager 2007;
Stein et al. 2007; Monk et al. 2008; Pujol et al. 2009)
Patients with obsessive-compulsive disorder (OCD)
typically show both higher scores on clinical scales
assessing general anxiety symptoms and a temperamental vulnerability to anxiety (Hoehn-Saric et al.
1995; Alonso et al. 2008). While several functional neuroimaging studies have reported that OCD patients
primarily show enhanced brain responses to specific
disorder-related stimulation (Mataix-Cols et al. 2004;
Schienle et al. 2005; van den Heuvel et al. 2005), it is
less clear to what extent these patients also respond
to basic (disease-unrelated) emotional cues. In two existing studies, the passive viewing of emotional faces
did not lead to hyperactivation of the amygdala
or other face-processing regions in OCD patients
(Cannistraro et al. 2004; Lawrence et al. 2007).
Despite these existing findings no study to date has
examined brain responses in OCD patients during
active emotional face-processing. Tasks in which subjects are required to form a decision and provide a
response based on stimulus features can more effectively engage dorsal prefrontal and parietal regions that
have become of increasing interest in the study of emotional dysregulation in psychiatric disorders (Davidson
2002; Phillips et al. 2003a; Bishop 2007). Altered striatal interaction with ventral and orbital frontal regions
is considered to be prominent in OCD (Pujol et al.
2004; Soriano-Mas et al. 2007; Menzies et al. 2008;
Harrison et al. 2009), but abnormal task activation
(Pujol et al. 1999;Yucel et al. 2007; Henseler et al. 2008;
Rotge et al. 2008; Jung et al. 2009) and altered functional connectivity at rest (Harrison et al. 2009) are also
present in the dorsal prefrontal cortex involving regions
that participate in the processing of emotional faces.
It is also noteworthy that no study has investigated
the integrity of functional interactions or “connectivity” of major regions of the putative face-processing
network in OCD patients. The analysis of functional
connectivity of this network may permit a more
detailed evaluation of its response to basic visual emotional stimuli, as demonstrated in other anxiety disorders (Evans et al. 2008; Monk et al. 2008; Pujol et al.
2009). Specifically, we were interested to investigate
interactions between posterior brain regions related to
the early stages of emotional stimuli perception and
higher-order prefrontal “attentional” regions which
are also of pathophysiological relevance to OCD
(Pujol et al. 1999; van den Heuvel et al. 2005).
In this study, we used fMRI to assess OCD
patients performing an active emotional face-processing task (Pujol et al. 2009), originally developed by Hariri et al. (2000) where the subject is
required to correctly match probe emotional faces
to a target face by forced-choice response. This
task has been shown to reliably activate visual cortical areas, the amygdala and the dorsolateral prefrontal cortex in healthy subjects (Sergent et al.
1992; Haxby et al. 2000; Ishai et al. 2005). We
sought to evaluate (i) whether a generally heightened
responsiveness of these regions to disease non-specific emotional face stimuli occurs in OCD patients,
and (ii) whether or not such disturbances reflect
an alteration of their functional connectivity during task performance. We also set out to investigate
how such findings may relate to the clinical severity
of obsessive-compulsive symptoms.
Materials and methods
Subjects
Twenty-four outpatients with OCD were recruited
for the study on the basis of their ongoing contact with
the OCD service at the Department of Psychiatry,
University Hospital of Bellvitge, Barcelona. All patients
were required to satisfy DSM-IV diagnostic criteria
for OCD in the absence of relevant medical, neurological and other major psychiatric disorders (First
et al. 1998). A primary diagnosis of OCD was
made when (i) OCD symptoms were the primary reason for patients seeking medical intervention, and
(ii) OCD symptoms were persistent and constituted
the primary cause of distress and interference with the
patient’s life. The Yale-Brown Obsessive-Compulsive
Scale (YBOCS) (Goodman et al. 1989) and a clinician-rated Yale-Brown Obsessive-Compulsive Scale
symptom checklist (Goodman et al. 1989) were used
to assess illness severity and to characterize OCD
symptoms (Mataix-Cols et al. 1999) (see Table I). None
of the patients met criteria for Tourette’s syndrome or
had a history of psychoactive drug use/abuse. Comorbid
anxious and depressive symptoms were not considered as an exclusion criterion, provided that OCD
was the primary clinical diagnosis. The severity of
comorbid symptoms of depression and anxiety was
measured by the Hamilton Depression (HAM-D)
(Hamilton 1960) and Anxiety (HAM-A) (Hamilton
1959) inventories. All patients were on stable doses
of medication for at least three months before scanning, except for one patient who had not received
medication for 1 month (Table I).
Emotional face-processing in OCD 351
Table I. Sample characteristics and task behavioral performance.
Characteristic
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Age, years
Sex, M/F, no.
Handedness, right/left, no.
WAIS Vocab, scaled score
Age at onset of OCD, years
Duration of illness, years
Y-BOCS-Total
Y-BOCS-Obsessions
Y-BOCS-Compulsions
HAM-D
HAM-A
Healthy controls (n ⫽ 21)
Mean (SD), range
OCD patients (n ⫽ 21)†
Mean (SD), range
26.2 (3.4), 21–33
10/11
19/2
11.71 (1.9), 10–14
28.52 (5.9), 19–39
10/11
19/2
12.43 (1.8), 9–16
20.4 (6.7), 9–34
8.7 (5.7), 2–28
20.7 (6.3), 11–36
10.5 (3.2), 5–18
10.2 (3.6), 2-18
7.6 (4.7), 0–19∗∗
11.2 (5.7), 2–21∗∗
2.8 (3.7), 0–13
4.8 (5.2), 0–17
Present
no. (% cases)
Comorbidity
Depressive and anxiety Disorders
Major depression
Generalized anxiety disorder
Social anxiety disorder
Panic disorder
7
2
2
2
1
OCD symptom dimensions‡
(33.3)
(9.5)
(9.5)
(9.5)
(4.8)
0 (absent)
Symmetry, ordering
Hoarding
Contamination, cleaning
Aggressive, checking
Sexual, religious obsessions
14
15
11
5
16
Treatment status
Never treated with an SSRI
1 previous SSRIs trial
2 previous SSRIs trials
3 or more previous SSRIs trials
Previous low-dose antipsychotic use
Absent
no. (% cases)
(66.7)
(71.4)
(52.4)
(23.8)
(76.2)
14
19
19
19
20
no. (% cases)
1 (mild)
3
6
6
3
1
(14.3)
(28.6)
(28.6)
(14.3)
(4.8)
(66.7)
(90.5)
(90.5)
(90.5)
(95.2)
2 (prom)
4
0
4
13
4
(19)
(0)
(19)
(61.9)
(19)
no. (% cases)
7 (33.3)
5 (23.8)
6 (28.6)
3 (14.3)
5 (23.8)
Cumulative SSRI treatments
Mean (SD)
1.33 (1.2)
Medication at study time
Medication-free (⬎4 weeks)
Fluoxetine
Fluvoxamine
Citalopram
Clomipramine
Clomipramine with SSRI
no. (% cases)
1 (4.8)
4 (19)
2 (9.5)
1 (4.8)
2 (9.5)
11 (52.4)
Response accuracy
Fearful face matching
Happy face matching
Shape matching
% correct, mean (SD)
93.6 (14)
94.9 (15)
94.8 (12)
% correct, mean (SD)
78.9 (24)
80.3 (29)
83.1 (25)
Reaction time
Fearful face matching
Happy face matching
Shape matching
milliseconds, mean (SD)
1464.1 (309)
1084.9 (210)
782.5 (95)
milliseconds, mean (SD)
1925 (607)
1433.7 (348)
1081.2 (269)
OCD, obsessive-compulsive disorder; WAIS, Wechsler Adult Intelligence Scale;Y-BOCS,Yale-Brown Obsessive-Compulsive Scale; HAM-D,
Hamilton Rating Scale for Depression; HAM-A, Hamilton Rating Scale for Anxiety; SSRI, selective serotonin reuptake inhibitor.
∗∗P ⬍ 0.001.
†The single unmedicated OCD patient recorded a total YBOCS score of 15 and was unremarkable across the other clinical domains.
‡The Yale-Brown Obsessive-Compulsive Scale symptom checklist was used to derive scores on five previously identified OC-symptom
dimensions: symmetry/ordering, hoarding, contamination/cleaning, aggression/checking, and sexual/religious obsessions, classified as absent,
present (mild), or prominent (Mataix-Cols et al. 1999).
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352 N. Cardoner et al.
Of the original sample, three patients were excluded
from the final analysis; one male patient due to
an incidental finding on MRI (medial wall hyperintensity); and two female subjects due to excessive
movement during scanning (⬎2 mm in z-axis translation). The remaining 21 patients were matched for age,
gender, handedness and estimated IQ to a sample of
twenty-one healthy control subjects (case-matched
prior to any analyses from a larger cohort obtained
through an ongoing research program), so that there
were no significant group differences in any of these
measures (Table I). General intelligence was estimated
using the vocabulary subtest of the WAIS (Wechsler
1999). Each control subject underwent the Structured
Clinical Interview for DSM-IV (SCID) non-patient
version (First et al. 2007) to exclude any Axis I or II
psychiatric disorders. None of this cohort had a personal history of neurological or psychiatric illness. All
participants had normal or corrected-to-normal vision
and gave written informed consent to participate, following a complete description of the protocol, which
was approved by the Institutional Review Board of the
University Hospital of Bellvitge, Barcelona.
Emotional Face Matching Task
Subjects were assessed using a modified version of
the emotional face-matching task originally reported
by Hariri et al. (2000). During each 5-s trial, subjects
were presented with a target face (centre top) and
two probe faces (bottom left and right) and were
instructed to match the probe expressing the same
emotion to the target by pressing a button in either
their left or right hand. A block consisted of six consecutive trials in which the target face was either
happy or fearful, and the probe faces included two
out of three possible emotional faces (happy, fearful
and angry). As a sensorimotor control condition, subjects were presented with 5-s trials of ovals or circles
in an analogous configuration and were instructed to
match the shape of the probe to the target. Shape
stimuli were preferred to neutral faces for the task as
the latter may be experienced as emotionally ambiguous or affectively laden, which has been shown to
evoke significant activation of amygdala and prefrontal regions (Forman 1995; Schwartz et al. 2003).
A total of six 30-s blocks of faces (three happy and
three fearful) and six 30-s blocks of the control condition
were presented interleaved in a pseudo-randomized
order. A fixation cross was interspersed between each
block. For each trial, response accuracy and response
latency (reaction time) were obtained. The paradigm
was presented visually on a laptop computer running
Presentation software (http://www.neurobehavioral
systems.com). MRI-compatible high-resolution goggles (VisuaStim Digital System, Resonance Technology
Inc., Northridge, CA) were used to display the stimuli. Subjects’ task responses were registered using
a right and a left hand response device based on
optical fibre transmission (Nordic Neuro Lab,
Bergen, Norway). Task responses were unavailable
for two OCD patients due to a technical error in
saving Presentation log files after scanning had been
completed.
Image acquisition and preprocessing
A 1.5-T Signa Excite system (General Electric,
Milwaukee, WI, USA) equipped with an eight-channel
phased-array head coil and single-shot echoplanar
imaging (EPI) software was used. Functional sequences
consisted of gradient recalled acquisition in the steady
state (time of repetition [TR], 2000 ms; time of echo
[TE], 50 ms; pulse angle, 90°) within a field of view
of 24 cm, with a 64 ⫻ 64-pixel matrix and a slice
thickness of 4 mm (inter-slice gap, 1 mm). Twenty-two
interleaved slices, parallel to the anterior-posterior commissure line, were acquired to cover the whole brain.
The functional time series consisted of 270 consecutive
image sets obtained over 9 min.
Imaging data were transferred and processed on
a Microsoft Windows platform running MATLAB
version 7 (The MathWorks Inc, Natick, Mass).
Image preprocessing was performed in SPM5 (http://
www.fil.ion.ucl.ac.uk/spm/), and involved motion
correction, spatial normalization and smoothing
using a Gaussian filter (full-width, half-maximum, 8
mm). Motion correction was performed by aligning
(within-subject) each time-series to the first image
volume using a least-squares minimization and a sixparameter (rigid body) spatial transformation. Data
were normalized to the standard SPM-EPI template
and resliced to 2 mm isotropic resolution in Montreal Neurological Institute (MNI) space.
Statistical analyses
Behavioural. Individual demographic measures of
sex, handedness, age, and premorbid IQ were compared across groups using univariate analyses of variance (ANOVAs) in Statistical Package for the Social
Sciences (SPSS) version 11.0. Analyses of behavioural
data were conducted using a mixed ANOVA with “task
condition” (fearful faces, happy faces or control condition) as the within-subject variable and “study group”
(healthy subjects, OCD patients) as the between-subject
variable. Response errors and reaction times (correct)
were estimated and compared separately for each condition. Errors were calculated by summing all commission errors (incorrect matching) and omissions
(missed responses) within each condition.
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Emotional face-processing in OCD 353
Functional MRI: main task effects. First-level (singlesubject) SPM contrast images were estimated for the
following three task effects of interest; (1) all faces
⬎ control task; (2) fearful faces ⬎ control task; (3) happy
faces ⬎ control task. For these analyses, the BOLD
response at each voxel was convolved with a canonical
hemodynamic response function and its temporal derivative (using a 128-s high-pass filter).The resulting first-level
contrast images for each subject were then carried forward to second-level random-effects (group) analyses.
For the main task effects, within-group activation maps
were thresholded at PFDR ⬍ 0.05 (corrected for wholebrain volume) with a minimum cluster size extent (KE)
of five contiguous voxels. To assess for differences in
the activation pattern across the task effects of interest,
the groups were compared using two-sample t-tests
and adopting a more lenient statistical threshold of
P ⬍ 0.005 (uncorrected; KE ⫽ 5 voxels), which provides a good balance against both Type I and Type II
errors (see Lieberman and Cunningham 2009). This
particular whole-brain threshold was adopted in order to
approximate the region-of-interest (ROI) based thresholds used in previous studies of amygdala function in
OCD (Cannistraro et al. 2004) and amygdala activation with our specific task (Paulus et al. 2005). We
reasoned that this lower threshold would allow us to
detect potential differences in amygdala activation
with the same sensitivity as relevant prior studies,
while facilitating a comparison of the groups at the
whole-brain level. Nevertheless, this whole-brain
uncorrected threshold may be considered liberal
and therefore the strength of corresponding results
should be interpreted accordingly.
Psychophysiological interactions analysis. To assess the
influence of task (the “psychological” factor) on the
strength of functional coupling (“functional connectivity”) between each brain region of interest (ROI)
(amygdala, prefrontal cortex and fusiform gyrus) and
the other brain voxels, we performed a series of psychophysiological interactions (PPI) analyses in SPM5
(Friston et al. 1997). Specifically, we evaluated an
effect of the task (emotional face matching in contrast
with shape matching) on the strength of time-course
correlations between the selected ROIs and all other
brain regions. First level analyses was performed for each
subject to map areas where activity was predicted by
the cross-product (PPI interaction term) of the “physiological” (deconvolved time-course of the given ROI)
and the “psychological” factor (regressor representing
the experimental paradigm). Both the physiological and
the psychological factors were also included in the final
SPM model as confound variables (Pujol et al. 2009).
First-level individual contrast images representing the
PPI effect for each subject were then included in second
level random-effects analyses to test within-group results
(one-sample t-test thresholded at PFDR ⬍ 0.05, wholebrain corrected) and between-group differences (two
sample t-test adopting the threshold of P ⬍ 0.005,
uncorrected; KE ⫽ 5 voxels) of each PPI analysis.
The placement of source ROIs was determined by
a conjunction analysis (global null approach) of the
task effect “all faces ⬎ control task”. This analysis
identified regions that were consistently activated in
both OCD patients and control subjects (PFDR ⬍ 0.05,
whole-brain corrected): peak activation for right
amygdala ROI (x, y, z ⫽ 20, –2, –24); right prefrontal ROI (x, y, z ⫽ 44, 12, 28); right fusiform gyrus
ROI (x, y, z ⫽ 40, –50, –30). The “physiological”
factor of each PPI analysis was the first eigenvariate time
series extracted, for each subject, from a 5-mm radial
sphere centred on the above-mentioned coordinates.
Brain-behavioural associations.We investigated the extent
to which patients’ symptom severity demonstrated
significant linear correlation with the patterns of brain
activation and functional connectivity reported in
association with the primary study contrast “ all
faces ⬎ control task”. Patients’ total YBOCS score
was entered as a regressor of interest in corresponding second-level analyses (one sample t-tests)
thresholded at P ⬍ 0.005 (uncorrected).
Results
Behavioural
Response accuracy and reaction time (RT) scores are
reported in Table I. There was no significant interaction between task condition and study group in relation to task accuracy (F(2,76) ⫽ 0.92, P ⫽ 0.40) and
no significant main effect of task condition
(F(2,76) ⫽ 2.49, P ⬍ 0.09). There was, however, a
group main effect with OCD patients showing less accuracy than their healthy counterparts (F(1,38) ⫽ 4.3,
P ⫽ 0.04).
There was no significant interaction between task
condition and study group in relation to RT performance (F(1,76) ⫽ 1.28, P ⫽ 0.29). There was a
main effect of task condition on RT performance in
both groups (F(2,76) ⫽ 10.4, P ⫽ 0.001) in that
RTs to fearful faces were ⬎ RTs to happy faces
which were ⬎ RTs to shapes (all P values ⬍ 0.05).
There was also a group main effect with OCD
patients’ RTs being slower overall in comparison to
healthy subjects (F(1,38) ⫽ 17.5, P ⫽ 0.001).
Functional MRI
Main task effects. Both groups demonstrated significant and overlapping activation of distributed brain
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Anatomya
Healthy controls
Faces ⬎ Shapes
Visual cortex
Fusiform gyr.
Middle frontal gyr.
Inf. frontal cortex
Amygdala
Premotor
Fear ⬎ Shapes
Visual cortex
Fusiform gyr.
Middle frontal gyr.
Supp. Motor area
Ant. insula cortex
Amygdala
Happy ⬎ Shapes
Visual cortex
Fusiform gyr.
Middle frontal gyr.
Amygdala
Statsb
Anatomya
x
y
z
CS
Z
–20
26
40
–38
44
–44
32
20
–22
8
–96
–98
–50
–48
12
20
32
–2
–2
14
–8
–2
–30
–28
26
22
–18
–24
–26
50
⬎8000
⬎8
⬎8
7.76
6.81
6.55
5.67
4.12
4.45
4.44
3.93
26
–24
–38
38
42
–52
8
–32
30
18
–22
–94
–92
–48
–52
12
34
14
22
28
–4
–2
–6
–10
–28
–30
28
16
50
–4
–6
–20
–26
⬎8000
–20
24
40
–40
42
–42
20
–22
–96
–98
–50
–56
12
–2
–2
–2
–8
0
–28
–20
28
54
–24
–26
⬎8000
OCD patients
Extrastriate/parietal
Ant. insula cortex
Happy ⬎ Fear
–
aActivity
Anatomya
x
y
z
CS
Z
–22
16
40
–38
–46
44
–4
–30
24
–22
32
–96
–96
–50
–48
18
12
16
22
–8
–2
28
–10
–10
–30
–28
22
28
50
–6
–22
–26
–8
⬎8000
⬎8
7.58
7.16
7.26
6.66
6.55
4.75
3.89
5.40
4.76
4.61
24
–22
–36
40
44
–42
6
30
–32
18
–18
–92
–96
–48
–50
10
18
16
28
22
–2
–8
–8
–10
–28
–28
28
20
52
–8
–6
–18
–16
⬎8000
–22
14
–38
40
42
–58
24
–18
30
–96
–96
–48
–48
12
15
–8
–8
34
–10
–10
–30
–26
28
26
–20
–16
–16
⬎8000
2733
2990
120
118
61
⬎8
7.72
6.71
6.71
5.60
4.45
5.21
3.96
2.96
40
–42
38
–28
8
–34
8
0
–78
–76
18
24
26
38
–4
24
52
–8
2586
2543
4182
4805
384
364
4.77
4.26
4.68
4.56
3.61
4.24
Faces ⬎ Shapes
4751
4722
388
74
59
591
6187
6066
901
376
413
66
23
1422
769
39
58
⬎8
7.81
6.91
7.75
6.59
5.89
4.35
4.48
3.97
4.01
3.14
⬎8
7.31
7.18
6.27
4.68
3.95
3.64
3.65
Visual cortex
Fusiform gyr.
Middle frontal gyr.
Supp. motor area
Ant. insula cortex
Amygdala
Fear ⬎ Shapes
Visual cortex
Fusiform gyr.
Middle frontal gyr.
Supp. Motor area
Ant. insula cortex
Amygdala
Happy ⬎ Shapes
Visual cortex
Fusiform gyr.
Middle frontal gyr.
Amygdala
Ant. insula cortex
Fear ⬎ Happy
Middle frontal gyr.
Statsb
44
–40
–28
28
–30
32
–
10
2
–74
–68
26
28
–
30
28
22
30
–4
0
–
1904
1226
2457
1208
294
145
–
5.28
4.51
4.61
4.23
4.36
3.50
–
Fear ⬎ Happy
Middle frontal gyr.
Extrastriate/parietal
Premotor
Ant. insula cortex
Happy ⬎ Fear
–
–
–
–
bMagnitude
co–ordinates (x, y, z) are given in Montreal Neurological Institute (MNI) Atlas space.
corrected). cResults correspond to statistical differences (OCD patients ⬎ healthy controls) of P
FDR
⬎8000
3828
1330
316
154
148
334
⬎8000
5602
1786
458
510
154
148
–
⬎8
⬎8
7.46
7.22
6.42
6.51
4.84
5.12
4.81
5.00
4.13
–
Differencec
Statsc
x
y
z
CS
Z
–4
–16
–2
–48
24
40
40
32
–16
36
18
–66
–32
–84
18
58
8
–32
–62
–32
–28
–6
–40
0
–8
48
14
50
–20
42
0
–4
–14
99
52
326
276
17
61
39
112
52
21
8
3.42
3.42
3.39
3.29
2.88
2.98
3.18
3.09
3.42
2.99
2.86
–6
–2
–26
28
–10
24
–52
40
20
–28
40
18
–14
–80
–66
–32
–36
–14
58
12
8
–2
–12
–30
0
–32
–4
38
–14
2
–14
14
38
52
8
–16
–20
–14
2
462
129
94
109
43
19
42
77
76
36
29
7
22
3.58
3.48
3.38
3.31
3.22
3.12
3.04
2.98
3.03
3.02
3.25
2.99
2.83
Intra parietal sul.
Visual cortex
Fusiform gyr.
Amygdala
–46
–52
30
–2
40
22
20
12
–68
–86
–36
–10
48
28
44
–8
–18
–18
48
71
74
26
10
6
3.30
2.91
2.99
2.89
2.74
2.70
Fear ⬎ Happy
Middle frontal gyr.
Ant. insula
28
–34
26
18
24
14
12
14
3.01
2.7
–
–
–
–
–
–
Happy ⬎ Fear
–
–
–
–
–
–
Faces ⬎ Shapes
Precuneus
Parahippocampal gyr.
Visual cortex
Middle frontal gyr.
Premotor
Fusiform gyr.
Intra parietal sul.
Thalamus
Hippocampus
Amygdala
Fear ⬎ Shapes
Visual cortex
Precuneus
Parahippocampal gyr.
Brainstem
Middle frontal gyr.
Globus pallidus
Hippocampus
Fusiform gyr
Amygdala
Thalamus
Happy ⬎ Shapes
Middle frontal gyrus
and extent statistics correspond to a minimum threshold of PFDR ⬍ 0.05 (whole–brain
⬍ 0.005 (whole–brain uncorrected). CS, cluster size.
354 N. Cardoner et al.
Table II. Activation of extended brain regions during performance of the emotional face recognition in patients with OCD and healthy control subjects.
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Emotional face-processing in OCD 355
regions for the contrasts that compared matching
emotional faces to matching shapes (Table II).
Regions included a large cluster encompassing visual
striate and extrastriate cortex and also the posterior
thalamus, the fusiform gyrus, hippocampus and
amygdala, dorsolateral frontal and pre-motor cortex
(Figure 1). When comparing groups, OCD patients
showed significantly greater activation of visual
striate areas, right fusiform gyrus, left posterior
thalamus, right amygdala and parahippocampal cortex as well as dorsolateral prefrontal and right premotor cortex. The extension of the significant differences
between OCD and control subjects was larger in the
contrast “fearful faces ⬎ control task” compared to
“happy faces ⬎ control task” (Table II). Conversely,
there was no significantly greater activation in control
subjects when compared to OCD patients.
Figure 1 highlights the corresponding distribution
of activations in both groups resulting from the primary contrast “all faces ⬎ control task”. Figure 2
highlights the corresponding activation of the amygdala
region in both groups across the three study contrasts “all faces ⬎ control task”, “fearful faces ⬎
control task” and “happy faces ⬎ control task”.
Amygdala activation was significantly larger in OCD
patients compared with healthy subjects across the
three contrasts (Table II).
For the contrast “fearful faces ⬎ happy faces” both
groups demonstrated significant extensive activation
of the visual extrastriate cortex extending to the
intraparietal sulcus, the dorsolateral frontal and the
premotor cortex, as well as the anterior insula (Table II).
When comparing groups, OCD patients showed significantly greater activation of the right dorsolateral
frontal cortex and the left anterior insula region.
There was no significantly greater activation in control subjects compared to OCD patients. There were
no significant between-group differences for the
contrast “happy faces ⬎ fearful faces” (Table II).
To assess the influence of comorbid anxiety and
depression symptoms on these results, all analyses
were repeated covarying for subjects scores on the
HAM-A and HAM-D. As highlighted in Supplementary Figure 1, minimal appreciable differences
were detected between the results of this approach
and all results described above.
between-group comparison, OCD patients had
significantly increased functional connectivity of the
amygdala ROI to right dorsolateral prefrontal,
right intraparietal and visual extrastriate cortex
(Table III).
Prefrontal cortex ROI. Significant task-induced functional connectivity of the right prefrontal ROI to
Functional connectivity (PPI) analysis
Right amygdala ROI. Significant task-induced functional connectivity of the right amygdala ROI to
visual striate and extrastriate cortex, fusiform gyrus,
intraparietal sulcus, dorsolateral frontal and premotor cortex was observed in OCD patients (Table III).
There was no significant amygdala functional connectivity observed in control subjects. In a direct
Figure 1. Brain activation during active emotional face processing
(A) healthy subjects; (B) OCD patients; and (C) OCD patients ⬎
healthy subjects. Results correspond to the main task contrast
“all faces ⬎ control task” and are displayed on a high-resolution
single-subject MRI in standard neuroanatomical space (Montreal
Neurological Institute). Results are displayed in neurological
convention (left ⫽ left).
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356 N. Cardoner et al.
Figure 2. Amygdala activation during emotional face matching in healthy subjects (top row) and OCD patients (bottom row, marked with
asterix) across the task contrasts (A) “all faces ⬎ control task”; (B) “fearful faces ⬎ control task”; and (C) “happy faces ⬎ control task”.
Results are displayed in neurological convention (left ⫽ left) on a high-resolution single-subject MRI in standard neuroanatomical space
(Montreal Neurological Institute).
visual striate and extrastriate cortex, fusiform gyrus
and intraparietal sulcus was observed in both groups.
OCD patients showed additional prefrontal functional
connectivity with dorsal premotor and prefrontal cortex, bilateral amygdala and parahippocampal gyrus
(Figure 3). In a direct comparison, OCD patients
had significantly greater functional connectivity of
the right prefrontal ROI to visual extrastriate and
parietal cortex, fusiform gyrus, bilateral amygdala
and additional dorsal prefrontal regions (Table III).
Fusiform gyrus ROI. Significant task-induced functional connectivity of the right fusiform ROI to bilateral visual striate and extrastriate cortex, left fusiform
gyrus and bilateral intraparietal sulcus was observed
in both groups. OCD patients showed greater and
additional fusiform functional connectivity with dorsal premotor and prefrontal cortex, superior parietal
cortex and parahippocampal gyrus. In a direct comparison, OCD patients had significantly greater
functional connectivity of the right fusiform ROI to
dorsal prefrontal, parietal and visual extrastriate
cortex (Table III).
Brain-behavioural associations
Symptom severity correlated significantly with clusters of activation and task-induced functional connectivity strength in visual extrastriate and fusiform
gyrus, and the corresponding anatomy of the results
showed substantial overlap (Figure 4).
Comment
This functional imaging study assessed brain responses during a task that involved active processing
of emotional faces in OCD patients. In contrast to
previous studies of passive emotional face viewing
(Cannistraro et al. 2004; Lawrence et al. 2007), we
observed increased activation of distributed “faceprocessing” regions in OCD patients including the
amygdala and dorsal prefrontal cortex. While our
results partially agree with reports of amygdala
hyperactivity as a common alteration across distinct
anxiety disorders (Etkin and Wager 2007; Fredrikson and
Furmark 2003), they diverge from such studies in terms
of the precise nature of amygdala hyperactivation in
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Table III. Amygdala and prefrontal ROI functional connectivity during emotional face matching in patients with OCD and healthy control subjects.
Anatomya
Healthy controls
x
y
Statsb
z
CS
Anatomya
Z
Amygdala PPI
OCD patients
Amygdala PPI
Visual cortex
Fusiform gyrus
Middle frontal gyrus
Intra parietal sulcus
Prefrontal PPI
Visual cortex
–10
36
Fusiform gyr.
38
–38
Intra parietal sul. –22
30
–98
–82
–54
–56
–50
–58
14
–10
–22
–20
40
52
⬎8000
290
156
5.74
5.69
4.62
4.59
3.64
3.36
Prefrontal PPI
Visual/parietal
Fusiform gyrus
Middle frontal gyrus
Parahipp. gyrus
Premotor
Amygdala
Fusiform PPI
Visual cortex
Medial frontal gyr.
–80
–74
–62
–10
–12
54
⬎8000
245
6.67
6.34
4.03
–22
40
48
–52
8
0
38
30
46
206
403
14
3.55
3.72
2.95
Fusiform PPI
Visual cortex
Intraparietal sulcus
Middle frontal gyrus.
Premotor
Parahipp. gyrus
Inferior frontal gyrus.
Anterior insula
aActivity
Anatomya
x
y
z
CS
Z
–20
40
–52
42
48
52
–42
28
–24
–84
–50
4
6
8
34
10
–68
–52
–24
–28
50
60
38
20
24
50
38
⬎8000
4.85
4.54
4.06
3.66
3.29
3.26
3.13
3.59
3.40
–28
32
40
–36
48
–42
22
–20
4
–30
26
–86
–92
–44
–54
4
–14
–30
–30
12
–2
–6
–4
16
–24
–24
58
26
–2
–6
54
–30
–26
⬎8000
–26
–36
–26
30
48
–6
–24
24
42
–32
–26
–86
–52
–64
–58
8
6
–30
–28
51
22
–26
–10
–28
50
46
36
52
–2
–2
–6
–8
38
⬎8000
136
363
64
47
39
278
193
3011
1882
280
352
694
72
25
4514
824
64
86
310
34
16
7.53
7.33
6.57
6.08
5.57
5.26
3.78
4.19
3.68
3.23
3.10
7.78
5.67
6.33
5.87
5.78
4.71
3.55
3.65
3.55
3.01
2.62
Statsc
Difference
x
y
z
CS
Z
Amygdala PPI
Visual cortex
Intra parietal sulcus
Middle frontal gyrus
–6
32
40
–74
–42
12
–32
44
54
312
148
100
3.38
3.22
2.83
–36
–24
26
48
–48
–34
–28
32
–44
–78
–84
4
40
–52
–2
–8
56
30
4
58
24
–32
–30
–28
636
1309
272
161
109
192
28
9
4.77
4.22
3.72
3.50
3.51
3.36
2.95
3.11
46
–54
–26
8
–44
–54
40
30
8
–34
–86
–94
44
12
–48
–60
52
56
–8
14
24
34
58
42
397
917
266
111
32
266
236
176
4.11
4.01
3.90
3.04
3.56
3.26
3.47
3.20
Prefrontal PPI
Supramarginal gyrus
Intra parietal sulcus
Visual cortex
Middle frontal gyrus.
Fusiform gyrus
Amygdala
Fusiform PPI
Medial frontal gyrus
Supramarginal gyrus
Visual extrastriate
Middle frontal gyrus
Intraparietal sulcus
co–ordinates (x, y, z) are given in Montreal Neurological Institute (MNI) Atlas space. bMagnitude and extent statistics correspond to a minimum threshold of P
correspond to statistical differences (OCD patients ⬎ healthy controls) of P ⬍ 0.005 (whole–brain uncorrected). CS, cluster size.
FDR
⬍ 0.05 (whole–brain corrected). cResults
Emotional face-processing in OCD 357
Intraparietal sul.
34
–36
30
Statsb
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358 N. Cardoner et al.
Figure 3. Dorsal prefrontal functional connectivity during emotional face matching (all faces ⬎ shapes) in (A) healthy subjects; and (B) OCD
patients. Results are displayed in neurological convention (left ⫽ left) on a high-resolution single-subject MRI in standard neuroanatomical space
(Montreal Neurological Institute).
OCD patients as well as the specific involvement of
the prefrontal cortex.
Although the current study appears to challenge
existing reports of amygdala responsiveness in
OCD patients (Shapira et al. 2003; Cannistraro
et al. 2004; Schienle et al. 2005; Lawrence et al.
2007), we consider that our results complement
previous studies in suggesting that amygdala function is altered in OCD patients, but specifically in
the context of an active emotional face-processing
task. Both study groups showed significant amygdala activation during fearful and happy face
matching trials. Although amygdala activation was
greater in OCD patients, such activation was unrelated to emotional stimulus valence. This is not a
common finding in primary anxiety disorders,
where a specific bias of amygdala activation
towards negatively valenced emotional faces has
been consistently reported (Shin et al. 2005; Phan
et al. 2006; Evans et al. 2008; Monk et al. 2008;
Beesdo et al. 2009). Interestingly, it has been previously shown that amygdala responses to fearful
faces occur with or without conscious awareness
(Williams et al. 2005; Vuilleumier and Driver
2007), whereas amygdala activation during happy
faces arises, predominantly, when faces are
attended selectively (Williams et al. 2005). This
may suggest that enhanced amygdala response to
emotional faces in OCD patients may be partially
related to attentional processes.
In keeping with the above idea is the fact that,
in addition to the heightened activation of limbic
components of the face-processing network, OCD
patients also showed significant hyperactivation of
dorsal prefrontal and parietal regions – the socalled “dorsal attention network”. This network
comprises dorsal frontal cortex and frontal eye
field areas, as well as the intraparietal sulcus, and
exhibits a right-hemisphere predominance. Numerous functional imaging studies have highlighted the
role of this network in sustained and selective attention processes, in keeping with “top-down” control
mechanism (reviewed recently in Vuilleumier and
Driver 2007; Corbetta et al. 2008).
The involvement of the “dorsal attention network”
in OCD pathophysiology is supported by both imaging and neuropsychological studies. Functional neuroimaging studies across a range of experimental task
contexts (Pujol et al. 1999; Yucel et al. 2007; Henseler
et al. 2008; Rotge et al. 2008; Jung et al. 2009) and
a recent structural neuroimaging meta-analysis (Radua
and Mataix-Cols 2009) have reported evidence of
significant alterations of dorsal attention regions in
OCD patients. In addition, neuropsychological studies
have reported deficits of sustained and selective attention (Clayton et al. 1999; Cohen et al. 2003; Muller
and Roberts 2005; Irak and Flament 2009). Considering other recent evidence of a “baseline” reduction in
the functional connectivity of the dorsal striatum and
prefrontal cortex in OCD patients (Harrison et al.
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Emotional face-processing in OCD 359
Figure 4. Correlation of total YBOCS scores with brain activation and functional connectivity during emotional face matching in OCD
patients. All results correspond to the main task contrast “all faces ⬎ control task” in (A) regional functional activation alone (B) functional
connectivity with right amygdala and (C) functional connectivity with right prefrontal cortex. The strongest associations were observed
between symptom severity and strength of right prefrontal-extrastriate (x, y, z ⫽ 24, –78, –10; z ⫽ 3.96, clustersize ⫽ 259, P ⬍ 0.0001)
and right prefrontal-fusiform (x, y, z ⫽ 34, –58, –16; z ⫽ 3.78, clustersize ⫽ 284, P ⬍ 0.0001) functional connectivity. In D is depicted
the strength of brain–behaviour correlation between right prefrontal-fusiform functional connectivity strength and total YBOCS scores by
re-plotting Pearson’s linear correlations (two-tailed) between these variables. This relationship accounted for 45.8% (adjusted R2 statistic)
of the modeled variance with a zero-order correlation coefficient of r ⫽ 0.69. Connectivity strength is represented as a summary score
(first eigenvariate) of contrast beta weights estimated from a 5-mm ROI centered on the right fusiform gyrus (x, y, z ⫽ 34, –58, –16).
Results are displayed in neurological convention (left ⫽ left) on a high-resolution single-subject MRI in standard neuroanatomical space
(Montreal Neurological Institute).
2009), it is plausible that increased activation of the
latter region in the current study represents a compensatory response to a primary level neuronal deficit.
We performed specific analyses to assess overall
differences in task-induced functional connectivity
of major regions of the putative face-processing network in OCD patients; an approach that has provided further insight into the dysfunction of this
network in other anxiety disorders (McClure et al.
2007; Monk et al. 2008; Simmons et al. 2008). In
summary, compared to control subjects our OCD
patients exhibed: (i) a significant increase in task-induced
reciprocal connectivity of the right dorsolateral prefrontal cortex and fusiform gyrus; (ii) significant
functional connectivity of the right amygdala to fusiform gyrus; and (iii) significant functional connectivity
between the right dorsolateral prefrontal cortex and
the amygdala. Although this analysis was not intended
to address causal links between the activities of distinct regions, the nature of our results are consistent
with the suggested alteration of “top-down” regulatory
processes in OCD patients.
The idea that our findings may represent a disorderspecific functional correlate of OCD is supported,
albeit indirectly, by comparisons with other anxiety
disorders, which emphasize a more specific processing bias to negative, threatening or fear provoking stimuli and corresponding limbic hyperactivity.
This alteration is typically coupled with a deficient
recruitment of prefrontal regions which, in turn, may
play a role in sustaining negative processing biases in
anxious individuals (Bishop 2007). OCD patients, by
comparison, showed distributed hyperactivity of relevant limbic and cortical face-processing regions,
and significantly enhanced functional connectivity
between the dorsolateral prefrontal cortex and
amygdala. We also observed direct correlations
between patients’ clinical symptom severity and both
task-related regional activation and functional connectivity, which overlapped focally on the right
fusiform gyrus. This correlation effect was more
pronounced in terms of increased functional connectivity between the fusiform gyrus and right dorsolateral prefrontal cortex.
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360 N. Cardoner et al.
Despite the current face matching paradigm being
widely used to investigate implicit emotional processing (Hariri et al. 2000; Stein et al. 2007), this
task also diverges from other face processing paradigms used in previous studies (Cannistraro et al.
2004; Shin et al. 2005; Lawrence et al. 2007; Monk
et al. 2008). For instance, the current paradigm involves
an important element of attentional-executive control (forced choice face matching) that may account
for the significant cortical activation observed here.
Additionally, the current paradigm is not intended
to discriminate brain responses associated with the
processing of specific emotional face expressions as
addressed in prior studies, as different emotional
faces (target and probe faces) appear in each individual trial. This feature is likely to generate a large
degree of overlap between the patterns of brain response
observed in the fearful and happy face matching conditions. Although in both groups we observed greater
activation of distributed cortical regions in association with the fearful compared to happy face matching
condition, this is likely due to the common finding
that matching fearful faces is generally more difficult
than matching happy faces.
The observation of dorsal prefrontal hyperactivity
and enhanced connectivity in OCD patients deserves
further comment. In symptom provocation studies, it
has been suggested that the activation of dorsal attention regions reflects patients’ efforts to resist obsessive processes (Rotge et al. 2008). In the study by
Mataix-Cols et al. (2004), checking-related symptom
provocation and patients’ induced checking-related
anxiety was associated with hyperactivation of dorsal
attention regions. The authors suggested that the
provocation of checking-related anxiety (or the suppression of checking rituals) was related to dysfunction of attentional and inhibitory control processes
assigned to these regions, as opposed to emotional
processing per se. It is plausible that such behaviour
may be evoked in other task scenarios in such a way
that stimuli unrelated to patients’ primary symptomatic concerns may also act as emotionally salient triggers on prefrontal control processes. Interestingly, a
pattern of positive correlation between amygdala and
dorsal prefrontal cortex has been previously reported
during a version of the emotional matching task (Hariri
et al. 2000, 2003), where healthy subjects performed
a cognitive (semantic) evaluation of emotional information. In OCD patients, exaggerated responses in
frontal regions related to cognitive reappraisal may
occur during basic emotional stimuli perception even
in low demanding tasks with no explicit cognitive
evaluation. Alternatively, it may be argued that our
results reflect a simple epiphenomenon of task performance and patients’ motivational state (i.e., desire
to perform well, no mistakes, emotional motivation).
However, this is difficult to reconcile with the fact
that hyperactivation of dorsal regions is not universally observed in fMRI studies of OCD (Remijnse
et al. 2006; Gu et al. 2008).
The study was neither designed nor powered to
delineate the effects of antidepressant medication on
brain activation, and we considered it ethically inappropriate to withdraw patients from their treatment
for the purposes of our research. All patients, except
one who was free of medication for at least 1 month,
were undergoing stable pharmacological treatment.
Our data do not allow us to exclude the effect of
antidepressant drugs. Treatment with antidepressants
could exert a modulatory effect on brain activity (i.e.
different SSRIs have been related to downregulation
in regions involved in face-processing) (Sheline et al.
2001; Fu et al. 2004). However, a recent study
revealed a similar pattern of brain functional alterations in treated OCD patients and untreated OCD
relatives (Chamberlain et al. 2008), suggesting that
OCD-related brain dysfunction may exist irrespective
of medication confounds.
In our study we used fearful and happy faces to
assess patients’ response to basic (disease non-specific) emotional stimuli. We explicitly eluded emotional expressions that might drive abnormal
emotional responses in specific subtypes, such as disgust in OCD patients with washing symptoms and
contamination (Stein et al. 2001; Lawrence et al.
2007). Previous neuroimaging studies of OCD using
a face-processing paradigm predominantly included
patients with washing and contamination symptoms
(Cannistraro et al. 2004; Lawrence et al. 2007). In
our study, by contrast, patients were characterized
by more prominent aggressive and checking symptoms. Findings from different larger-scale neuroimaging studies now support the idea that different
OCD symptom dimensions may be mediated by
partly overlapping and distinct brain systems (Pujol
et al. 2004; van den Heuvel et al. 2009). However,
due to our smaller sample size and the absence of
certain symptoms in our patient group (i.e. no prominent hoarders), we were unable to appropriately test
whether our results could be related to one or another
major symptom dimension or generalized to all
patients with the disorder. Studies involving larger
samples of OCD patients will be needed to test the
specificity of the current findings.
In conclusion, OCD patients showed enhanced brain
responsiveness during active emotional face-processing.
Our findings diverge from previously described alterations in anxiety disorders, particularly in relation to
amygdala and prefrontal cortex relationships. OCD
patients showed enhanced amygdala–prefrontal connectivity as opposed to negative reciprocal interaction. This pattern appears to be disorder-specific and
Emotional face-processing in OCD 361
was significantly related to symptom severity. With
respect to the amygdala, our findings suggest that
heightened activity of the region was not due to primary
alteration in emotional processing, however it is most
likely modulated through a heightened engagement
of dorsal attention regions.
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Acknowledgments
This study was supported in part by the Instituto de
Salud Carlos III, Centro de Investigación en Red de
Salud Mental, CIBERSAM (FIS, I.D. PI050884 &
PI071029). Dr Harrison is supported by a National
Health and Medical Research Council of Australia
(NHMRC) Clinical Career Development Award
(I.D. 628509). Dr Pujol acknowledges contribution
from the Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBERBBN), Barcelona, Spain. Dr. Soriano-Mas is funded
by a Miguel Servet contract from the Carlos III
Health Institute (CP10/00604). Ms López-Solà is
supported by FPU grants from the Spanish Ministry
of Education (I.D. AP2005-0408). Ms Real was
funded by the Institut d’Investigació Biomèdica de
Bellvitge (IDIBELL). We thank Gerald Fannon for
revising the manuscript. The authors thank all the
study participants and staff from the Department of
Psychiatry of Hospital Universitari de Bellvitge who
helped enroll the study sample. Dr Cardoner had full
access to all the data in the study and takes responsibility for the integrity of the data and the accuracy
of the data analysis.
Statement of Interest
The authors have no biomedical financial interests
or potential conflicts of interest.
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