Biological Psychology 84 (2010) 304–312

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Biological Psychology
journal homepage: www.elsevier.com/locate/biopsycho

Task-dependent neural correlates of the processing of verbal threat-related

stimuli in social phobia
Stephanie Schmidt, Alexander Mohr, Wolfgang H.R. Miltner, Thomas Straube ∗
Department of Biological and Clinical Psychology, Friedrich Schiller University Jena, Am Steiger 3//1, D-07743 Jena, Germany

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

Article history: The neural basis of abnormal processing of phobia-related linguistic cues in individuals suffering from
Received 8 July 2009 social phobia is unknown, particularly in respect to different task conditions. Using event-related
Accepted 7 March 2010 functional magnetic resonance imaging, this study investigated brain activation to phobia-related and
Available online 20 March 2010
phobia-unrelated words in 19 socially phobic patients and 18 healthy control subjects (HC) while sub-
jects had to attend either to social meaning or to grammatical category of words (direct or indirect task).
Keywords:
During the indirect task, patients, compared to HC, showed an increased activation of the amygdala
Social phobia
and orbitofrontal cortex (OFC) in response to phobia-related vs. phobia-unrelated words. Activation of
Words
fMRI
the insula was positively correlated with patients’ symptom severity during the direct task. The results
Attention suggest a specific role of the amygdala and OFC during the processing of verbal phobia-relevant dis-
Amygdala tracting information. In contrast, insula activation seems to be more important for direct processing of
Insula disorder-related words, especially in more severe cases of social phobia.
© 2010 Elsevier B.V. All rights reserved.

1. Introduction
Individuals suffering from social phobia show exaggerated fear
symptoms in social performance or interaction situations and are
excessively concerned about being negatively evaluated by oth-
ers (DSM-IV-TR; APA, 2000). It has been suggested that biased
information processing plays a central role in developing and main-
taining social phobia (Beck et al., 1985; Clark and Wells, 1995).
Several studies have shown that individuals with social phobia dis-
play an increased sensitivity towards disorder-related cues, such
as phobia-related words, aversive facial expressions (for a review
see Heinrichs and Hofmann, 2001; Hirsch et al., 2006), and also
aversive prosodic utterances (Quadflieg et al., 2008, 2007).
Even though verbal cues are very prominent in research on
information processing biases in social phobia (see Heinrichs and
Hofmann, 2001), primarily the neural correlates of aversive emo-
tional face processing were investigated by neuroimaging studies
(Amir et al., 2005; Birbaumer et al., 1998; Cooney et al., 2006;
McNeil et al., 1995; Phan et al., 2006; Stein et al., 2002; Straube et
al., 2004a, 2005; Yoon et al., 2007). Several investigations which
presented aversive emotional faces showed a relatively stable
hyperactivation of the amygdala in patients with social phobia as
compared to non-phobic individuals (Amir et al., 2005; Campbell
et al., 2007; Cooney et al., 2006; Gentili et al., 2008; Phan et al.,
∗ Corresponding author. Tel.: +49 3641 9 45 154; fax: +49 3641 9 45 142.
E-mail address: straube@biopsy.uni-jena.de (T. Straube).
2006; Stein et al., 2002; Straube et al., 2004a, 2005; Yoon et al.,
2007). Additionally, a positive association between amygdala acti-
vation and symptom severity in social phobia (Blair et al., 2008;
Phan et al., 2006), in general anxiety disorder (Monk et al., 2008),
and in anxiety proneness (Stein et al., 2007b) was found. Taken
together, these results support the widely recognized role of the
amygdala in the processing of threat-relevant stimuli (Büchel et
al., 1999; LeDoux, 1998; Öhman and Mineka, 2001; Straube and
Miltner, 2006; Straube et al., 2007b).
The insular cortex is another region that seems to be impor-
tant during threat processing in patients with social phobia (Amir
et al., 2005; Etkin and Wager, 2007; Gentili et al., 2008; Straube
et al., 2004a, 2005; Yoon et al., 2007). Current theories suggest
that the insula is involved in emotional experiences, particular
in relation to sensed dangers (e.g. Critchley et al., 2004; Damasio
et al., 2000; Straube et al., 2006; Straube and Miltner, 2006) due
to the role of the insula in interoception (Critchley et al., 2004).
Craig (2002, 2009) identified different parts of the insula which
have different functions in emotion processing. Especially, the right
anterior insula is related to an increased awareness of bodily states
e.g. arousal states of the organism and is proposed to play a spe-
cial role in anxiety proneness (Craig, 2002, 2003, 2004; Critchley
et al., 2004; Paulus and Stein, 2006; Straube et al., 2004a, 2005).
Craig (2002) suggested that the insula might provide an integra-
tive centre for the generation of a mental image of one’s physical
state. Posterior and mid-insula receives all homoeostatic input.
This input is re-represented in the anterior insula, which is the
basis for emotional and motivational states, for example through

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 S. Schmidt et al. / Biological Psychology 84 (2010) 304–312
forwarding the subjective evaluation of the interoceptive state to
the orbitofrontal cortex (OFC), where hedonic valence is repre-
sented. Especially the right anterior insula might be involved in
the re-representation of sympathetic activity. Furthermore, insula
activation during anxiety-provoking paradigms has been shown
repeatedly (e.g. Chua et al., 1999; Lorberbaum et al., 2004; Ploghaus
et al., 1999; Rauch et al., 1997; Reiman, 1997; Straube et al., 2006,
2007a). As pointed out by Paulus and Stein (2006), the insula might
be especially important for understanding anxiety disorders. In
contrast to the amygdala, the insular activation seems to be more
pronounced during more direct or explicit processing of threat-
ening stimuli (e.g., Anderson and Sobel, 2003; Gorno-Tempini et
al., 2001; Straube et al., 2004a,b, 2005, 2006; Straube and Miltner,
2006; Winston et al., 2003; but see Gentili et al., 2008; Lange et
al., 2003). However, several studies also failed to show an insu-
lar hyperactivation in social phobic patients during the processing
of disorder-related cues or situations (Quadflieg et al., 2008; Stein
et al., 2002; Tillfors et al., 2001). Thus, the effects of experimen-
tal conditions and inter-individual differences in symptom severity
and emotional responses on the activation of the insula are poorly
understood.
Some studies suggested that the OFC is also involved in the
processing of social cues in social phobia (e.g. Quadflieg et al.,
2008; Veit et al., 2002; but see Lorberbaum et al., 2004; Tillfors
et al., 2001). Thus, the relevance of the OFC in aversive information
processing in socially phobic patients is far from being clear and fur-
ther investigations across several stimulus categories are needed.
The OFC seems to be important for emotion regulation (Davidson
et al., 2000) and might be associated with behavioural inhibition
(Damasio et al., 2000; Rolls, 2000, 2004), which is strongly asso-
ciated with social phobia. However, the OFC is a heterogeneous
region concerning cytoarchitecture, connections, and functions. For
example, a lateral vs. medial distinction of the OFC concerning the
valence of stimuli has been proposed (see Kringelbach and Rolls,
2004). The more lateral part of the human OFC is activated dur-
ing the processing of unpleasant stimuli, whereas the medial OFC
is involved in the processing of pleasant or reward stimuli (see
Kringelbach and Rolls, 2004; O’Doherty et al., 2001; Rolls, 2007;
Rolls et al., 2003a,b). Similarly, a posterior–anterior distinction has
been suggested with more complex or abstract reinforcers being
represented more anteriorly in the orbitofrontal cortex than less-
complex reinforcers.
While there are several findings concerning the processing of
faces, the neural correlates during the processing of disorder-
related verbal stimuli have not been investigated in social phobia.
Increased responses to verbal cues would test whether the abnor-
mal activation in several brain regions, in particular the amygdala,
in response to threat-related faces in socially phobic individuals
is due to the evolutionary relevance of such stimuli as proposed
by Öhman and Mineka (2001), or whether the differential activa-
tion to threatening versus neutral stimuli is also typical in response
to verbal information that acquire personal significance during
ontogenetic learning. However, amygdala activation has been also
found during the processing of anxiety-related anticipatory cues
(Lorberbaum et al., 2004) and negative self-related information
(Blair et al., 2008). Furthermore, there is evidence that the pro-
cessing of negative versus neutral words can activate the amygdala
in healthy subjects (Hamann and Mao, 2002; Isenberg et al., 1999;
Maddock et al., 2003) and in patients with obsessive compulsive or
panic disorder (e.g. van den Heuvel et al., 2005), while in specific
phobia no amygdala hyperactivation to phobia-related words has
been found (Straube et al., 2004b). Furthermore, the involvement
of other emotion-related regions such as the insula and OFC, which
have been suggested to be relevant for abnormal information pro-
cessing in social phobia, in the processing of disorder-related words
in social phobia is unknown.
305
The present study investigated the neural system activated
by the processing of phobia-related vs. phobia-unrelated words
in patients suffering from generalized social phobia and in non-
phobic individuals. Additionally, the attentional focus during the
presentation of the stimuli was manipulated by using two differ-
ent task instructions. Subjects were requested to either focus their
attention onto the social meaning (direct task) or on grammati-
cal aspects (indirect task) of each presented word. In particular,
the present study aimed to answer the following questions: (1)
Is there increased activation of the amygdala, insula, and OFC to
phobia-related vs. phobia-unrelated words in patients suffering
from generalized social phobia as compared to healthy controls;
(2) Does the attentional focus modulate brain activation patterns;
and (3) Is symptom severity of social anxiety associated with brain
activation?
2. Materials and methods
2.1. Subjects
Forty-two right-handed subjects with normal or to normal corrected vision par-
ticipated in the study. Five socially phobic individuals had to be excluded from
statistical analysis due to large head movements (>3 mm) during brain imaging
(one person), missing manual responses to the stimuli (one person), and being
outliers concerning the behavioural data (three subjects who were outliers in cor-
rect responses according to a conventional 2SD outlier criterion). Thus the analysis
based on 19 individuals diagnosed with generalized social phobia (GSP; according to
DSM-IV-TR as well as a SPIN-value above 25; Social Phobia Inventory, German ver-
sion, Sosic, 2003) and on 18 healthy controls (HC) free of any psychopathology and
matched for age (see Table 1) and gender (GSP: 10 females; HC: 9 females; 2 = 0.03;
p > 0.05). GSP underwent a structured clinical interview for the assessment of DSM-
IV-TR Axis I and II disorders (SCID I and II; Fydrich et al., 1997; Wittchen et al.,
1997) by an experienced interviewer (diploma-psychologist with extended train-
ing in diagnosis and therapy of psychological disorders). Exclusion criteria were
(1) A diagnosis of panic disorder and/or agoraphobia, obsessive-compulsive disor-
der, current alcohol/substance abuse, psychotic disorder, dementia, and primary or
secondary major depression; (2) A history of seizures or head injury with loss of
consciousness; (3) A severe uncontrollable medical condition; and (4) The use of
any psychotropic medication within the preceding six months. Individuals in the
GSP group suffered from moderate to severe social phobia (severity of social phobia
was rated by the experienced interviewer; according to a 7-point scale, whereby
1 means normal level of functioning and 7 means most severe impairment due
to phobic symptoms). Seven GSP also met the criteria of another anxiety disorder
(specific phobia and generalized anxiety disorder) and one individual was addi-
tionally diagnosed with affective disorder (major depressive disorder, recurrent, in
full remission). Also the criteria of DSM-Axis II disorders were fulfilled by seven
patients (avoidant and dependent personality disorder). Additionally, all partici-
pants completed the following questionnaires: SPIN, SCL-90-R (Symptom Checklist,
German version; Franke, 1995), and BDI (Beck Depression Inventory, German ver-
sion; Hautzinger et al., 1995). GSP showed significant greater scores in all these
questionnaires than HC did (see Table 1). All participants provided written informed
consent for the study. The study was approved by the ethics committee of the
Friedrich-Schiller-University Jena.
2.2. Paradigm
The phobia-related words were chosen to cover typical problems concerning
social anxiety. So, the words were related to aspects of public speaking, interpersonal
interaction situations, negative social evaluation and common anxiety symptoms
in social phobia. The phobia-unrelated words were related to neutral objects or
abstract terms without a social context. In a pilot study, 120 phobia-related and
phobia-unrelated words were evaluated for unpleasantness, arousal, and anxiety
feelings by 20 non-phobic subjects. Based on these evaluations, 50 phobia-related
words, which were rated as most unpleasant, arousing, and anxiety-inducing, and 50
phobia-unrelated words, matched with respect to the number of syllables, grammat-
ical category (25 nouns and 25 verbs, adverbs, or adjectives for either phobia-related
or phobia-unrelated words) and frequency in German language via the program
COSMAS II (version 3.6.1, Institute for German language, Mannheim, Germany)
were selected for the current study (see Supplementary Table). During scanning,
words were shown in capital letters and in random order (once in each of the two
scanning-runs) via a back-projection screen on an overhead mirror for 1 s each with
a stimulus onset asynchrony of 4.2 s. This SOA allows exactly a double sampling of
the BOLD response (each 1.4 s instead of 2.8 s, the TR, see below), is an effective
interval for event-related designs (according to our previous studies), and allows
sufficient jittering with parallel strong power per sampling time point. Addition-
ally, 50 null events (a fixation cross indistinguishable from the fixation cross seen
during the inter-stimulus intervals; see Josephs and Henson, 1999) were randomly
306 S. Schmidt et al. / Biological Psychology 84 (2010) 304–312

Table 1
Mean differences between patients with generalized social phobia (GSP) and healthy control subjects (HC) concerning age, symptom severity (SPIN), depression (BDI), and
bodily as well as psychological symptom affliction (GSI, PSDI, and PST from the SCL-90-R [Symptom Checklist]).

GSPM ± SD (range) HC M ± SD (range) t-Value p-Value

Age 23.84 ± 2.79 (20–29) 23.67 ± 2.72 (20–30) 0.19 0.848

SPIN 41.58 ± 7.06 (29–54) 7.94 ± 4.47 (2–16) 17.21 0.000
BDI 12.37 ± 4.68 (2–18) 3.33 ± 3.36 (0–11) 6.77 0.000

SCL-90-R
GSI 53.74 ± 6.87 (34–64) 37.67 ± 7.3 (22–52) 6.89 0.000
PSDI 50.74 ± 6.59 (40–60) 38.28 ± 6.81 (22–51) 5.65 0.000
PST 55.37 ± 7.88 (33–67) 38.83 ± 8.16 (22–58) 6.27 0.000

M = Mean; SD = standard deviation (displayed in parentheses).

intermixed. During word presentation all subjects had to perform one of the two
tasks (one task per run). During the indirect task condition, subjects were requested
to decide whether the word represents a noun or not. In the direct task condition,
participants were asked to decide if the presented word is related to a social con-
text or not. Participants received a written instruction where the definition of social
and non-social words was given and additionally the investigator trained the two
tasks with each participant and answered potential questions. Social words were
defined as words that refer to social situations, such interpersonal interactions and
confrontations (for example public talks), or feelings and behavioural responses of
subjects involved in social situations. Subjects’ behavioural responses, by pressing
a button with either the right index or middle finger, were detected via an optic
response box. The order of tasks and the assignment of response buttons to the two
tasks were counterbalanced across individuals. After the scanning session, partici-
pants rated all words using a nine-point Likert scale (SAM, Self-Assessment Manikin;
Bradley and Lang, 1994) to assess how much each stimulus induced unpleasantness
(1 = very pleasant, 9 = very unpleasant), arousal (1 = not arousing, 9 = very arousing),
and anxiety feelings (1 = not anxious, 9 = very anxious).
Behavioural data were analysed by repeated measures analyses of variance
(ANOVA) and subsequent t-tests using the software SPSS (Version 16.0.2, SPSS, Inc.).
Additionally, variance analyses including BDI-values as a covariate were conducted
to control for effects of the depressive mood. For ANOVA and ANCOVA a probability
level of p < 0.05 was considered statistically significant. For better interpretating the
results the effect seizes of F- and t-values were calculated. According to F-tests 2
was calculated by using SPSS. Cohen’s d was used to define the effect size of t-values
from unpaired t-tests and dz was used to define the effect size of t-values from
paired t-tests. These indices were calculated using the software package G*Power
(http://www.psycho.uni-duesseldorf.de/aap/projects/gpower) with the following
formula d = (1 − 2 )/, where 1 and 2 are the population means of SP and HC
and  is the standard deviation of the population and dz = (|x–y |)/ x–y , where x–y
is the population mean of the difference and  x–y is the standard deviation of the
difference (see Faul et al., 2007). Cohen, 1992 defines d = 0.2, d = 0.5, and d = 0.8 as
“small”, “medium”, and “large” effects, respectively.
daemon software; http://www.ric.uthscsa.edu/projects/talairachdaemon.html] and
across the whole brain (exploratory analyses). Statistical parametric maps result-
ing from voxel-wise analyses were considered statistically significant for clusters
that survived a correction for multiple comparisons. For that purpose we used the
approach as implemented in Brain Voyager (see Goebel et al., 2006; based on a 3D
extension of the randomization procedure described by Forman et al., 1995). First,
voxel-level threshold was set at p < 0.005 (uncorrected). Threshold maps were then
submitted to a ROI- or whole brain-based correction for multiple comparisons. The
correction is based on the estimation of the cluster threshold that is the minimal
number of voxels, which are necessary to control for multiple comparisons. The
cluster threshold criterion was based on the estimate of map’s spatial smoothness
(Forman et al., 1995) and on an iterative procedure (Monte Carlo simulation). The
Monte-Carlo simulation used 1000 iterations in order to estimate the minimum
cluster size threshold that yielded a cluster-level false-positive rate of 5%. This clus-
ter size threshold was applied to the statistical maps. The minimal cluster thresholds
for the comparison of GSP vs. HC were 135 voxels for amygdala as well as insula,
162 voxels for OFC, and 378 voxels for whole brain analyses. Finally, correlation
analyses were conducted between brain activation within the ROIs and symptom
severity of the individuals with social phobia (as measured by SPIN). In case of
significant correlation BOLD response of the same voxel was correlated with SPIN-
values in HC. The two correlation coefficients were than transformated to Fisher-Z
by using the formula Z = (1/2) × ln([1 + r]/[1 − r]). Significant differences of the two
Fisher-Z values were analysed by using the test z = (ZHC − ZGSP )/ (ZHC–ZGSP) whereby
√
 (ZHC–ZGSP) = ([1/nHC − 3] + [1/nGSP − 3]). The difference between the two correlation
coefficients is considered significant at ˛ ≤ 0.05 when z is smaller than z5% = −1.65
(see Bortz, 1999).
3. Results
3.1. Behavioural data

2.3. Functional MRI 3.1.1. Accuracy

Scanning was performed in a 1.5 T magnetic resonance scanner (“Magnetom
Vision plus”, Siemens, Medical Systems, Erlangen, Germany). After a T1-weighted
anatomical scan, two runs (either indirect or direct task) each consisting of 229 vol-
umes (30 axial slices [thickness = 3 mm, gap = 1 mm, in plane resolution = 3 × 3 mm])
were conducted using a T2*-weighted echo-planar sequence (TE = 93.3 ms, flip
angle = 90◦ , matrix = 64 × 64, FOV = 192 mm, TR = 2.8 s). To minimize susceptibil-
ity artefacts in the OFC the slices were acquired with a tilted slice orientation
(Deichmann et al., 2003). The first four volumes of each run were discarded from
analyses to ensure steady-state tissue magnetization.
Functional MRI (fMRI)-data preprocessing and analyses were conducted by
using BrainVoyager QX (Version 1.8.6; Brain Innovation, Maastricht, The Nether-
lands). Primarily, all volumes were realigned to the first volume in order to minimize
artefacts due to head movements and a slice time correction was conducted. Further
data preprocessing comprised spatial (8 mm full-width half-maximum isotropic
Gaussian kernel) and temporal smoothing (high pass filter: 5 cycles per run; low
pass filter: 2.8 s; linear trend removal). The anatomical and functional images were
co-registered and normalized to the Talairach space (Talairach and Tournoux, 1988).
Statistical analyses were performed by multiple linear regression of the sig-
nal time course at each voxel. The expected blood oxygen-level-dependent (BOLD)
signal change for each event type (predictor) was modeled by a canonical hemody-
namic response function. The phobia-related and phobia-unrelated words during
either the direct or the indirect task condition were defined as events of interest
and motion correction parameters as events of no interest. Statistical comparisons
were conducted using a mixed effect analysis, which considers inter-subject vari-
ance and permits population-level inferences. Firstly, voxel-wise statistical maps
were generated and the relevant, planned contrasts of predictor estimates (beta-
weights) which were computed for each individual. Secondly, a random effect
group analysis of these individual contrasts was performed. Analyses were con-
ducted for specific ROIs [amygdala, insula, and OFC defined with the Talairach
The number of correct responses did not differ between GSP
and HC when testing main effects and interactions with a 2 × 2 × 2
(Group by Word category by Task) repeated measures ANOVA. Only
a main effect of Task was found (F[1,35] = 6.30; p < 0.05; 2 = 0.15).
During the indirect task condition, all participants answered
more correct (98.41 ± 1.34%) than during the direct task condi-
tion (97.49 ± 2.09%; d = 0.42). Analysing the percentage of correct
answers with a repeated measures ANCOVA (BDI as covariate)
reached comparable results. There was only a significant effect of
Task (F[1,34] = 5.14, p < 0.05; 2 = 0.13), too.
3.1.2. Reaction times
Analyses of reaction times with a repeated measures ANOVA
revealed a main effect of Task (F[1,35] = 18.30; p < 0.05; 2 = 0.34).
Reactions were faster in the indirect than in the direct task condi-
tion (see Table 2). There was also a significant interaction of Task
by Word category (F[1,35] = 35.72; p < 0.05; 2 = 0.51) which was
based on increased reaction times to phobia-related in compar-
ison to phobia-unrelated words during the indirect (t[36] = 4.44;
p < 0.05; dz = 0.73) and a faster reaction to phobia-related than
to phobia-unrelated words during the direct task (t[36] = 4.58;
p < 0.05; dz = 0.75). There were no significant interactions of Group
by Word category (F[1,35] = 1.63; p > 0.05; 2 = 0.04) or Group by
Word category by Task (F[1,35] = 1.98; p > 0.05; 2 = 0.05).
 S. Schmidt et al. / Biological Psychology 84 (2010) 304–312 307

Table 2 Table 4
Reaction times to phobia-related and phobia-unrelated words in patients with gen- Differential brain activation in phobic (GSP) > non-phobic (HC) individuals in
eralized social phobia (GSP) and healthy control subjects (HC) during the direct and response to phobia-related > phobia-unrelated words during the indirect task in the
indirect task (in ms; for details see text). ROIs.

GSP HC ROI Side GSP > HC/phobia-related > phobia-unrelated

Direct task Talairach

Phobia-related 865.26 (133.88) 865.85 (128.63)
Phobia-unrelated 906.34 (161.62) 904.32 (143.82) x y z Size t-Value

Indirect task Indirect task

Phobia-related 848.54 (157.96) 794.48 (103.00) Amygdala L −21 −4 −17 256 3.37
Phobia-unrelated 811.47 (137.74) 784.57 (100.21) OFC R 24 17 −14 515 4.23

Mean and standard deviation (displayed in parentheses). L = left; R = right; OFC = orbitofrontal cortex; size = number of 1 mm × 1 mm × 1 mm
voxels (activation threshold: p < 0.005, corrected).

Additionally ANCOVA analyses (with BDI as covariate) revealed

slightly different results. The main effect of Task (F[1,34] = 1.34;
p > 0.05; 2 = 0.04) did not reached significance whereas the interac-
tion of Task by Word category remained significant (F[1,34] = 25.47;
p < 0.05; 2 = 0.43). Furthermore, there was an interaction of Task
by Word category by Group (F[1,34] = 7.90; p < 0.05; 2 = 0.19).
This was due to differential reaction times to phobia-related vs.
phobia-unrelated words during the indirect task condition between
GSP and HC. The difference between the two word categories
was greater in GSP (phobia-related: 848.54 ± 36.27 vs. phobia-
unrelated: 811.47 ± 28.18; ANCOVA-corrected values; dz = 1.12)
than in HC (phobia-related: 794.48 ± 26.04 vs. phobia-unrelated:
784.57 ± 20.23; ANCOVA-corrected values; dz = 0.42). Finally, there
was a significant interaction of Task by Word category by BDI
(F[1,34] = 5.87; p < 0.05; 2 = 0.15) indicating that BDI-scores inter-
act with reaction times depending on task condition and word
category.
3.1.3. Rating data
Analyses of post-scanning unpleasantness, arousal, and anxiety
ratings (see Table 3) showed a main effect of Word category
(unpleasantness: F[1,35] = 439.77; p < 0.05; 2 = 0.93; arousal:
F[1,35] = 99.11; p < 0.05; 2 = 0.74; anxiety: F[1,35] = 270.14;
p < 0.05; 2 = 0.89) indicating that all participants rated phobia-
related words as more negative (phobia-related: 6.27 ± 1.00 vs.
phobia-unrelated: 4.85 ± 0.17; dz = 1.42), more arousing (phobia-
related: 5.90 ± 1.34 vs. phobia-unrelated: 4.23 ± 0.60; dz = 1.22),
and more anxiety-inducing (phobia-related: 3.87 ± 1.91 vs.
phobia-unrelated: 1.10 ± 0.18; dz = 1.46) than phobia-unrelated
words. There was also an interaction of Group by Word cate-
gory (unpleasantness: F[1,35] = 182.78; p < 0.05; 2 = 0.84; arousal:
F[1,35] = 32.40; p < 0.05; 2 = 0.48; anxiety: F[1,35] = 92.39; p < 0.05;
2 = 0.73). Post hoc t-tests revealed that GSP rated phobia-related
words as more negative (t[36] = 13.25; p < 0.05; d = 5.23), more
arousing (t[36] = 6.40; p < 0.05; d = 6.48) and more anxiety-inducing
(t[36] = 9.56; p < 0.05; d = 3.41) than HC did. Such a significant group
Table 3
Post-scanning rating data of unpleasantness, arousal, and anxiety to phobia-related
and phobia-unrelated words by patients with generalized social phobia (GSP) and
healthy control subjects (HC).
GSP HC
Unpleasantness
Phobia-related 7.15 (0.19) 5.37 (0.14)
Phobia-unrelated 4.85 (0.47) 4.85 (0.31)
Arousal
Phobia-related 6.84 (0.58) 4.76 (0.61)
Phobia-unrelated 4.25 (0.47) 4.18 (1.35)
Anxiety
Phobia-related 5.44 (1.24) 2.11 (0.70)
Phobia-unrelated 1.11 (0.19) 1.08 (0.18)
Mean and standard deviation (displayed in parentheses).
difference did not occur for phobia-unrelated words (unpleasant-
ness: t[36] = 0.10; p > 0.05; arousal: t[36] = −0.29; p > 0.05; anxiety:
t[36] = −0.41; p > 0.05). Additionally ANCOVA analyses (with
BDI as covariate) yielded comparable results: significant effect of
Word category (unpleasantness: F[1,34] = 70.45; p < 0.05; 2 = 0.67;
arousal: F[1,34] = 21.46; p < 0.05; 2 = 0.39; anxiety: F[1,34] = 55.74;
p < 0.05; 2 = 0.62) as well as significant interaction of Group by
Word category (unpleasantness: F[1,34] = 64.51; p < 0.05; 2 = 0.66;
arousal: F[1,34] = 14.00; p < 0.05; 2 = 0.31; anxiety: F[1,34] = 40.71;
p < 0. 0.05; 2 = 0.55).
3.2. fMRI-data – indirect task
3.2.1. Interaction Group by Word category
When comparing the BOLD response of phobia-related vs.
phobia-unrelated words during the indirect task condition,
increased activation in the amygdala and OFC in GSP as compared
to HC was found. Thus, a cluster in the left amygdala (peak voxel
Talairach coordinates: x = −21; y = −4; z = −17; size = 256 mm3 ; t-
value = 3.37; d = 4.41) was stronger activated in GSP (see Fig. 1a).
Furthermore, there was an increased activation in the right
OFC (peak voxel Talairach coordinates: x = 24; y = 17; z = −14;
size = 515 mm3 ; t-value = 4.23; d = 5.64; see Fig. 1b). However, there
was no effect in the left or right insula. Table 4 summarizes the
statistics for significant effects. Finally, exploratory analyses of
brain activation did not reveal significant differential brain activa-
tion between GSP and HC. Additional comparison of BOLD response
to phobia-unrelated > phobia-related words between GSP and HC
yielded no significant differences in the ROIs or whole brain in an
exploratory analysis.
3.2.2. Correlation analysis
There was no association between symptom severity of the
patients with social phobia and activation to phobia-related vs.
phobia-unrelated words in any brain region.
3.3. fMRI-data – direct task
3.3.1. Interaction Group by Word category
To answer the question of differential activation between GSP
and HC, a between-group analysis was conducted for the con-
trast phobia-related > phobia-unrelated words. This comparison
revealed no differential brain activation in the ROI or exploratory
analysis. There were also no significant cluster in the ROI or in the
exploratory analyses when contrasting phobia-unrelated > phobia-
related words.
3.3.2. Correlation analyses
Although the factorial analysis showed no differential effect
in the insula, activation to phobia-related vs. phobia-unrelated
words in the right insula was positively correlated with symp-
tom severity of the individuals with social phobia (peak voxel
308 S. Schmidt et al. / Biological Psychology 84 (2010) 304–312

Fig. 1. Differential brain activation during the indirect task condition. Patients with generalized social phobia (GSP) display an enhanced activation in the left amygdala (a)
and the right orbitofrontal cortex (b) as compared to healthy control subjects (HC; phobia-related > phobia-unrelated words). Statistical parametric maps are overlaid on a T1
scan (radiological convention: left = right). The plots at the right side display contrasts of parameter estimates (phobia-related vs. phobia-unrelated words; mean ± standard
error for maximally activated voxel).

Fig. 2. Brain activation in the right insular cortex correlated significantly with symptom severity as measured by SPIN (Social Phobia Inventory) in patients with generalized
social phobia (GSP) during the direct task condition and this correlation was significantly greater than the association of SPIN-values and BOLD response in healthy controls
(HC). Statistical parametric maps are overlaid on a T1 scan (radiological convention: left = right). The scatter plot displays the relationship between contrasts of parameter
estimates (phobia-related–phobia-unrelated words) and means of symptom severity separately illustrated for GSP and HC.

Talairach coordinates: x = 39; y = −1; z = 4; cluster size = 129 mm3 ;
r = 0.700; p < 0.005; see Fig. 2). The correlation between BOLD
response and SPIN-values in HC revealed no significant associa-
tion (r = −0.281; p > 0.005). After Fisher-Z transformation the z-test
indicates a significant difference between the two correlation coef-
ficients (ZGSP = 0.867; ZHC = −0.289; z = −2.73). There was no further
ROI showing an association between symptom severity and brain
activation.
4. Discussion
This study aimed to investigate the neural correlates of the
processing of disorder-related words in patients with generalized
social phobia as compared to healthy control subjects under two
different task conditions. Results showed increased activation of
the amygdala and OFC in patients as compared to control subjects
during the indirect task, in which the social meaning of the words
had to be ignored. During the direct task, no differential activation
between patients and control subjects was found. Nevertheless,
activation of the insula was strongly correlated with symptom
severity in patients.
It is remarkable that the analyses of the fMRI-data in the
direct task condition did not reveal statistically significant differ-
ences between patients and control subjects. This suggests that
explicit processing of disorder-related words does not distinguish
between phobic and non-phobic individuals. This partially repli-
cates findings of a previous study (Straube et al., 2004a), where
an indirect task produced differential activation in several brain
regions including the amygdala during face processing, while the
direct task condition was associated with differential activation of
the insula only. Although the present study did not find a differen-
tial activation between patients and control subjects in the insula
during the direct processing of phobia-related words, the insula
activation during this task condition was positively correlated
 S. Schmidt et al. / Biological Psychology 84 (2010) 304–312
with patients’ symptom severity. Thus correlation analysis might
emphasize aspects not detected with conventional between-group
comparisons. The absence of effects in the between-group compar-
ison might trace back to differential strategies of coping with words
depending on severity of social phobia. Furthermore, there might
be a general difference between groups, such as increased baseline
activation in phobic participants, which prevents the detection of
significant factorial effects.
A stronger insular activation during threat-relevant word pro-
cessing could indicate an increased processing of bodily inner states
especially in more severe cases of social phobia. Several studies
have shown an insular involvement in the processing of aversive
emotional cues in specific phobia (Dilger et al., 2003; Straube et
al., 2004b, 2006; Wright et al., 2003; but see Paquette et al., 2003)
as well as in social phobia (Amir et al., 2005; Lorberbaum et al.,
2004; Straube et al., 2004a, 2005; Yoon et al., 2007; but see Furmark
et al., 2005; Stein et al., 2002; Tillfors et al., 2001), and also in
other anxiety disorders (Etkin and Wager, 2007; Rauch et al., 1997).
Taken together, the insula seems to be involved in the processing
of phobia-related information in anxiety disorders. Furthermore,
the insular region is proposed to play an important role in the
representation of visceral and autonomic responses to emotional
stimuli (e.g. Critchley et al., 2004; Damasio et al., 2000) and the
integration of upcoming feelings with other current contingen-
cies (Craig, 2009). An attentional shift to bodily fear responses is
often associated with the generation as well as maintenance of
anxiety disorders (Clark and Ehlers, 2002) and the internal monitor-
ing seems to be an crucial maintaining factor in patients suffering
from social phobia (Clark and Wells, 1995). Therefore, increased
activation of the insula should be especially pronounced in more
social anxious individuals and rather during explicit processing of
threat-related stimuli when an attentional shift to bodily states is
more evident (Clark and Wells, 1995). Previous studies reported an
association of symptom severity with amygdala activation to faces
(Phan et al., 2006) or with anterior cingulate glutamate/creatine
levels (Phan et al., 2005). Our findings implicate also the role of the
insula especially in more severe cases in social phobia. However,
at the moment it remains unclear which experimental conditions
are associated with the relation between symptom severity and
activation in different brain areas.
In contrast to the direct task, the indirect task condition revealed
differential activation between socially phobic patients and control
subjects in the amygdala and OFC. These activations, however, seem
to be associated with more general differences between control
subjects and patients suffering from social phobia, since there was
no correlation between activation in these regions and patients’
symptom severity. The observed activation in the amygdala is in
accordance with previous studies that showed increased amygdala
responses to negative emotional facial expressions in social phobia
(Amir et al., 2005; Campbell et al., 2007; Cooney et al., 2006; Phan et
al., 2006; Stein et al., 2002; Straube et al., 2004a, 2005; Yoon et al.,
2007). However, the current study demonstrates that the amygdala
activation is not restricted to the processing of phylogenetic threat-
related cues like angry facial expressions. The amygdala has been
proposed as being involved in the rapid detection of threat cues
and in the mediation of bodily fear responses (Büchel et al., 1999;
LeDoux, 1998; Öhman and Mineka, 2001; Straube and Miltner,
2006). In addition, several studies reported differential amygdala
activation rather during indirect than during direct or explicit pro-
cessing of threat-related stimuli (Critchley et al., 2000; Keightley
et al., 2003; Lange et al., 2003; Straube et al., 2004a, 2006; but see
Anderson and Sobel, 2003; Gur et al., 2002). In explicit task con-
ditions, a suppression of the amygdala activation by cortical areas
is discussed (Etkin et al., 2006; Hariri et al., 2003; Keightley et al.,
2003; Straube et al., 2007b). Our study also suggests that, although
the social relevance of the stimuli had not to be explicitly attended
309
to, the phobia-related meaning of words was strongly processed by
socially phobic patients during the indirect task.
There was also an increased activation of the OFC in patients
suffering from social phobia as compared to control subjects during
the indirect task condition which was located rather in the lateral
part of the OFC. Results for the OFC are partly in accordance with
previous studies (Quadflieg et al., 2008; Veit et al., 2002; but see
Schneider et al., 1999) and the location of the activation difference
is in accordance to previous investigations that found a more lat-
eral part of the OFC involved in aversive emotional processing (for a
review see Kringelbach and Rolls, 2004). In line with this, Quadflieg
et al. (2008) showed an involvement of the more lateral OFC in an
indirect as well as in a direct task condition during the processing of
aversive prosody. The OFC has been proposed to evaluate sensory
signals and being involved in affective and behavioural responses
(Damasio, 1994; Davidson et al., 2000; Hornak et al., 2003; Kalin
et al., 2007; Rolls, 2000, 2004). In healthy subjects, orbitofrontal
responses to angry voices were found to correlate positively with
inter-individual differences in the sensitivity of the behavioural
inhibition system (Sander et al., 2005). This suggests a strong role
of the OFC in anxious avoidance of punishment. It has been gen-
erally proposed (e.g. Damasio, 1994; Frey et al., 2000; Rolls, 2000,
2004; Rolls et al., 1994) that the OFC is crucial for the representa-
tion of reward and punishment guiding learning and behavioural
adjustments. For socially phobic individuals, social threat stimuli
represent (potential) punishment which inhibits or disturbs ongo-
ing behaviour. The increased OFC activation in patients during the
indirect task condition suggests a high automaticity of neural and
potentially behavioural reactions in social phobia in response to
verbal threat-related stimuli.
The OFC, amygdala, and insula are strongly functionally and
anatomically interconnected (e.g. Ghashghaei and Barbas, 2002;
Meyer-Lindenberg et al., 2005) and are involved in different stages
of information processing. These brain regions are assumed to be
part of an emotion generating/regulating network (e.g. Birbaumer
et al., 2005; Davidson, 2002; Ochsner and Gross, 2005; Phillips et al.,
2003; Veit et al., 2002). Several authors have highlighted the impor-
tance of the amygdala as well as the prefrontal cortex (PFC) in the
neural circuitry of emotion processing (e.g. Birbaumer et al., 2005;
Bishop, 2007; Davidson, 2002; Deckersbach et al., 2006; Drevets
et al., 2008; Hariri et al., 2003; Ochsner and Gross, 2005) and a
hyperactivation of this brain circuit was already shown in social
phobia and has been put in the context of increased processing
of feedback from the autonomic, musculoskeletal, and endocrine
system to cortical areas leading to adequate emotional responses
(see Veit et al., 2002). In a recent study with healthy subjects,
Stein et al. (2007a) investigated functional connectivity between
several emotion-related regions. They found a strong functional
connectivity between OFC and amygdala and between the insula
and amygdala as well. These regions are considered to be part of
a ventral stream of emotional cognition as suggested by Phillips
et al. (2003). The authors hypothesized that the ventral stream
is important in identifying the emotional significance of external
stimuli and the production of affective states. Additionally, the
ventral stream seems to be important in regulating and medi-
ating autonomic responses to emotional stimuli (see Phillips et
al., 2003). Moreover, Ochsner and Gross (2005) accentuated the
role of the ventral PFC/OFC in cognitive control processes which
were directed to subcortical areas (including the amygdala) dur-
ing emotional processing. This top-down mediation is said to be
important when associations between outcomes and preceding
choices or events are learned with the objective to regulate emo-
tions. In accordance to this the paired hyperactivation of OFC and
amygdala may indicate an enhanced effort to regulate or medi-
ate emotional responses when verbal phobia-related material is
processed indirectly in social phobia. With a view to our study
310 S. Schmidt et al. / Biological Psychology 84 (2010) 304–312
and other investigations mentioned above conclusions about the
causality of this paired activation pattern cannot be drawn.
The focus of this paper was to investigate the role of the amyg-
dala, OFC, and insula in the processing of phobia-related verbal
information in social phobia. However, future studies should focus
on the investigation of the interconnection of these areas. It would
also be interesting to reveal the role of the language network in
processing social phobia-related stimuli. The exploratory analy-
sis did not reveal greater activation of the language network (left
ventrolateral PFC, left posterior middle temporal gyrus, and left
supramarginal gyrus) in response to phobia-related words in social
phobia. However, since we did not define these areas as regions of
interest, potential effects might have not been detected.
Furthermore, tasks were created to investigate brain activation
under two different attentional foci regarding phobia-relative word
meaning. The direct task required to process the phobia-related rel-
evance of presented words and therefore can be regarded as explicit
task concerning word meaning. Nevertheless, the task instruction
for the indirect task may have shifted the focus of attention away
from emotional processing to more abstract cognitive processing.
Future studies might use task instructions that focus attention
to subjective emotional involvement or the emotional relevance
of stimuli. Further investigations might also use measurements
or electrodermal activity and analysis of BOLD responses might
include reference functions based on word-specific behavioural or
autonomic responses.
To summarize, the present study revealed neural correlates
of abnormal processing of disorder-related words in individuals
with social phobia. The amygdala and OFC activation was specifi-
cally observed during the indirect condition and suggests a rather
automatic processing of disorder-related words. Furthermore, acti-
vation of the insula seems to be specifically related to direct
processing of threatening words, especially in more severe cases
of social phobia.
Acknowledgements
The study was supported by grants of the Deutsche Forschungs-
gemeinschaft awarded to Thomas Straube and Wolfgang H.R.
Miltner and by a grant of the Federal State of Thuringia and the
Friedrich-Schiller-University Jena awarded to Thomas Straube.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.biopsycho.2010.03.005.
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