Anticipation of aversive visual stimuli is associated with increased insula activation in anxiety-prone subjects.
ABSTRACT Anticipation is a critical component of affective processing in general and for anxiety in particular. Prior research suggests that the right insula plays an important role in anticipation of affective processing during aversive images. This study aimed to test the hypothesis that individuals with increased anxiety-related temperamental traits (anxiety-prone [AP]) relative to anxiety-normative (AN) subjects would show an exaggerated insula response during anticipation of an aversive image.
16 AP and 16 AN individuals performed a task in the functional magnetic resonance imaging scanner, during which they viewed pictures of spiders and snakes. Subjects were prompted 4-6 sec before the onset of each aversive image. Blood oxygenation level-dependent signal was contrasted during cued anticipation of images versus non-anticipatory task performance as well as viewing images.
As hypothesized, AP subjects showed greater response than AN subjects in the bilateral insula during anticipation. In addition, these individuals had lower activity within the superior/medial frontal gyrus. During the image presentation phase, AN subjects showed greater activation than AP subjects in the bilateral temporal lobes and left superior frontal gyrus. Moreover, bilateral temporal lobe activation during image presentation was inversely correlated with bilateral insula activation during anticipation both within groups and in the combined group.
These data suggest that greater activation of the insula during visual anticipation is associated with visual processing of aversive stimuli in AP individuals. Insula hyperactivity might be a common feature in persons with elevated trait anxiety and, as such, might be a neuroimaging marker for anxiety proneness.
- SourceAvailable from: Ursula F Bailer[Show abstract] [Hide abstract]
ABSTRACT: The primary defining characteristic of a diagnosis of an eating disorder (ED) is the "disturbance of eating or eating-related behavior that results in the altered consumption or absorption of food" (DSM V; American Psychiatric Association, 2013). There is a spectrum, ranging from those who severely restrict eating and become emaciated on one end to those who binge and overconsume, usually accompanied by some form of compensatory behaviors, on the other. How can we understand reasons for such extremes of food consummatory behaviors? Recent work on obesity and substance use disorders has identified behaviors and neural pathways that play a powerful role in human consummatory behaviors. That is, corticostriatal limbic and dorsal cognitive neural circuitry can make drugs and food rewarding, but also engage self-control mechanisms that may inhibit their use. Importantly, there is considerable evidence that alterations of these systems also occur in ED. This paper explores the hypothesis that an altered balance of reward and inhibition contributes to altered extremes of response to salient stimuli, such as food. We will review recent studies that show altered sensitivity to reward and punishment in ED, with evidence of altered activity in corticostriatal and insula processes with respect to monetary gains or losses, and tastes of palatable foods. We will also discuss evidence for a spectrum of extremes of inhibition and dysregulation behaviors in ED supported by studies suggesting that this is related to top-down self-control mechanisms. The lack of a mechanistic understanding of ED has thwarted efforts for evidence-based approaches to develop interventions. Understanding how ED behavior is encoded in neural circuits would provide a foundation for developing more specific and effective treatment approaches.Frontiers in Behavioral Neuroscience 12/2014; 8:410. · 4.16 Impact Factor
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ABSTRACT: Prior studies suggest that hyperactive insula responding to unpredictable aversiveness is a core feature of anxiety disorders. However, no study to date has investigated the neural correlates of unpredictable aversiveness in those with panic disorder (PD) with comorbid major depressive disorder (MDD). The aim of the current study was to examine group differences in neural responses to unpredictable and predictable aversiveness in 41 adults with either 1) current PD with comorbid MDD (PD-MDD), 2) current MDD with no lifetime diagnosis of an anxiety disorder (MDD-only), or 3) no lifetime diagnosis of psychopathology. All participants completed a functional magnetic resonance imaging (fMRI) scan while viewing temporally predictable or unpredictable negative or neutral images.Biology of Mood & Anxiety Disorders. 01/2014; 4(1):9.
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ABSTRACT: This study reviews research on the construct of intolerance of uncertainty (IU). A recent factor analysis (Journal of Anxiety Disorders, 25, 2012, p. 533) has been used to extend the transdiagnostic model articulated by Mansell (2005, p. 141) to focus on the role of IU as a facet of the model that is important to address in treatment. Research suggests that individual differences in IU may compromise resilience and that individuals high in IU are susceptible to increased negative affect. The model extension provides a guide for the treatment of clients presenting with uncertainty in the context of either a single disorder or several comorbid disorders. By applying the extension, the clinician is assisted to explore two facets of IU, “Need for Predictability” and “Uncertainty Arousal.”Clinical Psychology Science and Practice 09/2014; 21(3). · 2.92 Impact Factor
Anticipation of Aversive Visual Stimuli Is Associated
With Increased Insula Activation in
Alan Simmons, Irina Strigo, Scott C. Matthews, Martin P. Paulus, and Murray B. Stein
Background: Anticipation is a critical component of affective processing in general and for anxiety in particular. Prior research
suggests that the right insula plays an important role in anticipation of affective processing during aversive images. This study aimed
to test the hypothesis that individuals with increased anxiety-related temperamental traits (anxiety-prone [AP]) relative to
anxiety-normative (AN) subjects would show an exaggerated insula response during anticipation of an aversive image.
Methods: 16 AP and 16 AN individuals performed a task in the functional magnetic resonance imaging scanner, during which they
viewed pictures of spiders and snakes. Subjects were prompted 4–6 sec before the onset of each aversive image. Blood oxygenation
level-dependent signal was contrasted during cued anticipation of images versus non-anticipatory task performance as well as viewing
Results: As hypothesized, AP subjects showed greater response than AN subjects in the bilateral insula during anticipation. In
addition, these individuals had lower activity within the superior/medial frontal gyrus. During the image presentation phase, AN
subjects showed greater activation than AP subjects in the bilateral temporal lobes and left superior frontal gyrus. Moreover, bilateral
temporal lobe activation during image presentation was inversely correlated with bilateral insula activation during anticipation both
within groups and in the combined group.
Conclusions: These data suggest that greater activation of the insula during visual anticipation is associated with visual processing
of aversive stimuli in AP individuals. Insula hyperactivity might be a common feature in persons with elevated trait anxiety and, as
such, might be a neuroimaging marker for anxiety proneness.
Key Words: Anticipation, anxiety, avoidance, fMRI, imaging
of the phobic object or situation (Tillfors et al 2002). Greater
anticipatory anxiety might be associated with avoiding phobic
stimuli, which limits extinction and might serve to further maintain
phobic responses. Therefore, exaggerated anticipatory process-
ing might be a vulnerability factor for the acquisition of phobias
(Ost 1987) and, perhaps, other anxiety disorders.
The insula, medial prefrontal cortex (MPFC), and anterior
cingulate cortex (ACC) seem to be critically involved in both
anxiety and anticipatory processing. Functional imaging studies
suggest the MPFC/ACC (Chua et al 1999; Sawamoto et al 2000;
Simpson et al 2001a) and insula (Chua et al 1999; Ploghaus et al
1999) activate during anticipation of an electric shock or of
noxious thermal stimulus. Similarly, activation in the MPFC/ACC
and insula has been observed during anticipation of feedback in
a decision-making task (Critchley et al 2001). In a prior functional
imaging study (Simmons et al 2004), we examined in healthy
volunteers anticipation of images of spiders and snakes, which
are among the most commonly reported phobic stimuli (Kendler
et al 2001). In that study, 20 of 23 subjects rated some images as
at least moderately distressing and showed an increase in
nticipation of future harm is a key aspect of anxiety
(Bradley et al 1997; Eysenck 1997). Specifically, phobic
anxiety occurs during both the expectation and presence
activation within the right insula during the anticipation phase of
The insula, a part of the extended limbic system, has afferent
and efferent connections to medial and orbitofrontal cortex,
anterior cingulate, and several nuclei of the amygdala (Augustine
1996). Although insula activation has been frequently associated
with disgust (Phillips et al 1998), there is increasing evidence of
a broader role for this brain structure in emotion processing
(Phan et al 2002). Insula activation is thought to be involved in
many emotional processes, including differential positive versus
negative (in particular, fear) emotion processing (Buchel et al
1998; Morris et al 1998), pain perception (Gelnar et al 1999;
Peyron et al 2000), anticipation and viewing of aversive images
(Phan et al 2006; Simmons et al 2004), and the making of
judgments about emotions (Gorno-Tempini et al 2001). Activa-
tion in the insula correlates with anxiety indices during a risk-taking
task (Paulus et al 2003), is greater in subjects with specific phobia
when viewing fearful faces (Wright et al 2003), and seems respon-
sive to treatment with anti-anxiety drugs (Paulus et al 2005). These
properties make this region a good candidate for showing the
combined effects of anxiety and anticipation.
Altered anticipation of aversive events might be based on
altered cognitive and/or perceptual processes. Riskind (1997)
has suggested that some people have a pervasive “looming
maladaptive style” that makes them susceptible to developing
anxiety disorders and, in particular, subjects with this style and fear
of spiders have perceptual distortions that the spider is approaching
them (Riskind et al 1995). This suggests the possibility that anxiety-
(or phobia-) prone individuals might differ in the way they process
visual information about potential phobic stimuli.
The aim of this study was to examine how the neural circuitry
involved in anticipating potentially aversive affective stimuli
differs in normal and anxiety-prone (AP; i.e., defined on the basis
of high trait anxiety) subjects. We hypothesized that AP individ-
uals would show heightened insular activation compared with
anxiety-normative (AN) individuals. Support for this hypothesis
From the Laboratory of Biological Dynamics and Theoretical Medicine (AS,
the Department of Psychiatry (AS, IS, SCM, MPP, MBS), University of
California San Diego; and the VA San Diego Healthcare System (MPP,
MBS), La Jolla, California.
San Diego, Department of Psychiatry (Mail Code 0985), Veterans Affairs
San Diego Health Care System, 8950 Villa La Jolla Drive, Suite C213, La
Jolla, CA 92037-0985; E-mail: email@example.com.
Received October 24, 2005; revised April 13, 2006; accepted April 18, 2006.
BIOL PSYCHIATRY 2006;60:402–409
© 2006 Society of Biological Psychiatry
would link a specific neural substrate, the insular cortex, with a
psychological process, anticipation, toward the development of a
vulnerability marker for individuals who are at elevated risk for
Methods and Materials
This study was approved by the University of California San
Diego and San Diego State University (SDSU) institutional review
boards, and all subjects provided written informed consent to
participate. Initially, approximately 3000 undergraduate SDSU
students participated in screening with the Spielberger Trait
Anxiety Questionnaire (Speilberger et al 1983). Subsequently,
subjects who scored high in trait anxiety (in the upper 15th
percentile of the distribution) and subjects who had normative
levels of trait anxiety (from the 40th to 60th percentile of the
distribution) were selected for further screening. Of these, ap-
proximately one in three expressed a willingness to participate in
a functional magnetic resonance imaging (fMRI) study; approx-
imately one in two of these could be contacted for further
assessment; and approximately one in two of these proved eligible.
Sixteen healthy AP subjects (13 women and 3 men), age 18.8 ? 1.3
years (range 18–22) with an average education level of 13.4 ? .7
years (range 13–15), and 16 healthy AN subjects (12 women and 4
men), age 18.7 years ? .7 (range 18–20) with an average
education level of 13.5 ? .8 years (range 13–15), were included
in the study.
All subjects underwent a structured diagnostic interview
(SCID; First et al 1997) that was modified to enable us to
document the presence of subthreshold (i.e., not fulfilling full
DSM-IV criteria because of insufficient number of symptoms
and/or below diagnostic threshold for distress and/or interfer-
ence) anxiety and mood disorders. The AP subjects could have a
DSM-IV diagnosis (full or subthreshold) but were not currently
seeking or had ever in the past sought treatment for their anxiety
symptoms. In the AP group, seven subjects had no DSM-IV
diagnosis (six of these subjects had subthreshold generalized
anxiety disorder [GAD] and/or social anxiety disorder [SAD]), five
subjects had GAD only, three subjects had GAD with SAD, and
one subject had GAD, SAD, panic disorder, and obsessive-
compulsive disorder. The AN subjects were those who were
determined to have no DSM-IV disorders, even at the subthresh-
old level. None of the subjects had taken any psychotropic
medications in the prior 12 months. Subjects habitually con-
sumed ? 400 mg of caffeine daily. All subjects gave their
informed written consent and performed an anticipatory anxiety
task during fMRI.
Before scanning, subjects gave a subjective rating of fear of
snakes and spiders with the following two self-ratings (with 7
point Likert scales): “If I saw a snake now, I would feel very
panicky” and “If I came across a spider now, I would leave the
room.” These two items were taken from the Fear of Spiders
Questionnaire (Szymanski and O’Donohue 1995) and the Fear of
Snakes Questionnaire (a modified version of the Fear of Spiders
Questionnaire). In a non-published dataset of 83 college-age
students we found that the scores on these two questions
correlated very highly with the total score on the Fear of Snakes
Questionnaire (r ? .932, p ? .001) and Fear of Spiders Ques-
tionnaire (r ? .913, p ? .001), respectively.
Stimulus and Apparatus
The task (described in detail in Simmons et al 2004) combined
a continuous performance task during fMRI similar to a task
described in a study by Huettel et al (2002) with the intermittent
presentation of aversive affective stimuli (Figure 1). During the
continuous performance task, subjects were asked to press a
LEFT mouse button whenever they saw a circle and a RIGHT
mouse button whenever they saw a square on the screen. Stimuli
were presented at a visual angle of 4° at a rate of .5 Hz.
Simultaneously, a 250-msec 500-Hz tone was presented at a rate
of 2 Hz. Subjects were instructed that during the task the pitch of
the tone would change (from 500 to 1000 Hz) 4–6 sec before the
appearance of a picture of a spider or a snake on the screen.
Thirty images of spiders or snakes that were largely taken from
the International Affective Picture System (Lang et al 1998) were
presented during the duration of the task. The total duration of
the task was 512 sec. Behavioral data were collected and scored
for accuracy and latency of response during the continuous
performance task. No response was required when an image of
a snake, spider, or fixation cross was presented on the screen.
Response accuracy and response latency were obtained for
the continuous performance task during the low tone (baseline),
high tone (anticipation), and post-stimulus (as depicted in Figure 1).
To examine the behavioral effect of anticipation, we examined
the difference between behavioral measures during the low and
During the task, an fMRI run sensitive to blood oxygenation
level-dependent contrast was collected for each subject with a
1.5 Tesla Siemens scanner (T2* weighted echo planar imaging,
repetition time [TR] ? 2000 msec, echo time [TE] ? 40 msec, 64 ?
64 matrix, 20 4-mm axial slices, 256 scans). The fMRI acquisitions
were time-locked to the onset of each trial. During the same
Figure 1. Task time series design visual depiction of task (low and high tone are depicted by yellow and red speakers, respectively) with example of the
A. Simmons et al
BIOL PSYCHIATRY 2006;60:402–409 403
experimental session, a high resolution T1-weighted image
(MPRAGE, TR ? 11.4 msec, TE ? 4.4 msec, flip angle ? 10°, field
of view ? 256 ? 256, 1 mm3voxels) was obtained for anatomical
Three regressors were constructed to quantify the neural
substrates contributing to the different components of the task: 1)
the low tone regressor, measuring the baseline performance
during the processing of the continuous performance task; 2) the
high tone regressor, capturing the anticipatory phase; and 3) the
stimulus regressor, which assesses the processing of aversive visual
stimuli (as depicted in Figure 1). In particular, the difference in
activation between the high tone and the low tone regressors was
interpreted to represent the activation due to anticipation.
Data were preprocessed and analyzed with the Analysis of
Functional NeuroImages software package (Cox 1996). Prepro-
cessed time series data for each individual were analyzed with a
multiple regression model. Regressors of interest included three
task-related regressors described earlier. In addition, five nui-
sance regressors were entered into the linear regression model:
three movement-related regressors used to account for residual
motion (in the roll, pitch, and yaw direction), and regressors for
baseline and linear trends used to eliminate slow signal drifts. A
Gaussian filter with full width at half maximum 6 mm was
applied to the voxel-wise percent signal change data to account
for individual variations in the anatomical landmarks. Data of
each subject were normalized to Talairach coordinates.
Voxel-wise percent signal change data for whole brain were
entered into an independent samples t test for activation (sepa-
rately during anticipation and image presentation) between AP
and AN. A threshold adjustment method on the basis of Monte-
Carlo simulations was used to guard against identifying false
positive areas of activation (Forman et al 1995). A prior voxel-
wise probability of p ? .05 in a cluster of 1024 ?L resulted in an
a-posteriori probability of p ? .05. Finally, the average percent
signal difference was extracted from regions of activation that were
found to survive this threshold/cluster method. All analyses for the
behavioral data were carried out with SPSS 10.0 (Norusis 1990).
To examine the relationship between anticipation and aver-
sive image processing, we correlated the activation magnitudes of
the clustered areas during anticipation with those obtained during
aversive stimulus presentation. Moreover, to examine the relation-
ship between behavioral performance and brain activation, we
correlated response accuracy and latency with activation magnitude
during both anticipation and aversive stimulus presentation.
Activation levels acquired from the functionally defined areas
that result from the whole brain analysis during the anticipation
and image presentation were correlated with response accuracy
and latency data.
The AP individuals did not differ from AN subjects on the
response latency or the ratings on the fear of spiders and fear of
snakes questions (see Table 1 and Figure 2).
fMRI Data: Task-Related Activation Differences
The AP subjects showed greater activation than did AN
subjects during the anticipation phase (i.e., during the high tone
trials relative to the low tone trials) in the right (x ? 42, y ? ?6,
z ? 3) and left insula (x ? ?44, y ? 0, z ? ?2). In comparison,
AN subjects activated more in the right superior/medial frontal
gyri (BA 9; x ? 6, y ? 53, z ? 30) than did the AP individuals
(see Table 2 and Figure 3). There were no differences between
AP and AN subjects during the actual presentation of the aversive
images. However, the right middle temporal gyrus (BA 39;
x ? 49, y ? ?65, z ? 23), right superior temporal gyrus (BA 22;
x ? 46, y ? ?29, z ? 12), left middle temporal gyrus (BA 39; x ?
?39, y ? ?67, z ? 23), and left superior frontal gyrus (BA 10;
x ? ?29, y ? 56, z ? ?3) were more active in the AN than the
AP group during the image presentation phase (Figure 4A and
Table 3). Figures 4B and 4C show the average hemodynamic
responses from these regions and corresponding average hemo-
dynamic responses in the primary visual cortex extracted to
examine whether the groups also differed in visual processing.
Unlike the differences observed in the temporal lobes during
image presentation, however, the percent signal change within
the primary visual cortex was not different between the groups
(Figure 4C), suggesting that basic visual processing was similar
between the two groups.
fMRI Data: Activation by Behavior Correlations
To determine whether neural activation differences between
the groups were associated with behavioral performance, we
extracted percent signal change in anticipation and image pro-
Table 1. Fear of Spider and Fear of Snake Questionnaire Responses and
Behavioral Response Latencies in AN and AP Groups
Fear questionnaire data on a likert scale from 1 (not at all), to 7 (very
much). Response latencies are in milliseconds.
AN, anxiety-normative; AP, anxiety-prone; CPT, continuous perfor-
mance task; Ant, CPT during High Tone (signaling impending onset of
Figure 2. Response time by group and condition. Conditions include con-
tinuous performance task (CPT) and anticipatory phase (CPT ? Tone). AP,
anxiety-prone; AN, anxiety-normative; CPT, continuous performance task.
Table 2. Differences in AN and AP Groups During Anticipation
GroupVolumexyzSideLocationBA t Value
AP ? AN
AN ? AP
AN, anxiety-normative; AP, anxiety-prone.
404 BIOL PSYCHIATRY 2006;60:402–409
A. Simmons et al
cessing phases. There were no correlations between activation
differences and response latency or the ratings on the fear of
spiders and/or fear of snakes questions (data not shown).
fMRI Data: Activation Correlations During Anticipation
and Visual Processing
One approach to evaluating the role of different neural
systems during the processing of anticipation and during visual
processing of aversive stimuli is to examine whether the amount
of activation during anticipation is related to the amount of
activation during visual processing. For example, increased
activation during anticipation might correspond to preparatory
affective or cognitive processes that are aimed at minimizing the
impact of the aversive visual stimulus. Thus, we performed
correlation analyses between the average percent signal changes
in areas that differed across groups, as shown in Table 4. We
found that the positive activation in the bilateral insular cortex
during the anticipation phase correlated significantly with nega-
tive activations (i.e., deactivations) in the temporal and frontal
lobes during the image presentation phase (see Table 4 and
Figure 5). These correlations were significant in the whole group
as well as in the AP and AN groups individually. There was no
correlation between response latency during anticipation and
brain activation during anticipation.
This investigation yielded three main results. First, during the
anticipation phase before the presentation of aversive images, AP
relative to AN subjects showed greater activation in bilateral
insula and less activation in superior/medial frontal gyrus. Sec-
ond, during the actual presentation of the images AN subjects
showed greater activation in the bilateral temporal lobes and left
superior frontal gyrus than AP subjects, but both groups showed
similar activation in the visual cortex. Third, the bilateral tempo-
ral lobe and left superior frontal gyrus activation during the
image presentation phase was inversely correlated with the
bilateral insula activation during the anticipation phase both
within groups and in the combined group. The inverse correla-
tion between activation in the insula during anticipation and
activation in secondary visual areas during image presentation is
consistent with the idea of a neural circuit that is important for
avoidance of unpleasant visual stimuli. Specifically, increased
insula activation during the anticipation phase might attenuate
processing of subsequently presented aversive images.
Lesion studies in both humans and animals support the notion
that the insular cortex is important for affective processing
(Adolphs et al 2000). Therefore, it is not surprising that numerous
imaging studies show activity in this area during presentation of
stimuli associated with high emotional distress (e.g., pain) in
normal subjects (Eisenberger et al 2003; Price 2002) and in-
creased activation across multiple anxiety populations (Rauch
et al 1997). Recent studies also suggest that the insula plays an
important role in anticipation of aversive stimuli; both when
subjects anticipate aversive painful stimuli (Ploghaus et al 1999;
Porro et al 2002) and when they expect the delivery of potentially
aversive visual stimuli (Simmons et al 2004).
Even though insular activation during anticipation of aversive
stimuli would be expected in both groups studied here, higher
insular activation in AP subjects is consistent with other studies in
groups of anxious subjects. For example, phobic individuals
were found to show increased insular cortex activation relative to
non-phobic comparison subjects in paradigms that use pictures
(Dilger et al 2003) or words (Straube et al 2004b) of spider-
related stimuli. Moreover, social phobic individuals showed
Figure 3. Cluster (A) and average percent signal change (B) in bilateral insula and right superior frontal gyrus (R SFG) during anticipation that differs
significantly between the anxiety-prone (AP) and anxiety-normative (AN) groups. The average extracted hemodynamic responses within the insula clusters
are shown (C) where the yellow block indicates anticipation phase. ROI, region of interest; TR, repetition time.
A. Simmons et al
BIOL PSYCHIATRY 2006;60:402–409 405
increased activation to fearful faces in the right insula (Wright et
al 2003) and to angry faces in the bilateral insula (Straube et al
2004a). These and other results of healthy volunteers processing
aversive sensory stimuli (Simmons et al 2004) are consistent with
the notion that insular activity might not only underlie the affective
process of emotional distress in normal and phobic individuals but
might also be involved in the action planning and selection related
to these stimuli (i.e., might mediate phobic behavior).
Furthermore, Critchley et al (2003, 2004) have found strong
and consistent correlations between insula activation and auto-
nomic arousal (e.g., heart rate and heart rate variability), anxiety,
and visceral changes associated with facial emotion processing
(Critchley et al 2005). Aversive physiological reactions are key in
avoidant behavior in the development of phobias (e.g., agora-
phobia) (Langs et al 2000; Starcevic et al 1993). Therefore, it is
reasonable to conclude that the insular cortex provides the
neural substrate that links emotional distress, anticipatory pro-
cessing, and autonomic arousal with action-planning aimed at
reducing exposure to the aversive stimuli. These processes take
place in full and sometimes painful awareness, which is consis-
tent with the role of the insula in mediating self-awareness
(Karnath et al 2005). The area within the insular cortex that
Figure 4. Differential activation between the AP and AN groups during image presentation. (A) The AN had greater activation in the left middle temporal
TR, repetition time.
Table 3. Differences in AN and AP Groups During Image Presentation
GroupVolumexyz SideLocationBAt Value
AP ? AN
AN ? AP
Middle temporal gyrus
Superior temporal gyrus
Middle temporal gyrus
Superior frontal gyrus
AN, anxiety-normative; AP, anxiety-prone.
406 BIOL PSYCHIATRY 2006;60:402–409
A. Simmons et al
differed across groups was more anterior than those areas that
showed common task-related activation. Because AN individuals
did not show significant activation in this area, we hypothesize
that AP subjects recruit a larger and more anterior part of the
insular cortex during anticipation. Taken together, insular hyper-
activity, particularly in the anterior part of this cortical structure,
in AP individuals might reflect an increased self-awareness of
impending aversive stimuli, which is subsequently associated
with attenuated processing of this stimulus by secondary visual
The AN individuals showed greater activation than AP indi-
viduals during the anticipatory period in the superior/medial
frontal gyrus. Several studies have implicated this area in affec-
tive processing (Hutcherson et al 2005; Simpson et al 2001b; Stein
et al 2002). Furthermore, activation in this region was observed
when subjects were rating their own emotions compared with
rating the emotions of others (Ochsner et al 2004) and during
attending to emotions over not attending (Gusnard et al 2001;
Northoff et al 2004; Taylor et al 2003), suggesting that this region
might be important in self-relevant processes (Wicker et al 2003)
such as understanding one’s own affective state (Castelli et al
2000). Activation of this area during anticipation of aversive
stimulation in AN but not AP individuals observed in this study
might indicate that AN subjects have a greater degree of self-
monitoring capacity in this regard, which might be important in
order to properly regulate emotional responsiveness in this
During aversive image presentation we found decreased
activity in AP compared with AN subjects in the areas of temporal
cortex thought to be involved in secondary visual processing.
Studies on visual attention (Beauchamp et al 1997) and visual
working memory, especially imagery (Baddeley 2003), indicate
that this area is important in attending to a visual stimulus. The
medial temporal lobe has been shown to have a direct connec-
tion to visual nodes of the thalamus in primates (Sincich et al
2004) and to down-modulate other visual areas (Friston and
Buchel 2000). Furthermore, lesions near the superior temporal
gyrus (BA 22) result in “spatial neglect”—a failure to explore the
contralateral side of space (Karnath et al 2001). In a recent study,
Paquette et al (2003) examined the effect of cognitive behavioral
therapy on neural responses to images of spiders in subjects with
spider phobias and found increased activation in occipital areas
directly inferior to temporal gyrus areas after treatment, implicat-
ing this regions in avoidance behavior. Although this interpreta-
tion is somewhat speculative, we would expect this area to play
a significant role in avoidance-related processing. Nevertheless,
future studies will need to replicate this finding with other
emotional picture tasks.
Riskind et al (1995) suggest that the fear of spiders actually
involves a perceptual misinterpretation that the spider is aggres-
sively moving toward them and that this fear of imminent danger
is part of a generalizable anxiety syndrome that they discuss as a
“looming maladaptive style.” This looming style is highly corre-
lated with other continuous measures of anxiety as well as
anxiety disorders (Williams et al 2005). This gives a potential
theoretical framework for the reduced temporal response we
observed in AP in our study, which could reflect activity within a
system geared toward avoidance of the imagined aggressive
approach of the image on the screen, similar to the process seen
in phobic individuals by Paquette et al (2003). Furthermore, the
inverse relationship between activity in insular and secondary
visual areas during image presentation found here suggests that
the insula might have a “top-down” modulatory effect, as has
Table 4. Correlation Between Anticipatory Clusters and Image
Anticipation ClusterRMTG RSTGLMTGLSFG
LMTG, left middle temporal gyrus; LSFG, left superior frontal gyrus; RSFG,
right superior frontal gyrus.
ap ? .001.
bp ? .05.
significantly negatively correlated with all areas that showed differential activation between anxiety-prone and anxiety-normative group during image
presentation; two representative correlations are displayed.
A. Simmons et al
BIOL PSYCHIATRY 2006;60:402–409 407
been suggested in prior research (Damasio et al 2000; Rauch et al
This study has several limitations. Primarily, we studied the
behavior of high trait anxious individuals and not clinically
anxiety-disordered or phobic subjects. This means that our
current findings might not extend to individuals with phobic or
anxiety disorders. For example, one might speculate that once a
clinically significant anxiety disorder has developed, different
neural pathways might operate to control the behavioral re-
sponse. However, the study of subjects with high trait anxiety,
some of which might exhibit subsyndromal anxiety disorders,
can give insight into the brain behaviors of those who, because
of their temperament, are prone to the development of anxiety
disorders (Riskind 1997; Riskind et al 1995; Williams et al 2005).
Another limitation is that images of spiders and snakes are not
highly aversive to all individuals. This might decrease both the
emotional and the statistical power of the current study. If more
aversive images were selected, a greater insula response might
be found. We did not examine anticipation to positively valenced
images; thus it is not possible to determine whether the groups
differ in the anticipation of a positive event or of a negative
event, or both.
The focus of this investigation is the neural substrates under-
lying aversive anticipatory processing. Future investigations
might need to include positive and neutral valence images to
examine whether AP individuals show altered modulation of
anticipatory processing as a function of valence. It is important to
note that we did not find differences in the fear ratings between
groups, which supports the idea that the brain pattern differences
do not merely reflect a phobic response by the AP subjects. It is
important to note that the concept of “looming anxiety” does not
necessitate that individuals have greater fear of the object,
instead it poses that individuals have a heightened anxious
reaction when anticipating an approaching aversive stimulus.
The significant neuroimaging differences between groups were
observed in the absence of differences in the behavioral task
data. One reason for this discrepancy, particularly as far as the
response latency data are concerned, could be the repetitive
pacing of the task. Thus, future studies might need to include a
randomized temporal jitter during the continuous performance
task response to better detect response time differences during
anticipation. Because the conditions of interest (anticipation and
stimulus) related in this paper were theorized to be psycholog-
ically related, main effect conditions from two different epochs
were compared. Voxel-based temporally linked correlations that
are commonly used in neuroimaging (Penny et al 2004) are more
appropriate when the conditions are linked neurophysiologi-
cally. Because a less common methodology was used, replication
of these findings is required.
Future studies should look at the activation patterns in patient
populations to see whether greater insula activation is associated
with reduced secondary visual activation in clinical samples (e.g.,
specific phobia, social phobia, posttraumatic stress disorder). It
would also be of critical interest to see if the insula of anxiety-
disordered subjects is differentially affected by psychopharma-
cological interventions that are commonly used to treat anxiety
disorders. The use of multiple anticipation conditions might help
determine to what degree the insula effect is due to the unpleas-
antness of the images versus the impact of anticipation itself. One
approach to examine altered processing of aversive stimuli in
secondary visual areas in AP individuals would be to present
individuals with an approaching threat object via video when
there is no prior information available, which would make
cognitive avoidance difficult.
To summarize, the current findings support the notion that
greater activation of the insula during anticipation of a visual
stimulus might lead to reduced secondary visual processing of
the stimulus and that this process is altered in anxiety prone
subjects. The enhanced anticipatory response in AP subjects
within the insula might lead to reduced engagement of poten-
tially aversive visual stimuli, evident from reduced activity in
areas of visual attention. These findings are the first step to
uncover a cognitive/affective process and neural circuitry for
formation/maintenance of phobic reactions in individuals who
are prone to the development of anxiety disorders.
This work was supported by grants from National Institute of
Mental Health (MH65413, MBS), support from the Veterans
Administration via Merit grants (to MPP and MBS), and a
National Institutes of Health training grant (5T32MH18399, to
ANS and SCM).
We would like to acknowledge the invaluable help of Shadha
Hami, Kelly Winternheimer, and Thuy Le.
Adolphs R, Damasio H, Tranel D, Cooper G, Damasio AR (2000): A role for
by three-dimensional lesion mapping. J Neurosci 20:2683–2690.
Augustine JR (1996): Circuitry and functional aspects of the insular lobe in
Baddeley A (2003): Working memory: Looking back and looking forward.
Beauchamp MS, Cox RW, DeYoe EA (1997): Graded effects of spatial and
areas. J Neurophysiol 78:516–520.
Bradley BP, Mogg K, Lee SC (1997): Attentional biases for negative informa-
tion in induced and naturally occurring dysphoria. Behav Res Ther 35:
Buchel C, Morris J, Dolan RJ, Friston KJ (1998): Brain systems mediating
imaging study of perception and interpretation of complex intentional
movement patterns. Neuroimage 12:314–325.
of anticipatory anxiety. Neuroimage 9:563–571.
Cox RW (1996): AFNI: Software for analysis and visualization of functional
magnetic resonance neuroimages. Comput Biomed Res 29:162–173.
relating to uncertainty and arousal during anticipation. Neuron 29:537–
Critchley HD, Mathias CJ, Josephs O, O’Doherty J, Zanini S, Dewar BK, et al
(2003): Human cingulate cortex and autonomic control: Converging
neuroimaging and clinical evidence. Brain 126:2139–2152.
Activity in the human brain predicting differential heart rate responses
to emotional facial expressions. Neuroimage 24:751–762.
Critchley HD, Wiens S, Rotshtein P, Ohman A, Dolan RJ (2004): Neural sys-
tems supporting interoceptive awareness. Nat Neurosci 7:189–195.
Damasio AR, Grabowski TJ, Bechara A, Damasio H, Ponto LL, Parvizi J, et al
(2000): Subcortical and cortical brain activity during the feeling of self-
generated emotions. Nat Neurosci 3:1049–1056.
Dilger S, Straube T, Mentzel HJ, Fitzek C, Reichenbach JR, Hecht H, et al
(2003): Brain activation to phobia-related pictures in spider phobic hu-
mans: An event-related functional magnetic resonance imaging study.
Eisenberger NI, Lieberman MD, Williams KD (2003): Does rejection hurt? An
FMRI study of social exclusion. Science 302:290–292.
Eysenck MW (1997): Anxiety and Cognition: A Unified Theory Hove, United
Kingdom: Psychology Press.
view for DSM-IV Axis I Disorders - Clinician Version (SCID-1). Washington
DC: American Psychiatric Press.
408 BIOL PSYCHIATRY 2006;60:402–409
A. Simmons et al
Forman SD, Cohen JD, Fitzgerald M, Eddy WF, Mintun MA, Noll DC (1995):
Improved assessment of significant activation in functional magnetic
resonance imaging (fMRI): Use of a cluster-size threshold. Magn Reson
Gelnar PA, Krauss BR, Sheehe PR, Szeverenyi NM, Apkarian AV (1999): A
comparative fMRI study of cortical representations for thermal painful,
vibrotactile, and motor performance tasks. Neuroimage 10:460–482.
Gorno-Tempini ML, Pradelli S, Serafini M, Pagnoni G, Baraldi P, Porro C, et al
(2001): Explicit and incidental facial expression processing: An fMRI
study. Neuroimage 14:465–473.
Gusnard DA, Akbudak E, Shulman GL, Raichle ME (2001): Medial prefrontal
cortex and self-referential mental activity: Relation to a default mode of
Huettel SA, Mack PB, McCarthy G (2002): Perceiving patterns in random
series: Dynamic processing of sequence in prefrontal cortex. Nat Neuro-
Hutcherson CA, Goldin PR, Ochsner KN, Gabrieli JD, Barrett LF, Gross JJ
(2005): Attention and emotion: Does rating emotion alter neural re-
sponses to amusing and sad films? Neuroimage 27:656–668.
Karnath HO, Baier B, Nagele T (2005): Awareness of the functioning of one’s
own limbs mediated by the insular cortex? J Neurosci 25:7134–7138.
of the temporal not the posterior parietal lobe. Nature 411:950–953.
of irrational fears and phobias in men. Arch Gen Psychiatry 58:257–265.
ing affective perception. J Clin Neurophysiol 15:397–408.
Langs G, Quehenberger F, Fabisch K, Klug G, Fabisch H, Zapotoczky HG
(2000): The development of agoraphobia in panic disorder: A predict-
facial expressions. Brain 121:47–57.
et al (2004): Reflecting upon feelings: An fMRI study of neural systems
supporting the attribution of emotion to self and other. J Cogn Neurosci
Ost LG (1987): Age of onset in different phobias. J Abnorm Psychol 96:
Paquette V, Levesque J, Mensour B, Leroux JM, Beaudoin G, Bourgouin P,
et al (2003): “Change the mind and you change the brain”: Effects of
Paulus MP, Feinstein JS, Castillo G, Simmons AN, Stein MB (2005): Dose-
dependent decrease of activation in bilateral amygdala and insula by
lorazepam during emotion processing. Arch Gen Psychiatry 62:282–288.
Paulus MP, Rogalsky C, Simmons A, Feinstein JS, Stein MB (2003): Increased
activation in the right insula during risk-taking decision making is re-
lated to harm avoidance and neuroticism. Neuroimage 19:1439–1448.
Penny WD, Stephan KE, Mechelli A, Friston KJ (2004): Comparing dynamic
causal models. Neuroimage 22:1157–1172.
Peyron R, Laurent B, Garcia-Larrea L (2000): Functional imaging of brain
responses to pain. A review and meta-analysis (2000). Neurophysiol Clin
Phan KL, Wager T, Taylor SF, Liberzon I (2002): Functional neuroanatomy of
Phillips ML, Young AW, Scott SK, Calder AJ, Andrew C, Giampietro V, et al
(1998): Neural responses to facial and vocal expressions of fear and
Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS, Matthews PM, et al (1999):
Dissociating pain from its anticipation in the human brain. Science 284:
Does anticipation of pain affect cortical nociceptive systems? J Neurosci
Price DD (2002): Central neural mechanisms that interrelate sensory and
affective dimensions of pain. Mol Interv 2:392–403.
Rauch SL, Savage CR, Alpert NM, Fischman AJ, Jenike MA (1997): The func-
tional neuroanatomy of anxiety: A study of three disorders using
Riskind JH, Moore R, Bowley L (1995): The looming of spiders: The fearful
perceptual distortion of movement and menace. Behav Res Ther 33:
Sawamoto N, Honda M, Okada T, Hanakawa T, Kanda M, Fukuyama H, et al
(2000): Expectation of pain enhances responses to nonpainful somato-
lum/posterior insula: An event-related functional magnetic resonance
imaging study. J Neurosci 20:7438–7445.
tionally aversive visual stimuli activates right insula. Neuroreport 15:
Simpson JR Jr., Drevets WC, Snyder AZ, Gusnard DA, Raichle ME (2001a):
Simpson JR Jr., Snyder AZ, Gusnard DA, Raichle ME (2001b): Emotion-in-
duced changes in human medial prefrontal cortex: I. During cognitive
Sincich LC, Park KF, Wohlgemuth MJ, Horton JC (2004): Bypassing V1: A
direct geniculate input to area MT. Nat Neurosci 7:1123–1128.
Speilberger CD (1983): Manual for State-Trait Anxiety Inventory Palo Alto,
California: Consulting Psychologists Press.
Starcevic V, Kellner R, Uhlenhuth EH, Pathak D (1993): The phenomenology
dala activation to angry and contemptuous faces in generalized social
Straube T, Mentzel HJ, Glauer M, Miltner WH (2004b): Brain activation to
phobia-related words in phobic subjects. Neurosci Lett 372:204–208.
Szymanski J, O’Donohue W (1995): Fear of Spiders Questionnaire. J Behav
Taylor SF, Phan KL, Decker LR, Liberzon I (2003): Subjective rating of emo-
tionally salient stimuli modulates neural activity. Neuroimage 18:650–
Tillfors M, Furmark T, Marteinsdottir I, Fredrikson M (2002): Cerebral blood
Wright CI, Martis B, McMullin K, Shin LM, Rauch SL (2003): Amygdala and
insular responses to emotionally valenced human faces in small animal
specific phobia. Biol Psychiatry 54:1067–1076.
A. Simmons et al
BIOL PSYCHIATRY 2006;60:402–409 409