Neural activity associated with monitoring the
oscillating threat value of a tarantula
Dean Mobbs
a,1
, Rongjun Yu
a
, James B. Rowe
a,b
, Hannah Eich
a
, Oriel FeldmanHall
a
, and Tim Dalgleish
a
a
Cognition and Brain Sciences Unit, Medical Research Council-Cognition and Brain Sciences Unit, Cambridge CB2 7EF, United Kingdom; and
b
Department of
Clinical Neurosciences, University of Cambridge, Cambridge CB2 2QQ, United Kingdom
Edited by Edward E. Smith, Columbia University, New York, NY, and approved October 13, 2010 (received for review June 24, 2010)
Phylogenetic threats such as spiders evoke our deepest primitive
fears. When close or looming, such threats engage evolutionarily
conserved monitoring systems and defense reactions that promote
self-preservation. With the use of a modi
fi
ed behavioral approach
task within functional MRI, we show that, as a tarantula was placed
closer to a subject
’
s foot, increased experiences of fear coincided
with augmented activity in a cascade of fear-related brain networks
includingthe periaqueductal gray, amygdala,andbed nucleus ofthe
stria terminalis. Activity in the amygdala was also associated with
underprediction of the tarantula
’
s threat value and, in addition to
the bed nucleus of the stria terminalis, with monitoring the taran-
tula
’
s threat value as indexed by its direction of movement. Con-
versely, the orbitofrontal cortex was engaged as the tarantula grew
more distant, suggesting that this region emits safety signals or
expels fear. Our
fi
ndings fractionate the neurobiological mecha-
nisms associated with basic fear and potentially illuminate the per-
turbed reactions that characterize clinical phobias.
expectancy errors
|
imminence
|
distance
E
volutionary pressures have selected for mechanisms that en-
courage the avoidance of close or looming threat (1
–
3). In
humans, this innate capacity is particularly evident with phyloge-
netic threats such as spiders, which rate among the most ubiqui-
tous of phobias (4). For example, in everyday life it is common to
experience a primal surge of terror when a spider crawls within our
personal space, yet we may observe a distant spider without trepi-
dation. In the clinical setting, behavioral approach tasks are used
to expose phobic patients to phobogenic stimuli (e.g., spiders or
snakes) at varying distances to evaluate and treat their fear re-
sponses. Such approaching threats elicit precipitous increases in
subjective fear and autonomic arousal (5, 6), which are charac-
teristics of the exaggerated emotional responses observed in
phobic subjects.
Research in rodents has shown that encountering a distant or
close natural predator (e.g., a cat) evokes distinct defense reac-
tions in the form of behavioral quiescence and vigorous
fl
ight,
respectively (7). In humans, functional neuroimaging has begun
to reveal the brain networks implicated in such situations of
immediate danger. One study showed that the active avoidance
of an arti
fi
cial predator with the ability to chase, capture, and in-
fl
ict pain resulted in brain activity switching from ventromedial
prefrontal cortex to the midbrain, including the periaqueductal
gray (PAG), as the threat became more imminent (8). Two recent
studies have also shown that tracking the increasing proximity of
a shock stimulus is associated with activity in the bed nucleus
of the stria terminalis (BNST), a region highly connected to the
amygdala (9), whereas courage associated with self-administered
movement of a snake toward the subject
’
s own head increases
activating the ventromedial prefrontal cortex (10). These studies
point to an anatomical network involved in the monitoring of
threat, the instigation of defensive reactions, and overcoming fear
(2, 11
–
13).
An outstanding issue not addressed in previous studies (e.g., ref.
9) is the extent to which different aspects of threat monitoring
linked to this brain network can be fractionated, in particular,
whether there is a critical distinction between threat proximity and
whether the threat level is on an escalating or descending trajec-
tory. For example, a close threat moving away from us is liable to
elicit a different response to an equally close threat moving toward
us. Two further unexplored questions include what neural sub-
strates are involved in monitoring any mismatch between threat/
fear expectations and actual threat/fear
—
a crucial mechanism
calibrating how the system deals with anticipated aversive events to
ensure that such predictions are accurate. Finally, to our knowl-
edge, no studies using phylogenetic threats have examined habit-
uation of the fear system over time and whether greater fear of
spiders results in sustained activation in core fear areas such as
the midbrain.
In the present study, we used functional MRI (fMRI) in
conjunction with a modi
fi
ed behavioral approach task to exam-
ine brain activation associated with these two putative functions
of the human fear network as healthy participants viewed a ta-
rantula spider being placed at varying distances from their foot.
When in the MRI scanner bore, participants placed their foot
into a custom-built
“
imminence box
”
containing six compart-
ments separated by sliding partitions (Fig. 1
A
). Via a video feed,
participants watched a live and active tarantula (
Lasiodora par-
ahybana
;
Fig. S1
A
) placed randomly into
fi
ve of these compart-
ments at distances of 1 to 18 cm, 19 to 36 cm, 37 to 54 cm, 55 to
72 cm, and 73 to 90 cm from their foot (
Fig. S1
B
and
C
). Un-
beknownst to participants, they were actually viewing pre-
recorded
fi
lms of the spider in the different compartments, which
were controlled for the movement of the spider (
SI Experimental
Procedures
). Each experimental trial commenced with viewing
a schematic representation of the imminence box indicating
which compartment the tarantula would enter next. Participants
then used a visual analog scale (VAS) to predict how afraid they
would feel when subsequently viewing the tarantula in the in-
dicated compartment (i.e., expected fear). The participants next
saw the tarantula in the compartment and directly after, rated
how afraid they felt (i.e., experienced fear;
Fig. S2
). A strength of
this behavioral approach task is the fact that the absolute prox-
imity of the phobogenic threat can be decoupled from its tra-
jectory, i.e., whether it is coming closer or moving away, thus
making this methodology an ideal test bed for exploring these
different components of threat.
With the use of this paradigm, we pursued two primary hy-
potheses:
fi
rst, increased proximity of the tarantula would in-
crease subjective fear ratings and progressively invoke the brain
’
s
fear network, including the midbrain PAG, amygdala, BNST,
striatum, and insula (8, 11), after controlling for whether the ta-
Author contributions: D.M., J.B.R., and T.D. designed research; D.M., R.Y., H.E., and O.F.
performed research; D.M. and R.Y. analyzed data; and D.M. and T.D. wrote the paper.
The authors declare no con
fl
ict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.
1
To whom correspondence should be addressed. E-mail: dmobbs@gmail.com.
This article contains supporting information online at
www.pnas.org/lookup/suppl/doi:10.
1073/pnas.1009076107/-/DCSupplemental
.
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rantula was approaching or retreating. Second, because the amyg-
dala and BNST have been implicated in
fi
ltering and monitoring
emotionally relevant information (9, 14), we hypothesized that,
irrespective of absolute distance, activity in these regions would
differentiate the tarantula
’
s approach versus retreat.
A further potentially important function of the fear-based
threat processing network is to index when events turn out to be
more threatening or fear-inducing than anticipated, not only
because such events may require the rapid deployment of addi-
tional processing resources, but because such mismatches would
need to be registered to calibrate the threat prediction system
over time. Inspired by the work of Gray and McNaughton (15),
Rachman
’
s match/mismatch theory (16), and attentional theories
of amygdala function (17, 18), we took advantage of the current
methodology to also explore whether subject-speci
fi
c differences
in the degree of expectancy errors (i.e., the underprediction of
the fear response to the tarantula) would be mediated by any
elements of the fear network, in particular the amygdala.
Results
How the Human Brain Responds to Absolute Proximity of the Tarantula.
We
fi
rst examined fear response as a function of the tarantula
’
s
absolute proximity, controlling for whether the tarantula was ap-
proaching or retreating. VAS-experienced fear ratings were pro-
gressively higher with increased proximity (Fig. 1
C
;repeated-
measures ANOVA,
F
1.8
= 20.5;
P
= 0.0001, Greenhouse
–
Geisser
corrected for nonsphericity). VAS-experienced fear also correlated
with mean Fear of Spider Questionnaire (FSQ) ratings (Spearman
r
, 0.405;
P
<
0.038). For the brain imaging data, we computed the
difference between the two nearest compartments and two most
distant compartments from the participant
’
s foot: (compartment
5+compartment4)
−
(compartment 1 + compartment 2). Sup-
porting our hypothesis, for this contrast indexing increased prox-
imity, we observed augmented activity in the bilateral amygdala,
midbrain PAG, ventral striatum, BNST, bilateral anterior insula,
and dorsal anterior cingulate cortex [dACC; all
P
<
0.05, family-
wise error (FWE) small volume corrected (svc) using independent
coordinates]. For the reverse contrast, we found increased activity
in the orbitomedial prefrontal cortex (omPFC;
Table S1
).
To further quantify the effect of spider proximity, we conducted
a parametric regression analysis. As the tarantula was placed
closer to the participant
’
s foot (using compartments 1
–
5as
parametric weights), we again observed increased activity in the
bilateral insula, BNST, dACC, ventral striatum, and midbrain
(Fig. 2
A
). With increased tarantula distance, increased activity in
omPFC and posterior cingulate cortex was observed (Fig. 2
B
and
Table S2
). The degree of increase in midbrain PAG activity with
greater proximity was also positively correlated with subject-spe-
ci
fi
c scores on the FSQ (19) and with ratings of the tarantula being
scarier than anticipated (
Tables S3
and
S4
).
Monitoring Approach Versus Retreat of the Tarantula.
We next in-
vestigated the effects of an approaching or looming spider by
comparing trials wherein the tarantula was approaching versus
retreating from the foot, relative to the previous trial, and irre-
spective of absolute proximity. For example, for compartment 3, we
compared approach to retreat by contrasting those trials in which
the previous trial position was 1 or 2 compartments further from
the foot (i.e., compartments 1 or 2) versus trials in which the pre-
vious position was 1 or 2 compartments closer to the foot (i.e.,
compartments 4 or 5; Fig. 3
A
). Independent of absolute proximity,
experienced fear ratings were signi
fi
cantly higher when the taran-
tula approached versus retreated (Wilcoxon Z,
−
0.3;
P
= 0.005), as
was activity in the right amygdala, bilateral BNST, ventral striatum,
and bilateral insula (Fig. 3
B
). These regions remained signi
fi
cantly
activated after covarying out subject-speci
fi
c FSQ scores (which
correlated with the approach minus retreat contrast;
r
=0.523;
P
=
0.009;
Table S5
) and suggest that the amygdala and BNST keep
track of the aversive value of the tarantula via its direction of move-
ment, independent of how close it is.
Expectancy Errors: Subject-Speci
fi
c Differences in Underestimating
the Fear Value of the Tarantula.
We
fi
nally explored the neural
substrates of individual tendencies to underestimate how much
fear was actually experienced when viewing the tarantula at dif-
ferent proximities (i.e., the degree to which fear on seeing the
tarantula exceeded expectations). As with experienced fear
scores, expected fear VAS ratings increased with greater prox-
imity (Fig. 1
B
;F
1.3
= 44.5;
P
= 0.0001, Greenhouse
–
Geisser
corrected) after controlling for tarantula approach/retreat. We
also found that postscan ratings of how much scarier the spider
was than expected correlated with how large subjects estimated
the tarantula to be (
r
= 0.413;
P
= 0.035). Expectancy errors
—
the
amount that fear was actually underestimated (calculated by
subtracting expected fear ratings from experienced fear reports
(16, 19)
—
were positively correlated with FSQ scores (
r
= 0.564;
P
= 0.005), a
fi
nding closely allied with theories from clinical
research (20
–
22). The brain imaging data showed that greater
subject-speci
fi
c differences in expectancy errors correlated with
greater left amygdala, ventral striatum, and right insula activation.
The left amygdala association remained signi
fi
cant after covarying
out experienced fear ratings, suggesting that it is independent of
the degree of fear experienced when viewing the spider (Fig. 4
A
).
Moreover, this left amygdala relationship was still signi
fi
cant after
covarying out FSQ scores (Fig. 4
B
), supporting the idea that the
activity associated with underestimating one
’
s fear responses is
not driven by a general fear of spiders (
Table S6
).
Habituation Effects over the Course of the Experiment.
To exam-
ine habituation effects over the course of the experiment, we
Fig. 1.
Experimental paradigm and key behavioral results. (
A
) Participants
were placed supine on the MRI scanner bed and asked to position their foot
with the shoe removed into the open-topped imminence box. Participants
believed that, via a camera feed, they could observe the experimenter
moving the tarantula closer or further away from their foot in real time. The
subjects
’
tasks were to predict how afraid they believed they would feel (i.e.,
expected fear) when the spider was placed in a compartment previously
indicated to them and then how scared they actually felt (i.e., experienced
fear) when viewing the tarantula in that compartment. Mean group ratings
for expected fear (
B
) and experienced fear (
C
) as a function of tarantula
proximity.
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divided the experimental session into four time bins and examined
the decreases in fear system response over time. Each time bin, 1
through 4, was used as a parametric weight. Trials across each
time bin were matched for spider distance, thus permitting an
independent analysis of the effects of time. The brain imaging data
showed a general decrease in activity in the fear network including
the midbrain PAG, amygdala, insula, and ventral medial PFC (Fig.
5and
Table S8
). Conversely, medial PFC activity increased over
the course of the experiment (
Table S8
). Subjective ratings of
expected fear decreased over time to a greater extent than expe-
rienced fear ratings, thus leading to a mean increase in expectancy
errors with time (
Fig. S3
A
). We found that subject-speci
fi
cdif-
ferences in this increase in expectancy errors correlated with
augmented amygdala activity over time (
Fig. S3
B
), mirroring the
previous analysis of expectancy errors (Fig. 3
B
and
C
). We
fi
nally
examined whether habituating activation would be attenuated in
any elements of the fear circuitry by a greater general fear of
spiders (e.g., FSQ scores). We found that higher subject-speci
fi
c
FSQ scores were correlated with relatively sustained activation
encompassing the midbrain PAG (
Fig. S3
C
).
Discussion
The ubiquitous nature of arachnophobia suggests such fear is
shaped by our evolutionary history (19) and that spiders are
therefore a potent stimulus with which to interrogate the func-
tioning of the human fear network. As a result of the intense
nature of our study, we used subjects with medium to low fear of
spiders. Nevertheless, we clearly demonstrate that perceived
greater proximity of a live tarantula is associated with both
marked subjective fear and pronounced activation in a network of
interconnected brain circuitry (11), including the amygdala,
BNST, insula, striatum, and midbrain PAG
—
regions implicated
in responses to intense fear-evoking events and
fi
tness-promoting
expressions of fear (2, 11, 12). Moreover, our results suggest that
the amygdala and BNST play a key role in monitoring whether the
threat value of the tarantula is on an escalating versus descending
trajectory, as indexed by its direction of movement. Finally, the
amygdala may augment attention toward the tarantula when the
subject underestimated their expected fear levels, supporting
mismatch theories of fear (22).
How the Fear Circuitry Responds to the Close and Distant Tarantula.
A prodigious amount of research suggests that the midbrain
PAG is the centerpiece of intense fear and hard-wired threat
reactions (2, 8, 13). In the present investigation, midbrain PAG
activation was associated with greater tarantula proximity and
positively correlated with elevated trait fear of spiders (FSQ
scores), suggesting this region comes online when the perceived
threat is more extreme. Although no studies have explored the
role of the PAG in ecologically valid phylogenetic fears, the
current study compares favorably with research showing that
stimulation of human PAG results in extreme expressions of fear
and panic (23). Despite overall habituation of the fear circuitry
(Fig. 5 and
Table S7
), midbrain PAG activation in the current
study remained relatively sustained over the course of the ex-
periment in those subjects with elevated fear of spiders (e.g.,
higher FSQ scores;
Fig S4
C
and
Table S9
). Together, our
fi
nd-
ings suggest that the PAG may be involved in the exaggerated
fear observed in phobic subjects and that such fear levels are
associated with mitigation of habituation effects.
In contrast to the circuitry activated by tarantula proximity, the
omPFC was increasingly active as a function of the tarantula
’
s
increased distance. The omPFC projections to the PAG are
believed to form a pathway involved in passive coping (e.g.,
Fig. 2.
(
A
) Parametric increases and decreases in BOLD signal.
Increased proximity was associated with activity in the mid-
brain PAG (4,
−
30,
−
24;
P
<
0.028, svc) and dACC (28, 36, 24;
P
<
0.001, whole-brain corrected). (
B
) Increased spider dis-
tance was associated with a parametric increase in activity in
the omPFC (
−
6, 54,
−
16;
P
<
0.016, svc).
Fig. 3.
Brain activity for the retreat minus approach contrast. (
A
)Anex-
ample of how approach/retreat was quanti
fi
ed. BOLD signal was taken from,
for example, compartment three depending on whether the tarantula had
moved forward or backward from a previous compartment. Independent of
any distance effects, the (
B
) amygdala (14,
−
2,
−
16;
P
<
0.024, svc) and BNST
(right, 12, 0,
−
4;
P
<
0.027, svc; left,
−
12, 4,
−
4;
P
<
0.014, svc) were differ-
entially more active for approach versus retreat of the tarantula.
Fig. 4.
Subject-speci
fi
c differences in expectancy errors and amygdala ac-
tivity. (
A
) Increased amygdala activity (
−
20, 0,
−
18;
P
<
0.043, svc) associated
with more marked under-prediction of forthcoming fear experience and (
B
)
activity in the amygdala associated with under-prediction of fear after
covarying ratings of experienced fear (
−
26,
−
6, 18;
P
<
0.004, svc).
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Mobbs et al.
freezing) associated with contextually distant threat, which
prompts the inhibition of motor behavior and down-regulation of
autonomic arousal (24). Ablation of the nonhuman primate and
squirrel omPFC homologues reduces fear reactivity to phyloge-
netic threats (25, 26). In human arachnophobic subjects, habit-
uated fear to spider pictures has been associated with augmented
omPFC activity (27). Conceptually, the omPFC may function to
simply suppress primitive fear responses (28), thereby permitting
strategic adaptive behaviors when danger is at a safe distance.
Monitoring the Tarantula
’
s Movements.
A number of forebrain
components of this fear network, most notably the amygdala,
BNST, insula, and striatum, were selectively more active when
threat levels were on an escalating trajectory, as indexed by com-
paring tarantula approach versus retreat, irrespective of absolute
distance. In an early study, it was shown that rhesus monkeys re-
spond to such approaching or
“
looming
”
objects with fear (1) and
recent evidence has shown that looming sounds activate the hu-
man amygdala (29), suggesting that the brain is primed to perceive
looming as a warning signal. With its intricate connections, the
amygdala is perfectly situated to code the oscillating value of ex-
ternal threat and for surveying the sensory landscape for potential
danger (30). Indeed, similar mechanisms have been observed in
both nonhuman and human primates in which the amygdala keeps
track of appetitive (14) and social stimuli (31). Intriguingly, theo-
rists have argued that forward movement (i.e., looming) magni
fi
es
the sense of danger and this is be magni
fi
ed in phobic subjects,
leading to distortions in threat magnitude (32).
Several observations of interest have been made concerning
the BNST. The BNST is strongly connected to the central nu-
cleus of the amygdala and is believed to act as a relay center for
coordinating motor, autonomic, and defense reaction (33). Re-
cently, the BNST has been implicated in monitoring signals
representing escalating threat levels in the environment (9, 17,
34). Although the literature is limited, the BNST has also been
implicated in phobia. For instance, one study conducted on
spider-phobic subjects showed marked activity in the BNST
during the anticipation of spiders in pictures. Despite not using
real spiders, this study suggests that spider-phobic subjects are
hyper-vigilant to the spider
’
s imminent presence (35). These
accumulated
fi
ndings suggest that the amygdala and BNST keep
track of escalating threat levels, independent of threat proximity,
and signaled in a variety of ways including by direction of
threat movement.
Individual Differences in Underestimating the Fear Value of the
Tarantula.
In line with consistency (36) and match/mismatch (20)
theories, we observed greater amygdala activity when the taran-
tula elicited fear that exceeded participants
’
prior expectations
(i.e., expectancy errors). Although correlational, and thus pre-
liminary, these results are consistent with prior evidence that
phobic subjects exhibit larger fear responses when fear is under-
estimated (20). Registering situations in which threat is dispro-
portionate to one
’
s predictions is clearly important in terms of the
processing resources allocated to the threat and for longer-term
calibration of threat-prediction algorithms. Indeed, theorists posit
that such mismatches drive the organism into
“
control mode
”
(15), which engenders elevated attention, avoidance, and anxiety
toward the threat
—
operations believed to be dependent on the
amygdala (2, 37). Intriguingly, greater expectancy errors were also
correlated with increased misperception of the size of the taran-
tula. This suggests one mechanism by which fear mediates the
cognitive biases surrounding threat that are exhibited by phobic
subjects (38).
Conclusions.
Our results provide direct evidence of how the human
brain monitors and responds to changing proximity of phylogenetic
threat. The
fi
ndings con
fi
rm that phylogenetic threats activate
similar fear pathways to ontogenetic threats (e.g., shocks) (8),
showing a cascade of fear systems that extend from the omPFC to
the midbrain PAG. Consistent with theoretical models, we show
that the amygdala and BNST are sensitive to escalation of threat
levels in terms of the tarantula
’
s direction of movement, in-
dependent of proximity. The amygdala was also active to the mag-
nitudeofexpectancy errors,thussupportingtheroleofthisregionin
coordinating responses to unexpected threat (2, 20). Identifying
how the brain responds to changing intensities of phylogenetic
threat may be one fertile source of understanding the exaggerated
fear observed in speci
fi
cphobicsubjects.
Experimental Procedures
Participants.
Twenty-
fi
ve healthy nonphobic volunteers took part in
the study. Subjects were rejected if they had any history of neu-
rological damage or psychiatric disorder. After the MRI scan,
fi
ve
participants were excluded as they expressed reservations about
whether the study was genuinely in real time during debrie
fi
ng.
This left 20 participants (10 female; mean age, 25.8
±
3.7 y). Trait
anxiety was measured using the Spielberger questionnaire, with
a mean score of 40
±
9.9. These scores are comparable to the
published norms for this age group mean (36
±
10) (39). Subjects
were remunerated £30 for time, travel, and inconvenience. All
subjects gave informed consent, and the study was approved by the
Essex Research Ethics Committee (United Kingdom).
Spider Stimuli Creation and Validation.
We recorded footage of
a Brazilian salmon pink tarantula (body size, 22 cm length
×
15 cm
width;
Fig. S1
A
) being placed in each compartment of the im-
minence box. Video clips were edited to 4 s and a border was
added to the footage to decontextualize the environment. Sixty
black-and-white 4-s
fi
lm clips of the tarantula were then presented
in the study (12 in each compartment of the imminence box).
Each
fi
lm was prerated for movement of the tarantula on a four-
point scale: 1, no movement; 2, very little movement (
<
25% of the
time); 3, movement 25% to 50% of the time; and 4, movement
50% to 100% of the time. Ratings were made by 10 independent
observers. No signi
fi
cant differences were found between com-
partments (
P
>
0.05).
There was also no signi
fi
cant relationship between participants
’
experienced fear ratings and movement (
r
= 0.211,
P
= 0.105). In
addition, we tested to see if the direction the spider was facing
(toward versus away from the foot) in
fl
uenced fear ratings. We
found no signi
fi
cant correlation between the tarantula
’
s angle of
orientation to the foot, from 0° to 180°, and fear ratings (
P
>
0.05).
Finally, mindful of likely habituation effects, we pseudorandom-
ized the presentation of the tarantula in each box so as to not
correlate distance from time (Pearson correlation,
P
<
0.495).
Image Acquisition.
MRI scanning was conducted at the Medical
Research Council Cognition and Brain Sciences Unit on a 3-T
Tim Trio MRI scanner (Siemens) by using a head coil gradient
set. Whole-brain data were acquired with echoplanar T2*-
weighted imaging [i.e., echoplanar imaging (EPI)], sensitive to
blood oxygen level-dependent (BOLD) signal contrast (48 sag-
Fig. 5.
Habituation analysis. Coronal slices moving anterior from the mid-
brain to the PFC. Blue clusters indicate signi
fi
cantly decreased activity over
the course of the experiment in the PAG (12,
−
32,
−
14;
P
<
0.029, svc) and
amygdala (
−
24,
−
2,
−
14;
P
<
0.029, svc).
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ittal slices, 3-mm thickness; repetition time, 2,400 ms; echo time,
30 ms;
fl
ip angle, 78°;
fi
eld of view, 192 mm; voxel size, 3
×
3
×
3
mm). To provide for equilibration effects, the
fi
rst
fi
ve volumes
were discarded. T1-weighted structural images were acquired at
a resolution of 1
×
1
×
1 mm.
Image Preprocessing.
SPM5 software (
www.
fi
l.ion.ucl.ac.uk/spm/
)
was used for data analysis. The echoplaner imaging (EPI) images
were sinc interpolated in time for correction of slice timing dif-
ferences and realignment to the
fi
rst scan by rigid body trans-
formations to correct for head movements. For each participant,
the mean EPI was calculated and examined to guarantee that none
exhibited excessive signal dropout in insula and ventral striatum.
Using linear and nonlinear transformations, and smoothing with
a Gaussian kernel of full-width-half-maximum 8 mm, EPI and
structural images were coregistered and normalized to the T1
standard template in Montreal Neurological Institute (MNI)
space (International Consortium for Brain Mapping). Moreover,
global changes were removed by proportional scaling, and high-
pass temporal
fi
ltering with a cutoff of 128 s was used to remove
low-frequency drifts in signal.
Statistical Analysis.
After preprocessing, statistical analysis was
performed by using the general linear model. Our regression
matrix included the cue periods (1 s), both expectancy (8 s) and
outcome VAS (8 s) time periods, and the 4-s period when the
spider was shown in the relevant box. Analysis was carried out to
establish each participant
’
s voxel-wise activation during the 4-s
presentation of the spider. Activated voxels in each experimental
context were identi
fi
ed using an event-related statistical model
representing each of the experimental contexts, convolved with
a canonical hemodynamic response function and mean-corrected.
Six head-motion parameters de
fi
ned by the realignment were
added to the model as regressors of no interest. Multiple linear
regression was then run to generate parameter estimates for each
regressor at every voxel. For group analysis, a random-effects
model was used with a small volume correction for FWE within
a priori regions of interest (ROIs) including the amygdala, BNST,
medial orbital frontal cortex, and midbrain PAG. Outside of these
ROIs, we also present results at
P
<
0.05, FWE corrected for
whole-brain multiple spatial comparisons. When false negative
results at these corrected thresholds would be of particular rele-
vance, we also provide results at the exploratory uncorrected
threshold
P
<
0.001 (
SI Experimental Procedures
).
Questionnaires.
Following the MRI scan, participants were asked
to complete the FSQ (40). These mean FSQ scores were in
medium to low ranges (mean
±
SD, 30.7
±
18.4; range, 14
–
86.1).
Overall, this mean score is signi
fi
cantly lower than that of di-
agnosed arachnophobic subjects (89.1
±
19.6) (41). Subjects were
also asked to rate how much scarier than expected the spider
was. We also asked subjects to complete a memory for tarantula
size test to rate how large they thought the tarantula was by using
fi
ve different sizes of the spider printed on an A3 sheet of paper
(
Fig. S4
). This was administered between 45 and 60 min after
the experiment.
ACKNOWLEDGMENTS.
We thank Simon Strangeways, Mark Townsend, and
Gary Chandler for creation of hardware and help with data acquisition. We
also thank Ray Dolan and Chris Frith for advice and Jay Wood of the Spider
Diaries (
www.thespiderdiaries.co.uk
). This work was funded by the UK Med-
ical Research Council and Wellcome Trust Grant 077029 (to J.B.R.).
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