Christopher S. Monk
Christian Grillon
Johanna M. P. Baas
Erin B. McClure
Eric E. Nelson
Mood and Anxiety Disorders Program
National Institute of Mental Health
National Institutes of Health
Department of Health and Human Services
Bethesda, MD 20892
E-mail: [email protected]
Eric Zarahn
Department of Psychiatry
Columbia University
New York, New York 10032
Dennis S. Charney
Monique Ernst
Daniel S. Pine
Mood and Anxiety Disorders Program
National Institute of Mental Health
National Institutes of Health
Department of Health and Human Services
Bethesda, MD 20892
A Neuroimaging Method for the
Study of Threat in Adolescents
ABSTRACT: Little is understood about the brain basis of anxiety, particularly
among youth. However, threat paradigms with animals are delineating the
relationship between anxietylike behaviors and brain function. We adapted a
threat paradigm for adolescents using functional magnetic resonance imaging. The
aim was to examine amygdala activation to fear. The threat was an aversive air
blast directed to the larynx. Participants were explicitly informed that they might
receive the air blast when viewing one stimulus (threat condition) and would not
receive the blast when viewing the other stimulus (safe condition). Participants
provided fear ratings immediately after each trial. Based on the relatively mild
nature of the air blast, we expected participants to report varying degrees of fear.
Those who reported increased fear showed right amygdala activation during the
threat condition and left amygdala activation in the safe condition. These
procedures offer a promising tool for studying youth with anxiety disorders.
ß 2003 Wiley Periodicals, Inc. Dev Psychobiol 43: 359–366, 2003.
Keywords: functional magnetic resonance imaging; fMRI; amygdala; fear;
anxiety
Despite their high prevalence and associated risk for later
debilitating psychopathology, very little is understood
about the neurobiology of adolescent anxiety disorders.
However, using threat paradigms, animal research provides an effective pathophysiological model for fear and
anxietylike behaviors (Hitchcock & Davis, 1986; Lee &
Davis, 1997; Morgan & LeDoux, 1995; Timms, 1977). In
a typical threat paradigm, a rat is placed in a context in
Received 10 March 2003; Accepted 24 June 2003
Correspondence to: C. S. Monk, 15K North Drive, Room 204, MSC
2670, Bethesda, MD 20892–2670.
Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/dev.10146
ß 2003 Wiley Periodicals, Inc.
which a shock is anticipated. Shock anticipation leads to a
number of physiological and behavioral signs of fear
such as freezing (Morgan & LeDoux, 1995; Morgan,
Romanski, & LeDoux, 1993) and increased startle
(Hitchcock & Davis, 1986). Work in animals with such
paradigms most consistently implicates the amygdala in
this fear response (Campeau et al., 1991; Hitchcock &
Davis, 1986). Because such fear behaviors may relate to
anxiety symptoms in humans (Fowles, 1980; Grillon,
Dierker, & Merikangas, 1998; Kagan, Reznick, &
Snidman, 1988), methods for inducing and monitoring
fear in a controlled laboratory environment may reveal
psychological and neurophysiological processes associated with anxiety disorders.
In an effort to measure comparable behaviors across
species, threat paradigms have been adapted for use with
humans (Grillon, Ameli, Merikangas, Woods, & Davis,
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Monk et al.
1993; Grillon, Ameli, Woods, Merikangas, & Davis,
1991). Threat paradigms are excellent candidates for
cross-species research because the startle response increases in humans as they anticipate an aversive shock,
much like it does in rodents (Hamm & Vaitl, 1996; Lipp,
Sheridan, & Siddle, 1994). Such a translational approach
permits the relatively well-specified models of anxietylike
behaviors in animals to inform perspectives on comparable behaviors in humans with anxiety disorders. Indeed,
startle threat paradigms differentiate between participants
with and without anxiety disorders (Grillon, Falls, Ameli,
& Davis, 1994; Grillon & Morgan, 1999; Grillon, Morgan,
Davis, & Southwick, 1998).
Given that most anxiety disorders in adults have strong
antecedents in childhood (Pine, Cohen, Gurley, Brook, &
Ma, 1998), it is vital to extend such research to pediatric
populations. This will facilitate examination across
development of the relationship between anxiety and
associated neurophysiology. Furthermore, a developmental approach might reveal factors that predict differential
risk for chronic impairment or health in later life.
However, highly anxiogenic stimuli such as shock may
not be ethically permissible for use with children.
Moreover, such stimuli may not be optimal for differentiating anxious and healthy individuals because they
may elicit strong fear in both patients and controls. If
anxiety disorders involve experiencing fear in situations
that are only mildly challenging to healthy individuals,
utilizing a milder stressor may offer advantages in
evaluating the symptoms of interest.
In a study with adults, patients with panic disorder and
healthy controls showed similar anxiety levels during
shock anticipation (Grillon, Ameli, Goddard, Woods, &
Davis, 1994). However, in the same study, the milder
contextual fear from participating in a stressful experiment differentiated the two groups (Grillon, Ameli, et al.,
1994). Similar results have been reported with patients
with posttraumatic stress disorder (Grillon, Ameli, et al.,
1994). These findings indicate that shock anticipation
may not reveal large differences between anxious and
nonanxious individuals. Finally, in a longitudinal study
of healthy children and adolescents over a 3-year
period, younger subjects were more fearful on a range
of issues relative to older subjects, and the fear levels
diminished with age (Gullone, King, & Ollendick, 2001).
Therefore, a milder stressor may be more appropriate for
examining healthy adolescents and those with anxiety
disorders.
As a less anxiogenic unconditioned stimulus for
children, investigators have used a strong blast of air to
the larynx (Grillon & Ameli, 1998; Grillon et al., 1999).
Grillon et al. (1999) used this procedure with adolescents
in a multisite study and found consistent startle potentiation in the threat-of-air-blast condition. Furthermore,
adolescents at risk for anxiety disorders were shown to
display larger startle responses than healthy adolescents
with this procedure (Grillon, Dierker, & Merikangas,
1997, 1998).
Relative to startle, neuroimaging methods provide a
means for more directly evaluating neural structures
involved in fear processing in humans. Existing neuroimaging research on healthy humans often employs facial
expressions to elicit fear. Many of these studies focus on
the relation between amygdala activation and fear-related
stimuli. In particular, the presentation of fearful faces to
healthy individuals is associated with increased amygdala
engagement (Breiter et al., 1996; Hariri, Bookheimer,
& Mazziotta, 2000; Morris et al., 1998; Morris et al.,
1996). In children and adolescents, presentation of fearful
faces has been shown to produce increased activation
in the amygdala (Baird et al., 1999; Killgore, Oki, &
Yurgelun-Todd, 2001; Monk et al., 2003; Thomas,
Drevets, Whalen, et al., 2001).
In individuals with anxiety disorders, previous imaging
studies implicate alterations in amygdala activation when
fear-triggering stimuli that are relevant to the disorder are
presented (Birbaumer et al., 1998; Fredrikson, Fischer, &
Wik, 1997; Fredrikson, Wik, Annas, Ericson, & StoneElander, 1995; Furmark et al., 2002; Rauch et al., 1995;
Tillfors et al., 2001). Consistent with these findings,
the one imaging study to examine anxious children
revealed greater amygdala activation in those with
generalized anxiety or panic disorders, relative to healthy
children (Thomas, Drevets, Dahl, et al., 2001). However,
while these findings demonstrate that fear-provoking
paradigms engage analogous brain structures in humans
and animals, the procedures utilized in the neuroimaging
studies are not comparable to those used in the animal
work. This complicates efforts to generate cross-species
comparisons.
Two recent neuroimaging studies with humans developed paradigms that more closely approximate fear
provocation procedures in animals. Phelps et al. (2001)
informed subjects that they might receive a shock when
they viewed one stimulus (threat condition), but would
definitely not be given a shock when they viewed a
different stimulus (safe condition). The authors reported
activation in the left amygdala to the threat relative to the
safe condition. Similarly, in an effort to develop a fearconditioning paradigm that utilizes a milder stressor than
shock, one of us (Pine et al., 2001) repeatedly paired an air
blast to the larynx with a visual stimulus in adult healthy
participants. A region-of-interest analysis showed increased amygdala activation among adults to the conditioned stimulus relative to the stimulus that was not paired
with the air blast. Such findings demonstrate that fear
paradigms adapted for neuroimaging with humans have
the capacity to elicit activation of the amygdala, a struc-
A Neuroimaging Method for the Study of Threat
ture that the animal work suggests is involved in fear
processing.
Because the air blast poses a milder threat than shock,
this aversive stimulus may be a particularly useful tool for
differentiating between healthy adolescents and those
with anxiety disorders. To establish the methodological
reliability of this approach, we studied the threat of airblast procedure with a sample of healthy adolescents using
functional magnetic resonance imaging (fMRI). Based on
the relatively mild nature of the air blast, we anticipated
variations across participants in subjective fear to the
threat of the air blast. We investigated whether participants who reported experiencing fear would show
amygdala activation.
METHODS
Subjects
Fifteen adolescents were scanned with a 3 Tesla scanner. Of the
15 adolescents who completed the MRI scanning session, 1 subject produced unacceptable movement (i.e., movement that was
greater than 3 mm along the x, y, or z planes). Adolescents
(7 females, 7 males) were between the ages of 10 and 17 years
(M ¼ 14.9, SD ¼ 2.3). The age range among females was 10 to 17
(M ¼ 14.57 years, SD ¼ 2.76); among males it was 12 to 17
(M ¼ 15.14 years, SD ¼ 1.77). All participants had age-adjusted
IQs greater than 70 (M ¼ 112.1, SD ¼ 11.8) as determined by the
Wechsler Abbreviated Scale of Intelligence (WASI; Wechsler
1999). In addition, all participants were determined to be healthy
based on a physical and a standardized, structured psychiatric
interview (Kaufman et al., 1997).
Procedures
Participants were acclimated to the MRI environment with an
MRI simulator. Before the scanning began, participants were
informed that they would view blue and green squares presented
sequentially. Half of the participants were told that they might
receive a blast of air to the larynx while viewing the blue square
(threat condition) and that they would never receive such a blast
when they viewed the green screen (safe condition). The other
half was told that the blue square represented the safe condition
and the green square was for the threat condition. Before participants were positioned in the MRI, they were given a sample
blast of air to the larynx. After they were placed in the MRI
and immediately before the task began, the experimenter reviewed the procedures with the participants and reminded them
which colored square was associated with the threat and safe
conditions.
The procedures for the air blast followed the work of one of us
(Grillon et al., 1999). The apparatus used for producing the blast
of air consisted of a compressed air cylinder, a regulator, and a
solenoid that received a signal from the task computer. These
items were placed in the control room adjacent to the MRI. A
tube was connected to the regulator, passed through the wave
361
guide, and placed approximately 1 cm from the larynx of each
participant. The duration of the blast was 10 ms, and the intensity
of the air blast was designed to be 60 psi, comparable to Grillon
et al. (1999).
The fMRI task consisted of 17 trials. Randomly intermixed
among these 17 trials were nine threat trials and eight safe trials.
In the third threat trial, a blast of air was delivered to the larynx at
the offset of the colored square. This trial was not included in the
analysis. The blast of air was delivered only once due to concerns that the aversive stimulus might induce movement. This
left eight threat trials and eight safe trials for inclusion in the
analysis.
As in other studies of threat or fear conditioning, duration of
trials varied from 25 to 39 s. The colored square was presented
for 10 s, followed by a 4-s fixation. After fixation, the visual
display system presented the following question: ‘‘How afraid
were you?’’ on a 1 to 5 scale. During training, participants
were instructed to indicate how afraid they had felt while they
had been viewing the square moments earlier. The fear-rating
screen was presented for 4 s. Following this, there was an
intertrial interval with a fixation that was presented for 7 to 21 s.
Such variability of the intertrial interval serves to decrease
expectancy of the onset of the subsequent trial. Stimuli were
displayed on the Avotec Silent Vision Glasses (Stuart, FL),
and the five-key button box was developed by MRI Devices
(Waukesha, WI).
Imaging and Data Analysis
Imaging acquisition was performed on a General Electric Signa
3 Tesla scanner. We acquired a sagittal localizer scan to orient
subsequent scans. For functional imaging scans, we used a series
of 23 contiguous, 5-mm axial slices covering the entire brain,
parallel to the AC–PC. The scans employed an echo-planar
single-shot gradient echo T2 weighting (TR ¼ 2000 ms, TE ¼
40 ms, FOV ¼ 240 mm; 64 64 matrix, 3.75-mm voxels). In
addition, high-resolution T1-weighted volumetric scans used a
magnetization prepared gradient echo sequence (MP-RAGE)
[180 1.0-mm sagittal slices; FOV ¼ 256 mm, NEX ¼ 1, TR ¼
11.4 ms, TE ¼ 4.4 ms; matrix ¼ 256 256; TI ¼ 300 ms,
bandwidth 130 Hz/pixel ¼33 kHz for 256 pixels in-plane
resolution ¼ 1 mm3].
Functional imaging data were analyzed using SPM
(SPM99b, Wellcome Department of Neurology, London,
England) (Frackowiak, Friston, Frith, Dolan, & Mazziotta,
1997) with an event-related model. In addition, other routines
were implemented with Matlab 5.3 from Mathworks (Natick,
MA). For anatomical definitions of the amygdala, we followed
established procedures (Szeszko et al., 1999). Functional data
were corrected for slice timing and motion, coregistered to the
anatomical data, aligned to the first volume for each participant,
spatially normalized to a Montreal Neurological Institute (MNI)
T1-weighted template image supplied with SPM99, and smoothed with an 8-mm full width at half-maximum Gaussian kernel.
Within-subject time series modeling accounted for threat as well
as safe conditions, fear rating period, and intertrial interval (rest).
In each condition, the fMRI response to each event type was
modeled as a rectangular pulse convolved with the hemodynamic response function specified in SPM99 (default para-
362
Monk et al.
meters). For each participant, we generated contrast images for
the pairwise comparison of the mean BOLD signal for each
condition. Brains were intensity normalized and smoothed at
11.4 full-width half-maximum.
For the group-level analysis, the data were subjected to a
random effects model to provide population-level inference
(Holmes & Friston, 1998). The model was comprised of all 14
adolescents, and there were 12 df. The analysis focused on the
amygdala, and we used a Bonferroni correction for multiple
comparisons across the small volume (Worsley et al., 1996).
We report activations that survived a Gaussian random field
threshold of p < 0.05 with small volume correction performed in
SPM99.
RESULTS
Behavioral Results
The mean rating for fear was 1.92 (SD ¼ .79) to the threat
condition and 1.05 (SD ¼ .14) to the safe condition,
t(13) ¼ 4.45, p < .002. Since the purpose of this study was
to better understand the relationship between fear and
amygdala engagement, we focused the analyses on those
who reported increased fear to the threat stimulus (fearful
group). A participant was selected for the fearful group
if the individual reported increased fear to the threat
stimulus in more than half of the threat trials. This yielded
8 participants for the fearful group and 6 participants for
the no fear or minimally fearful group. The fearful group
was comprised of 5 females and 3 males with an age range
of 10 to 17 years (M ¼ 14.25, SD ¼ 2.60); the not fearful/
minimally fearful group had 2 females and 4 males with an
age range of 14 to 17 years (M age ¼ 15.67, SD ¼ 1.51).
The mean rating of fear for the fearful group was 2.52
(SD ¼ .51) to the threat condition and 1.08 (SD ¼ .18) for
the safe condition. Of the other 6 participants who
reported less fear, only 2 reported any increase in fear to
the threat stimulus, and this increase was minimal. The
mean rating of fear for those who reported no fear or
minimal fear was 1.18 (SD ¼ .28) to the threat condition
and 1.02 (SD ¼ .05) for the safe condition.
fMRI Results
Within the fearful group, the contrast of the threat condition relative to rest revealed activation in the right
amygdala (Table 1, Figure 1). Furthermore, the contrast of
the safe condition compared to rest showed left amygdala
activation (Table 1, Figure 2). No significant differences in
amygdala activation were found in the group with no or
minimal fear even when the p value was relaxed to 0.2.
In addition, no significant differences emerged in direct
comparisons of the fearful versus no or minimally fearful
groups. However, this comparison possesses limited
statistical power due to small sample sizes. Therefore,
an exploratory analysis was carried out to further evaluate
the amygdala engagement between the fearful and no or
minimally fearful groups. The unsmoothed voxel activation for each participant from the contrast of the threat and
rest conditions was evaluated by group with a t test. The
voxel (30 6 22) that was evaluated was the same one
that was found to be significant in the analysis of the
fearful participants alone. However, the t test was not
protected for the multiple comparisons within the amygdala. These exploratory procedures revealed that the
fearful group showed greater right amygdala activation
relative to the no or minimally fearful group, t(12) ¼ 2.20,
p < 0.05. Figure 3 presents a scatter plot of amygdala
activation separated by the fearful and no or minimal fear
groups.
While the threat and safe conditions were conceptualized as both containing emotional content, we performed
a direct comparison of the threat relative to the safe
conditions among the fearful participants to more closely
approximate the work of Phelps et al. (2001). In this
exploratory analysis, a 3-mm sphere correction was placed around the location of peak activation in the right
amygdala from the threat minus rest contrast (voxel
coordinate ¼ 30 6 22), and a significant effect was
found, t(12) ¼ 2.03, p < 0.05. Furthermore, this same
contrast did not approach significance in the left
amygdala. Finally, no gender or age effects were found
for amygdala activation in the threat condition.
Table 1. fMRI Activation Among Adolescents Who Reported Increased Fear to the
Threat Condition. Coordinates are Reported in Montreal Neurological Institute Space
(Collins et al., 1998)
Contrast
Threat minus Rest
Safe minus Rest
ROI ¼ region of interest.
ROI
xyz
Cluster Size
p Corrected
t
Right amygdala
Left amygdala
30 6 22
14 2 16
71
220
.045
.015
2.34
3.48
A Neuroimaging Method for the Study of Threat
363
FIGURE 1 Comparison of the Threat minus Rest for
participants with higher fear ratings. The image depicts
activation in the right amygdala ( p < .05 corrected for the
region of interest).
FIGURE 2 Comparison of the Safe minus Rest for subjects
with higher fear ratings. Activation in the left amygdala is
significant ( p < .05 corrected for the region of interest).
DISCUSSION
The overarching objective of this work is to develop
a neuroimaging task that is appropriate for studying
juveniles with anxiety disorders. These procedures successfully identified a subgroup of participants who reported experiencing elevated fear; these participants
had differential amygdala engagement to the threat
and safe stimuli. Nevertheless, the increase in fear, even
among those who reported it, was mild. This may carry
advantages in terms of the tolerability of this procedure for
pediatric clinical populations. People with anxiety disorders have been shown to exhibit greater subjective fear
The purpose of this study was to determine whether subjective fear related to engagement of the amygdala.
Participants who reported fear in response to threat
revealed activation in the right amygdala during the threat
condition. In addition, these participants engaged the left
amygdala during the safe condition. In contrast, adolescents who reported no or minimal fear during the threat
presentation did not show amygdala engagement to the
threat or safe conditions.
FIGURE 3 Individual participant right amygdala voxel (30 6 22) activation for the threat
condition relative to rest separated by those who reported increased fear and those who reported no fear
or minimal fear in the threat condition. As in the group analysis, the individual participant activation is
reported as the contrast value, which is derived from the coefficent for threat minus the coefficient
for rest.
364
Monk et al.
levels to threats (Klein & Pine, 2002; Pine et al., 2000),
raising concerns about tolerability of more extreme
threats. Thus, even though it is anticipated that anxious
adolescents will find the threat of the air blast more
frightening than the fearful participants in the present
study, this approach is expected to still be tolerable.
The results of this study also are relevant to findings on
laterality effects of affective processing. Evidence from
electrophysiology, neuroimaging, and neuropsychology
indicates that positively valenced stimuli are associated
with processing in the left hemisphere and negatively
valenced stimuli are implicated in processing in the right
hemisphere (Canli, Desmond, Zhao, Glover, & Gabrieli,
1998; Davidson, Ekman, Saron, Senulis, & Friesen, 1990;
Sackeim et al., 1982). Enhanced activation of the left
amygdala is related to winning in a game, and right
amygdala engagement is linked to losing (Zalla et al.,
2000). In addition, the degree of left amygdala activation
to happy faces is associated with the personality trait of
extroversion (Canli, Sivers, Whitfield, Gotlib, & Gabrieli,
2002). Finally, in a recent developmental study, adolescents showed activation in the right amygdala in response
to negatively valenced stimuli, fearful faces (Monk et al.,
2003).
Investigations of clinical disorders also suggest that
right amygdala activation may relate to negative affect.
Posttraumatic stress disorder and social phobia are associated with enhanced right amygdala activation relative to
that seen in healthy controls in emotionally engaging tasks
(Rauch et al., 1996; Tillfors et al., 2001). Among a group
of depressed adults, resting metabolic rate in the right
amygdala is positively correlated with negative affect
(Abercrombie et al., 1998). Finally, in a study of children
with generalized anxiety or panic disorder, those with
anxiety showed greater right amygdala activation compared to healthy children (Thomas, Drevets, Dahl, et al.,
2001).
However, these laterality findings in the amygdala
from healthy participants and patients with mood and
anxiety disorders are not entirely consistent (Birbaumer
et al., 1998; Blair, Morris, Frith, Perrett, & Dolan, 1999;
Hariri et al., 2000; Sheline et al., 2001; Thomas, Drevets,
Whalen, et al., 2001). Indeed, as described earlier, threat
of shock was associated with increased left amygdala
activation among healthy adults (Phelps et al., 2001). This
suggests that differences in the procedures may account
for the disparity in the results between the present work
and that of Phelps et al. For example, differences in
participants’ ages across the two studies may account for
differences in laterality. Indeed, since pronounced differences in the neurophysiological processing of emotional
information have been documented between adolescents
and adults (Monk et al., 2003; Thomas, Drevets, Whalen,
et al., 2001), one might expect threat tasks to recruit
different neural structures in different age groups. In
addition, it is possible that threat of a puff of air and threat
of shock may be processed differently at a neuroanatomical level. While these stimuli are conceptualized as
differing only in degree of aversiveness, the threat of these
stimuli may differ qualitatively. The findings in the present study also are inconsistent with some neuroimaging
studies using emotional facial expressions with adults.
Across a range of procedures, such studies often document bilateral amygdala activation in response to negative
emotional expressions (Baird et al., 1999; Hariri et al.,
2000; Pessoa, McKenna, Gutierrez, & Ungerleider, 2002;
Phillips et al., 2001). However, other studies reported left
amygdala activation to negative facial expressions (Blair
et al., 1999; Iidaka et al., 2001; Thomas, Drevets, Whalen,
et al., 2001). Thus, while the amygdala appears to be
engaged during the presentation of affective information, specialization of the left and right amygdalae is not
certain.
In summary, these procedures offer a tool to examine
neural circuits engaged in the processing of fear among
adolescents. Those who reported experiencing fear showed increased right amygdala activation to the threat
stimulus and increased left amygdala activation to the safe
stimulus. Since these procedures induced only moderate
fear in healthy adolescents, it is likely that anxious
adolescents will tolerate them. In addition to using these
procedures to examine adolescents with anxiety disorders,
an important direction for future research will be to extend
this work to populations at high risk for anxiety disorders,
but who are not currently presenting symptoms. Such
work may help uncover how changes in neural function at
adolescence relate to both healthy development and risk
for psychopathology.
NOTES
We thank K. Towbin and A. Zametkin for medical oversight,
and H. Iwamoto, J. Ebron, A. Hoberman, A. Merikangas, L. A.
Montgomery, and S. Munson for technical support.
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