Amygdala Response to Fearful Faces

in Anxious and Depressed Children

Kathleen M. Thomas, PhD; Wayne C. Drevets, MD; Ronald E. Dahl, MD; Neal D. Ryan, MD; Boris Birmaher,
MD; Clayton H. Eccard; David Axelson, MD; Paul J. Whalen, PhD; B. J. Casey, PhD

pared with 5 anxious and 5 healthy girls from the

Background: Alterations in amygdala function have pre-vious sample.
been implicated in the pathophysiological
characteristics of adult anxiety and depressive Results: Children with anxiety disorders showed an ex-
disorders. Studies with healthy adults and children, as aggerated amygdala response to fearful faces compared
well as with adults who have amygdala lesions, have with healthy children, whereas depressed children
found facial expressions of emotion to be useful probes showed a blunted amygdala response to these faces. In
of amygdala activity. Our study examined the amygdala addition, the magnitude of the amygdalas signal change
response to fearful and neu-tral facial expressions in between fearful and neutral faces was positively
healthy, anxious, and de-pressed children. We correlated with the severity of everyday anxiety
hypothesized that children with anxiety and depression symptoms.
may show atypical amygdala re-sponses to emotional
stimuli. Conclusions: Our results suggest that amygdala func-
tion is affected in both anxiety and depression during
Methods: Twelve children (8-16 years of age) with childhood and adolescence. Moreover, this disruption
gen-eralized anxiety or panic disorder and 12 healthy ap-pears to be specific to the childs own rating of
com-parison children underwent noninvasive functional everyday anxiety.
mag-netic resonance imaging while viewing
photographs of fearful and neutral facial expressions. In
a second com-parison, 5 girls with major depressive Arch Gen Psychiatry. 2001;58:1057-1063
disorder were com-

studies of anxiety and depression. 15,16

Adults with social phobia show in-

T
creased bilateral amygdala responses to
faces judged by healthy controls to be af-
HE AMYGDALA and its
are thought to re-lated structures
play a key role in
evalu-ating the emotional
signifi-cance of sensory and so-
fectively neutral.17 Hyperreactivity of the
cial stimuli. 1,2
Stimulation of the amygdala has been observed in adults
From the Sackler Institute
amygdala produces autonomic reactions with posttraumatic stress disorder
for Developmental
Psychobiology, Department associated with the fight or flight (PTSD) in re-sponse to reminders of
of Psychiatry, Weill Medical response, includ-ing increased heart rate traumatic events18,19 and to general
College of Cornell and blood pres-sure, freezing behavior in negative stimuli.20,21 Fi-nally, positron
University, New York, NY animals, feel-ings of fear and anxiety in emission tomography (PET) studies of
(Drs Thomas and Casey and humans, and increased plasma stress
depressed adults report an elevated
Mr Eccard); the Mood and hormone lev-els.2-4 Human resting blood flow and glu-cose
Anxiety Disorders neuroimaging studies have shown that
Neuroimaging Section, amygdala activity increases during metabolism in the amygdala that
correlate positively with depression se-
National Institute of Mental exposure to fear conditioned5,6 and other
Health, Bethesda, Md emotionally valenced stimuli.7-11 In verity.22,23
(Dr Drevets); the
contrast, amygdala lesions result in di- One common probe of human
Department of Psychiatry,
University of Pittsburgh,
minished fear reactions in animals 12,13 amyg-dala function has been facial
Pittsburgh, Pa (Drs Drevets, and an impaired recognition of negative expressions of emotion. Results from
Dahl, Ryan, Birmaher, and fa-cial expressions, particularly fearful several func-tional neuroimaging studies
Axelson); and the ex-pressions, in humans.14 have sug-gested that in healthy adults,
Departments of Psychiatry Abnormal amygdala function has the amyg-dala responds more strongly to
and Psychology, University been implicated in adult neuroimaging fearful faces than to other expressions
of Wisconsin, Madison such as neutral or happy faces. 6,9-11,24,25
(Dr Whalen). This pattern of ac-
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block design, and object assembly subtests of the Wech-sler
SUBJECTS AND METHODS Intelligence Scale for ChildrenThird Edition (WISC-III), 36
the 12 handedness items from the Revised Physical and
SUBJECTS Neurological Examination for Soft Signs (PANESS)
Inventory,37 the Tanner Scales of Pubertal Development, 38
Two pediatric patient groups and healthy comparison groups and the Screen for Child Anxiety Related Emotional Dis-
participated. Twelve children and adolescents (meanSD, orders (SCARED).39,40 The SCARED is a 41-item parent
12.82.1 years; range, 8-16 years; 7 boys, 5 girls) who met report and child self-report instrument. It consists of 5
DSM-IV34 criteria for GAD (n=11) and/or panic disorder (n=2) factors that parallel the DSM-IV classification of anxiety
were compared with 12 healthy children (meanSD, 12.12.6 disorders: somatic/panic, generalized anxiety, separation
years; range, 8-15 years; 7 boys, 5 girls), some of whose data anxiety, social phobia, and school phobia. This measure was
were reported previously.32 In a second com-parison, 5 girls used to assess the severity of the anxiety symptoms.
Exclusionary criteria for all participants included (1) a
(meanSD, 12.32.7 years; range, 8-16 years) with DSM-IV positive urine screen for cigarette, alcohol, or illicit drug
diagnoses of major depressive disor-der (MDD) were use; (2) the use or presence of medication with central
compared with the previously studied healthy girls and girls nervous system effects within the prior 2 weeks; (3) the
with anxiety disorders. All subjects were right-handed. Groups presence of a significant medical or neurological illness;
were similar in pubertal devel-opment (range, Tanner stage 1/1 (4) extreme obesity (weight 150% of the subjects ideal
to 5/5 for anxious and de-pressed children and 1/1 to 5/4 for body weight) or growth failure (height or weight the third
healthy children) and estimated IQ (meanSD, 12416 for percentile for the childs age); (5) an IQ lower than 80; (6)
anxious subjects, 12712 for depressed subjects, and 13714 anorexia nervosa, autism, or schizophrenia by DSM-IV
for healthy subjects). One child with GAD had comorbid social criteria; (7) GAD chronologically secondary to conduct
pho-bia. Two children with MDD had comorbid GAD. disorder; (8) specific learning disabilities; (9) a current
Children with anxiety or depression were recruited from diagnosis of PTSD; or (10) any contraindication for an
the Child and Adolescent Anxiety and Depression Pro-gram of MRI.
the Western Psychiatric Institute and Clinic, Uni-versity of The study was approved by the institutional review
Pittsburgh, Pittsburgh, Pa. Children were evalu-ated by trained board of the University of Pittsburgh Medical Center. Writ-
research physicians blind to the subjects clinical status and ten parental consent and child assent were acquired prior to
with the supervision of child psychia-trists using a modified the study, and subjects were compensated $50 for their
version of the Schedule for Affec-tive Disorders and participation in the MRI portion of the study.
Schizophrenia for School-Age Children Present and Lifetime
Version (K-SADS-PL)35 with the participation of both the child PROCEDURES
and parent(s). A psychia-trist then heard the case to confirm the
presence of a psy-chiatric disorder. Healthy control children Stimuli and Task
were required to have a low familial risk for depression as
The task consisted of the rapid (1 Hz) and successive pre-
defined by the absence of any current or past psychiatric
disorders, no first-degree relatives with mood or psychotic
sentation of a standard photographic set of faces 41 in blocks
of neutral and emotional expressions. A total of 8 different
disorders, no sec-ond-degree relatives with childhood-onset
actors (4 men, 4 women) demonstrating both fearful and
recurrent psy-chotic or bipolar depression, schizoaffective neutral expressions were used ( Figure 1). Hair was stripped
disorder, or schizophrenic disorder, and no more than 20% of from the images to remove any nonfa-cial features, and
second-degree relatives with a single episode of major both fear and exaggerated fear poses were used for each
depression. All children were screened using the vocabulary, actor.42 Facial stimuli were presented
digit span,

ety disorder (GAD), suggesting that amygdala

tivity is generally lateralized, with a greater amygdala abnormali-ties may be associated with childhood-onset
re-sponse in the left hemisphere than in the right for as well as adult anxiety disorders.30 However, few
stan-dard face presentations. However, when the facial functional imaging stud-ies have examined amygdala
expressions are masked so that the initial emotion is not responses in children. Baird et al31 found that healthy
consciously perceived, the right amygdala shows adolescents showed bilateral amygdala activity in
greater activity than the left.6,10,25 This unconscious response to unmasked fearful faces when compared
amygdala re-sponse to fearful vs happy faces has been with neutral nonface scrambled images. Recently we
shown to be enhanced in adults with PTSD. 21 In reported that although children exhibited amygdala
addition, adults with amygdala lesions exhibit deficits increases with fearful faces compared with a non-face
in the ability to recog-nize certain facial expressions, baseline stimulus, they actually showed less amyg-dala
especially fear.14,26-29 activity with fearful faces than with neutral faces.32 The
There is an increasing recognition of the impor- implications of this continued development in the
tance of understanding mechanistic changes in emo- processing and understanding of facial expressions are
tional processing that are evident early in the develop- not entirely clear but have been attributed to ambiguity
ment of anxiety and depression, in ways that may in the emotional significance of a neutral face. 32,33 In
ultimately lead to more effective early interventions. A our study, we use fearful and neutral facial expressions
recent ana-tomical magnetic resonance imaging (MRI) to examine amygdala responsiveness in children with
study ob-served an increased volume of the right anxi-ety and depression, keeping in mind that the
amygdala but not of other brain regions in children with normal pat-
generalized anxi-
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for 200 milliseconds followed by an 800-millisecond in- fromtheanalysisbecauseofexcessivemovement( 0.5voxels).
terstimulus interval containing a flashing central asterisk Individual structural and functional images were cross-
(fixation point). In each behavioral run, a block of fixa-tion registered with a representative subjects brain, smoothed (8-
trials was presented for 45 seconds followed by alter-nating mm full width at half-maximum kernel), and pooled across
42-second blocks of either neutral or fearful expres-sions subjects to improve the signal-to-noise ratio. Resulting group
and a final 45-second epoch of fixation. This procedure was data were transformed into Talairach space for comparison with
repeated in 3 runs of trials with the presentation or-der previous functional imaging studies.
counterbalanced across runs and across subjects (ie, F-N-F-
N-F or N-F-N-F-N, where F indicates fearful ex-pressions STATISTICAL ANALYSES
and N indicates neutral expressions). No overt response was
required. Subjects were instructed to fixate centrally and to Voxelwise diagnosis condition analyses of variance (ANOVAs)
try to get an overall sense of the faces. 11,32 The stimulus were conducted on pooled functional MRI data for all voxels in the
parameters and task design were specifically selected to acquired slices using normalized signal intensity as the dependent
replicate previous studies of the amygdala re-sponse to variable. Statistical maps of F ra-tios for each voxel were
facial expressions. calculated using a cluster-size algo-rithm45 that takes into account
the spatial extent of activation to correct for multiple comparisons.
MRI Methods Significant activations were defined by at least 3 contiguous voxels
Structural and functional MRI scans were acquired on a 1.5 (120 mm3) and =.05.
Tesla General Electric (Milwaukee, Wis) Signa scanner with Separateanalyseswereconductedcomparinganxious and healthy
anAdvancedNMR(Wilmington,Mass)systemforecho-planar children (n=12 per group) and anxious, healthy,
imaging(EPI)andaquadratureheadcoil. AT1-weightedsag-ittal anddepressedgirls(n=5pergroup)acrosspairsofconditions (fearful vs
localizer image was used to identify the position of the head neutral faces, fearful faces vs fixation, and neutral faces vs
and to prescribe the subsequent slice locations (repeti-tion time fixation). Post-hoc Tukey Honestly Significant Dif-
[TR], 400 milliseconds; echo time [TE], 25 milli-seconds; 15 ferencetestswereusedtoidentifysignificantmeandifferences among
groups and within interaction effects. Amygdala ac-tivation was
slices; thickness, 5 mm; spacing, 2.5 mm; field
ofview[FOV],200mm;matrix,256 256pixels).T1-weighted confirmed on a reference brain using standard atlases 43,46 and
structural images were acquired in 4-mm contiguous coro-nal consensus among 3 raters (B.J.C., K.M.T., and P.J.W.). Significant
slices across the whole brain (TR, 500 milliseconds; TE, 14 activations extending outside the brain or with large standard
milliseconds; matrix, 256 256 pixels; FOV, 200 mm) for deviations were excluded. Discussion was limited to significant
purposesoflocalizingthefunctionalactivityandaligningim-ages to activation in mesotemporal brain regions given the implication of
a reference brain. Functional images (T2*-weighted) were these structures in previous neuroimaging studies of facial
acquired at 12 of these slice locations (approximately A20 to expressions of emotion.10,11
P24 in Talairach43 coordinates) spanning the amyg-dala and Following the identification of significant regions of
portions of the posterior orbitofrontal cortex using a gradient activity showing a diagnosis condition interaction, cor-
EPI sequence (TR, 3000 milliseconds; TE, 40 mil- relation analyses were performed relating the percent
liseconds;flipangle,90matrix,64 64pixels;FOV,200mm; change in magnetic resonance signal intensity in those
slicethickness,4mmcontiguous). Eachparticipantcompleted 3 regions to behavioral SCARED scores. Separate
runs of 100 images totaling 300 images per slice. Each sub- correlations were con-ducted for the larger sample of
jects images were motion corrected and aligned to the cor- anxious and healthy chil-dren and for the smaller sample of
depressed, anxious, and healthy girls. Scores from the
responding structural data set using AIR software. 44 All sub- SCARED were not available for some of the healthy and
jectshadlessthan0.5voxelsofin-planemotion. Anadditional 6 anxious children. The re-ported correlations reflect an
children (4 healthy, 2 anxious) were tested but excluded analysis for the subset of chil-dren with behavioral data.

tern of amygdala activity appears to differ between

adults and children.

ANXIOUS VS HEALTHY CHILDREN

The 2 2 (diagnosis condition) ANOVAs comparing

anxious and healthy children showed a main effect of
con-dition for the comparisons of fearful faces and
fixation and of neutral faces and fixation, as well as a
significant interaction between groups for fearful
compared with neutral faces. Both anxious and healthy
children showed bilateral increases in the blood oxygen
leveldependent (BOLD) signal in the amygdala for
fearful faces com-pared with fixation. The maximum
activation in the right amygdala was centered at x =18,
y = 8, z = 20 (maxi-mum F=9.56; 29 voxels); that in
the left amygdala was
 maximum F=8.10; 8 voxels). Post hoc t tests indicate
that anxious children dem-onstrated larger responses in
the right amygdala for fear-ful faces than for neutral
centered at x=14, y=8, z=11 (maximum F=10.27; 9 faces, whereas healthy children did not (Figure 2B). In
voxels). A similar signal increase was observed in the addition, the magnitude of this sig-nal change (fearful
left amygdala for neutral faces compared with fixation vs neutral) was positively correlated with child self-
(x=18, y=4, z=19; maximum F=5.86; 9 voxels). reported anxiety symptoms as measured by the
How-ever, anxious children differed from healthy SCARED (r17=0.62; P=.004) (Figure 2C). This cor-
children when fearful expressions were compared with relation remained significant even when potential outli-
neutral expres-sions. Figure 2A shows the significant ers were removed (r16 =0.56; P = .02; r15 =0.55; P = .
region of activity in the right amygdala for this 02).
diagnosis condition in-teraction (x =11, y = 7, z = 14;

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DEPRESSED VS ANXIOUS is among the first to relate clinical symptoms to the
VS HEALTHY CHILDREN neu-rophysiological response to social stimuli, as
evidenced by the correlation between severity of
The 3 2 (diagnosis condition) ANOVAs among the everyday anxiety and BOLD signal change.
depressed, anxious, and healthy girls showed signifi- Furthermore, this study ex-emplifies the ability to
cant interactions for fearful faces compared with assess functional brain responses to emotional
neu-tral faces and for fearful faces compared with stimuli at the onset of a childhood disor-der rather
fixation. Anxious children showed more activity in than in adulthood after the disorder has pro-gressed
the right amyg-dala for fearful faces than for neutral and/or been treated.
faces (Figure 3A). In contrast, depressed children did Abnormalities in the response of the right
not exhibit signifi-cant differences in the BOLD amyg-dala to fear stimuli in anxious children are
response to fearful and neu-tral faces in the right consistent with previous anatomical and functional
amygdala. Child self-reported anxi-ety symptoms as studies of chil-dren and adults. A morphometric MRI
measured by the SCARED were positively study of child-hood anxiety that included some of the
correlated with the signal difference between fearful same children tested in our functional study reported
and neutral facial expressions (r9=0.79; P .001) a significantly larger volume of the right amygdala in
(Figure 3B). Depressed children showed a reduction children and adolescents with generalized anxiety
in the BOLD signal in the left amygdala for fearful compared with healthy children,30 suggesting the
expressions vs fixation, whereas anxious and healthy possibility of a rela-tionship between structure and
children did not (x = 13, y = 4, z = 16; maximum function. Our results complement findings of an
F = 5.07; 6 voxels) (Figure 3C-D). exaggerated amygdala re-sponse to fearful faces in
adults with PTSD,21 as well as PET studies
suggesting that adults with high trait anxi-ety scores
show greater right vs left cerebral metabolism than
Our findings suggest functional differences in the adults with low trait anxiety.47 The correlation be-
amyg-dala for children with anxiety and depressive tween amygdala responsiveness and severity of
disorders relative to healthy children. To our every-day anxiety in the current study was robust
knowledge, this study even with a sample size of 5 subjects per group,
arguing that the dif-ferential amygdala response in
anxious children is likely related to chronic or
persistent anxiety symptoms rather than anxiety
specific to the scanning environ-ment. The
hyperreactivity of the amygdala appears to be a
characteristic of anxiety disorders and may reflect a
trait rather than a state effect.
In contrast to the anxious children, girls with
MDD demonstrated a decreased response in the left
amygdala to all facial stimuli regardless of the
emotional content, perhaps reflecting a general blunted
response to social stimuli or emotional probes.
Alternatively, given previ-ous reports of elevated
resting blood flow in the left amyg-dala in depressed
adults,23 our findings may reflect pri-marily increased
baseline activation or be specific to the emotional
Figure 1. Examples of neutral and fearful categories used in this study (fearful and neu-tral
41
expressions used in the passive-viewing task. expressions). Additional research with larger sample

.
0 Right
A 1 Amyg
.05
dala
P
 B C
0

1.5 0.5
r
0.4

% Signal Change in Right Amygdala

% Signal Change in Right Amygdala

0.6
2 1.0 0 10 20 30 40 50 60
0.2 = .
004 Child-Reported SCARED Score
1
.
0
0.2

0
0.4 .
5

Figure 2. A, Significant region of the right amygdala (x =11, y = 7, z = 14) observed in the diagnosis (anxious vs healthy
children) condition (fearful vs neutral faces) interaction. B, Percent change in normalized magnetic resonance signal intensity in
the right amygdala for the comparison between fearful and neutral faces for anxious and healthy children. Bars reflect the SEM.
C, Correlation between the percent change in normalized magnetic resonance signal intensity in the right amygdala and the
child-reported score from the Screen for Child Anxiety Related Emotional Disorders (SCARED). Squares reflect healthy children
(n=9); circles reflect children with generalized anxiety and/or panic disorder (n=10).

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A B

0.6 1.5 r = 0.79

P <.001
% Signal Change in Right Amygdala

% Signal Change in Right Amygdala

1.0
0.3

0.5
0

0.3 0.5

1.0
0.6 0 10 20 30 40 50
Child-Reported SCARED Score
Healthy Anxious Depressed
Children Children Children
(n = 5) (n = 5) (n = 5)

C Left Amygdala
% Signal Change in Left Amygdala

.01

.05
 D

0.6

0.3

0.3

0.6 Healthy Anxious Depressed

Children Children Children

(n = 5) (n = 5) (n = 5)

Figure 3. A, Percent change in normalized magnetic resonance signal intensity in the right amygdala for the diagnosis (anxious vs depressed vs healthy
children) condition (fearful vs neutral faces) interaction. B, Correlation between the child-reported score from the Screen for Child Anxiety Related Emotional
Disorders (SCARED) and the normalized magnetic resonance signal change in the right amygdala for the comparison between fearful and neutral faces.
Squares reflect healthy children (n = 3), circles reflect anxious children (n = 3), and triangles reflect depressed children (n = 5). C, Diagnosis condition
interaction in the left amygdala (x = 13, y = 4, z = 16) for the comparison between fearful faces and fixation. D, Percent change in normalized magnetic
resonance signal intensity
in the left amygdala for fearful faces vs fixation by diagnosis (healthy vs anxious vs depressed children). Bars reflect the SEM.
laterality differences in cortical activity have been
sizes and multiple emotional categories will be hypothesized to reflect activation of approach and
required to address the generalizability of this withdrawal-related networks, respectively.50,51
response. How-ever, our results are generally Studies of electroencephalogram (EEG) asymmetry
consistent with those of recent reports suggesting in the fron-tal cortex suggest that depressed adults
decreased volume and histo-pathological changes in demonstrate a decrease in left frontal activity that
the amygdala, predominantly on the left side, in maps onto a behav-ioral decrease in approach
imaging and postmortem studies of adult behaviors. In contrast, indi-viduals with anxiety or
with a socially inhibited tem-perament tend to show
MDD.48,49 increased right compared with left frontal baseline
There is evidence to suggest that relative laterality
EEG activity, perhaps indicating greater activation of
differences in the amygdala response to facial expres-
sions in healthy adults may reflect top-down vs bottom- a withdrawal or avoidance net-work.51,52 Our results
up processing of the emotional stimuli. Studies of suggest that the amygdala may respond in a parallel
rapidly presented masked facial expressions have
manner. Depressed girls showed a decrease in
activity of the left amygdala for faces com-pared
typically shown greater right than left activation to fear- with fixation, which could be interpreted as
ful faces, whereas longer stimulus presentations gener- decreased activity in an approach network. Similarly,
ally result in greater activity of the left amygdala. 6,10 anxious children exhibited an increase in activity of
The exaggerated right amygdala response observed in the right amygdala for fearful faces, perhaps
anx-ious children may reflect increased automatic or reflecting increased activity in a withdrawal or
uncon-scious processing of the fear stimuli, as avoidance net-work. With either hypothesis, such
suggested for adult subjects. 21 However, this hypothesis laterality findings should be viewed with caution
is clearly speculative; the current stimuli were because they are not always replicated.
consciously per-ceived, and the paradigm was not
designed to compare conscious and unconscious
processing. Alternatively,

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LIMITATIONS children when the symptoms are no longer present.
Future studies will need to address several limi-tations
Our data do not address the etiology of the observed in this work. In particular, the specificity of the
group differences. It is unclear whether an abnormal differential amygdala responses must be addressed by
amygdala response reflects a neurobiological in-cluding positive stimuli in addition to other types of
vulnerability to child-hood emotional disorders, or nega-tive emotional stimuli, and by comparing more
whether the presence of these disorders leads to the homo-geneous diagnostic groups with larger sample
development of an abnor-mal amygdala response. sizes and equal sex representation. Similarly, the lack
Imaging studies of the amyg-dala response before and of online be-havioral data regarding recognition and
after effective treatment for anxi-ety or depression may evaluation of both the portrayed emotions as well as
help address whether the size and function of this any emotion elicited in the child make cognitive
structure become more similar to the pat-tern in healthy interpretations speculative. In future work, such
behavioral data may be useful in determining whether
the exaggerated response ob-served in anxious children
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