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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
Arch Gen Psychiatry. 2001;58:1057-1063.
ABSTRACT
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Background Alterations in amygdala function have been implicated in the pathophysiological
characteristics of adult anxiety and depressive disorders. Studies with healthy
adults and children, as well as with adults who have amygdala lesions, have
found facial expressions of emotion to be useful probes of amygdala activity.
Our study examined the amygdala response to fearful and neutral facial expressions
in healthy, anxious, and depressed children. We hypothesized that children
with anxiety and depression may show atypical amygdala responses to emotional
stimuli.
Methods Twelve children (8-16 years of age) with generalized anxiety or panic
disorder and 12 healthy comparison children underwent noninvasive functional
magnetic resonance imaging while viewing photographs of fearful and neutral
facial expressions. In a second comparison, 5 girls with major depressive
disorder were compared with 5 anxious and 5 healthy girls from the previous
sample.
Results Children with anxiety disorders showed an exaggerated amygdala response
to fearful faces compared with healthy children, whereas depressed children
showed a blunted amygdala response to these faces. In addition, the magnitude
of the amygdala's signal change between fearful and neutral faces was positively
correlated with the severity of everyday anxiety symptoms.
Conclusions Our results suggest that amygdala function is affected in both anxiety
and depression during childhood and adolescence. Moreover, this disruption
appears to be specific to the child's own rating of everyday anxiety.
INTRODUCTION
THE AMYGDALA and its related structures are thought to play a key role
in evaluating the emotional significance of sensory and social stimuli.1, 2 Stimulation of the amygdala produces
autonomic reactions associated with the fight or flight response, including
increased heart rate and blood pressure, freezing behavior in animals, feelings
of fear and anxiety in humans, and increased plasma stress hormone levels.2, 3, 4 Human neuroimaging studies
have shown that amygdala activity increases during exposure to fear conditioned5, 6 and other emotionally valenced stimuli.7, 8, 9, 10, 11
In contrast, amygdala lesions result in diminished fear reactions in animals12, 13 and an impaired recognition of negative
facial expressions, particularly fearful expressions, in humans.14
Abnormal amygdala function has been implicated in adult neuroimaging
studies of anxiety and depression.15, 16
Adults with social phobia show increased bilateral amygdala responses to faces
judged by healthy controls to be affectively neutral.17
Hyperreactivity of the amygdala has been observed in adults with posttraumatic
stress disorder (PTSD) in response to reminders of traumatic events18, 19 and to general negative stimuli.20, 21 Finally, positron emission tomography
(PET) studies of depressed adults report an elevated resting blood flow and
glucose metabolism in the amygdala that correlate positively with depression
severity.22, 23
One common probe of human amygdala function has been facial expressions
of emotion. Results from several functional neuroimaging studies have suggested
that in healthy adults, the amygdala responds more strongly to fearful faces
than to other expressions such as neutral or happy faces.6, 9, 10, 11, 24, 25
This pattern of activity is generally lateralized, with a greater amygdala
response in the left hemisphere than in the right for standard face presentations.
However, when the facial expressions are masked so that the initial emotion
is not consciously perceived, the right amygdala shows greater activity than
the left.6, 10, 25
This unconscious amygdala response to fearful vs happy faces has been shown
to be enhanced in adults with PTSD.21 In addition,
adults with amygdala lesions exhibit deficits in the ability to recognize
certain facial expressions, especially fear.14, 26, 27, 28, 29
There is an increasing recognition of the importance of understanding
mechanistic changes in emotional processing that are evident early in the
development of anxiety and depression, in ways that may ultimately lead to
more effective early interventions. A recent anatomical magnetic resonance
imaging (MRI) study observed an increased volume of the right amygdala but
not of other brain regions in children with generalized anxiety disorder (GAD),
suggesting that amygdala abnormalities may be associated with childhood-onset
as well as adult anxiety disorders.30 However,
few functional imaging studies have examined amygdala responses in children.
Baird et al31 found that healthy adolescents
showed bilateral amygdala activity in response to unmasked fearful faces when
compared with neutral nonface scrambled images. Recently we reported that
although children exhibited amygdala increases with fearful faces compared
with a nonface baseline stimulus, they actually showed less amygdala activity
with fearful faces than with neutral faces.32
The implications of this continued development in the processing and understanding
of facial expressions are not entirely clear but have been attributed to ambiguity
in the emotional significance of a neutral face.32, 33
In our study, we use fearful and neutral facial expressions to examine amygdala
responsiveness in children with anxiety and depression, keeping in mind that
the normal pattern of amygdala activity appears to differ between adults and
children.
SUBJECTS AND METHODS
SUBJECTS
Two pediatric patient groups and healthy comparison groups participated.
Twelve children and adolescents (mean ± SD, 12.8 ± 2.1 years;
range, 8-16 years; 7 boys, 5 girls) who met DSM-IV34 criteria for GAD (n = 11) and/or panic disorder (n
= 2) were compared with 12 healthy children (mean ± SD, 12.1 ±
2.6 years; range, 8-15 years; 7 boys, 5 girls), some of whose data were reported
previously.32 In a second comparison, 5 girls
(mean ± SD, 12.3 ± 2.7 years; range, 8-16 years) with DSM-IV diagnoses of major depressive disorder (MDD) were
compared with the previously studied healthy girls and girls with anxiety
disorders. All subjects were right-handed. Groups were similar in pubertal
development (range, Tanner stage 1/1 to 5/5 for anxious and depressed children
and 1/1 to 5/4 for healthy children) and estimated IQ (mean ± SD, 124
± 16 for anxious subjects, 127 ± 12 for depressed subjects,
and 137 ± 14 for healthy subjects). One child with GAD had comorbid
social phobia. Two children with MDD had comorbid GAD.
Children with anxiety or depression were recruited from the Child and
Adolescent Anxiety and Depression Program of the Western Psychiatric Institute
and Clinic, University of Pittsburgh, Pittsburgh, Pa. Children were evaluated
by trained research physicians blind to the subject's clinical status and
with the supervision of child psychiatrists using a modified version of the
Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present
and Lifetime Version (K-SADS-PL)35 with the
participation of both the child and parent(s). A psychiatrist then heard the
case to confirm the presence of a psychiatric disorder. Healthy control children
were required to have a low familial risk for depression as defined by the
absence of any current or past psychiatric disorders, no first-degree relatives
with mood or psychotic disorders, no second-degree relatives with childhood-onset
recurrent psychotic or bipolar depression, schizoaffective disorder, or schizophrenic
disorder, and no more than 20% of second-degree relatives with a single episode
of major depression. All children were screened using the vocabulary, digit
span, block design, and object assembly subtests of the Wechsler Intelligence
Scale for Children–Third Edition (WISC-III),36
the 12 handedness items from the Revised Physical and Neurological Examination
for Soft Signs (PANESS) Inventory,37 the Tanner
Scales of Pubertal Development,38 and the Screen
for Child Anxiety Related Emotional Disorders (SCARED).39, 40
The SCARED is a 41-item parent report and child self-report instrument. It
consists of 5 factors that parallel the DSM-IV classification
of anxiety disorders: somatic/panic, generalized anxiety, separation anxiety,
social phobia, and school phobia. This measure was used to assess the severity
of the anxiety symptoms. Exclusionary criteria for all participants included
(1) a positive urine screen for cigarette, alcohol, or illicit drug use; (2)
the use or presence of medication with central nervous system effects within
the prior 2 weeks; (3) the presence of a significant medical or neurological
illness; (4) extreme obesity (weight > 150% of the subject's ideal body weight)
or growth failure (height or weight < the third percentile for the child's
age); (5) an IQ lower than 80; (6) anorexia nervosa, autism, or schizophrenia
by DSM-IV criteria; (7) GAD chronologically secondary
to conduct disorder; (8) specific learning disabilities; (9) a current diagnosis
of PTSD; or (10) any contraindication for an MRI.
The study was approved by the institutional review board of the University
of Pittsburgh Medical Center. Written parental consent and child assent were
acquired prior to the study, and subjects were compensated $50 for their participation
in the MRI portion of the study.
PROCEDURES
Stimuli and Task
The task consisted of the rapid (1 Hz) and successive presentation of
a standard photographic set of faces41 in blocks
of neutral and emotional expressions. A total of 8 different actors (4 men,
4 women) demonstrating both fearful and neutral expressions were used (Figure 1). Hair was stripped from the images
to remove any nonfacial features, and both fear and exaggerated fear poses
were used for each actor.42 Facial stimuli
were presented for 200 milliseconds followed by an 800-millisecond interstimulus
interval containing a flashing central asterisk (fixation point). In each
behavioral run, a block of fixation trials was presented for 45 seconds followed
by alternating 42-second blocks of either neutral or fearful expressions and
a final 45-second epoch of fixation. This procedure was repeated in 3 runs
of trials with the presentation order counterbalanced across runs and across
subjects (ie, F-N-F-N-F or N-F-N-F-N, where F indicates
fearful expressions and N indicates neutral expressions).
No overt response was required. Subjects were instructed to fixate centrally
and to try to get an overall sense of the faces.11, 32
The stimulus parameters and task design were specifically selected to replicate
previous studies of the amygdala response to facial expressions.
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Figure 1. Examples of neutral and fearful
expressions used in the passive-viewing task.41
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MRI Methods
Structural and functional MRI scans were acquired on a 1.5 Tesla General
Electric (Milwaukee, Wis) Signa scanner with an Advanced NMR (Wilmington,
Mass) system for echo-planar imaging (EPI) and a quadrature head coil. A T1-weighted
sagittal localizer image was used to identify the position of the head and
to prescribe the subsequent slice locations (repetition time [TR], 400 milliseconds;
echo time [TE], 25 milliseconds; 15 slices; thickness, 5 mm; spacing, 2.5
mm; field of view [FOV], 200 mm; matrix, 256 x 256 pixels). T1-weighted
structural images were acquired in 4-mm contiguous coronal slices across the
whole brain (TR, 500 milliseconds; TE, 14 milliseconds; matrix, 256 x
256 pixels; FOV, 200 mm) for purposes of localizing the functional activity
and aligning images to a reference brain. Functional images (T2*-weighted)
were acquired at 12 of these slice locations (approximately A20 to P24 in
Talairach43 coordinates) spanning the amygdala
and portions of the posterior orbitofrontal cortex using a gradient EPI sequence
(TR, 3000 milliseconds; TE, 40 milliseconds; flip angle, 90° matrix, 64
x 64 pixels; FOV, 200 mm; slice thickness, 4 mm contiguous). Each participant
completed 3 runs of 100 images totaling 300 images per slice. Each subject's
images were motion corrected and aligned to the corresponding structural data
set using AIR software.44 All subjects had
less than 0.5 voxels of in-plane motion. An additional 6 children (4 healthy,
2 anxious) were tested but excluded from the analysis because of excessive
movement (> 0.5 voxels). Individual structural and functional images were
cross-registered with a representative subject's brain, smoothed (8-mm full
width at half-maximum kernel), and pooled across subjects to improve the signal-to-noise
ratio. Resulting group data were transformed into Talairach space for comparison
with previous functional imaging studies.
STATISTICAL ANALYSES
Voxelwise diagnosis x condition analyses of variance (ANOVAs)
were conducted on pooled functional MRI data for all voxels in the acquired
slices using normalized signal intensity as the dependent variable. Statistical
maps of F ratios for each voxel were calculated using a cluster-size algorithm45 that takes into account the spatial extent of activation
to correct for multiple comparisons. Significant activations were defined
by at least 3 contiguous voxels (120 mm3) and  = .05. Separate
analyses were conducted comparing anxious and healthy children (n = 12 per
group) and anxious, healthy, and depressed girls (n = 5 per group) across
pairs of conditions (fearful vs neutral faces, fearful faces vs fixation,
and neutral faces vs fixation). Post-hoc Tukey Honestly Significant Difference
tests were used to identify significant mean differences among groups and
within interaction effects. Amygdala activation was confirmed on a reference
brain using standard atlases43, 46
and consensus among 3 raters (B.J.C., K.M.T., and P.J.W.). Significant activations
extending outside the brain or with large standard deviations were excluded.
Discussion was limited to significant activation in mesotemporal brain regions
given the implication of these structures in previous neuroimaging studies
of facial expressions of emotion.10, 11
Following the identification of significant regions of activity showing
a diagnosis x condition interaction, correlation analyses were performed
relating the percent change in magnetic resonance signal intensity in those
regions to behavioral SCARED scores. Separate correlations were conducted
for the larger sample of anxious and healthy children and for the smaller
sample of depressed, anxious, and healthy girls. Scores from the SCARED were
not available for some of the healthy and anxious children. The reported correlations
reflect an analysis for the subset of children with behavioral data.
RESULTS
ANXIOUS VS HEALTHY CHILDREN
The 2 x 2 (diagnosis x condition) ANOVAs comparing anxious
and healthy children showed a main effect of condition 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 level–dependent (BOLD) signal in the amygdala for fearful
faces compared with fixation. The maximum activation in the right amygdala
was centered at x = 18, y
= -8, z = -20 (maximum F = 9.56; 29 voxels);
that in the left amygdala was centered at x = -14, y = -8, z = -11 (maximum
F = 10.27; 9 voxels). A similar signal increase was observed in the left amygdala
for neutral faces compared with fixation (x = -18, y = -4, z = -19; maximum
F = 5.86; 9 voxels). However, anxious children differed from healthy children
when fearful expressions were compared with neutral expressions. Figure 2A shows the significant region of
activity in the right amygdala for this diagnosis x condition interaction
(x = 11, y = -7, z = -14; maximum F = 8.10; 8 voxels). Post hoc t tests indicate that anxious children demonstrated larger
responses in the right amygdala for fearful faces than for neutral faces,
whereas healthy children did not (Figure 2B). In addition, the magnitude of this signal change (fearful vs
neutral) was positively correlated with child self-reported anxiety symptoms
as measured by the SCARED (r17 = 0.62; P = .004) (Figure 2C).
This correlation remained significant even when potential outliers were removed
(r16 = 0.56; P
= .02; r15 = 0.55; P = .02).
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Figure 2. A, Significant region of the right
amygdala (x = 11, y = - 7, z
= -14) observed in the diagnosis (anxious vs healthy children) x
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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DEPRESSED VS ANXIOUS VS HEALTHY CHILDREN
The 3 x 2 (diagnosis x condition) ANOVAs among the depressed,
anxious, and healthy girls showed significant interactions for fearful faces
compared with neutral faces and for fearful faces compared with fixation.
Anxious children showed more activity in the right amygdala for fearful faces
than for neutral faces (Figure 3A). In contrast, depressed children did not exhibit significant differences in
the BOLD response to fearful and neutral faces in the right amygdala. Child
self-reported anxiety symptoms as measured by the SCARED were positively correlated
with the signal difference between fearful and neutral facial expressions
(r9 = 0.79; P<.001)
(Figure 3B). Depressed children
showed a reduction in the BOLD signal in the left amygdala for fearful expressions
vs fixation, whereas anxious and healthy children did not (x = -13, y = -4, z = -16; maximum F = 5.07; 6 voxels) (Figure 3C-D).
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Figure 3. A, Percent change in normalized
magnetic resonance signal intensity in the right amygdala for the diagnosis
(anxious vs depressed vs healthy children) x 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 x 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.
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COMMENT
Our findings suggest functional differences in the amygdala for children
with anxiety and depressive disorders relative to healthy children. To our
knowledge, this study is among the first to relate clinical symptoms to the
neurophysiological response to social stimuli, as evidenced by the correlation
between severity of everyday anxiety and BOLD signal change. Furthermore,
this study exemplifies the ability to assess functional brain responses to
emotional stimuli at the onset of a childhood disorder rather than in adulthood
after the disorder has progressed and/or been treated.
Abnormalities in the response of the right amygdala to fear stimuli
in anxious children are consistent with previous anatomical and functional
studies of children and adults. A morphometric MRI study of childhood anxiety
that included some of the same children tested in our functional study reported
a significantly larger volume of the right amygdala in children and adolescents
with generalized anxiety compared with healthy children,30
suggesting the possibility of a relationship between structure and function.
Our results complement findings of an exaggerated amygdala response to fearful
faces in adults with PTSD,21 as well as PET
studies suggesting that adults with high trait anxiety scores show greater
right vs left cerebral metabolism than adults with low trait anxiety.47 The correlation between amygdala responsiveness and
severity of everyday anxiety in the current study was robust even with a sample
size of 5 subjects per group, arguing that the differential amygdala response
in anxious children is likely related to chronic or persistent anxiety symptoms
rather than anxiety specific to the scanning environment. 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 previous reports of elevated resting
blood flow in the left amygdala in depressed adults,23
our findings may reflect primarily increased baseline activation or be specific
to the emotional categories used in this study (fearful and neutral expressions).
Additional research with larger sample sizes and multiple emotional categories
will be required to address the generalizability of this response. However,
our results are generally consistent with those of recent reports suggesting
decreased volume and histopathological changes in the amygdala, predominantly
on the left side, in imaging and postmortem studies of adult MDD.48, 49
There is evidence to suggest that relative laterality differences in
the amygdala response to facial expressions in healthy adults may reflect
top-down vs bottom-up processing of the emotional stimuli. Studies of rapidly
presented masked facial expressions have typically shown greater right than
left activation to fearful faces, whereas longer stimulus presentations generally
result in greater activity of the left amygdala.6, 10
The exaggerated right amygdala response observed in anxious children may reflect
increased automatic or unconscious processing of the fear stimuli, as suggested
for adult subjects.21 However, this hypothesis
is clearly speculative; the current stimuli were consciously perceived, and
the paradigm was not designed to compare conscious and unconscious processing.
Alternatively, laterality differences in cortical activity have been hypothesized
to reflect activation of approach and withdrawal-related networks, respectively.50, 51 Studies of electroencephalogram (EEG)
asymmetry in the frontal cortex suggest that depressed adults demonstrate
a decrease in left frontal activity that maps onto a behavioral decrease in
approach behaviors. In contrast, individuals with anxiety or with a socially
inhibited temperament tend to show increased right compared with left frontal
baseline EEG activity, perhaps indicating greater activation of a withdrawal
or avoidance network.51, 52 Our
results suggest that the amygdala may respond in a parallel manner. Depressed
girls showed a decrease in activity of the left amygdala for faces compared
with fixation, which could be interpreted as decreased activity in an approach
network. Similarly, anxious children exhibited an increase in activity of
the right amygdala for fearful faces, perhaps reflecting increased activity
in a withdrawal or avoidance network. With either hypothesis, such laterality
findings should be viewed with caution because they are not always replicated.
LIMITATIONS
Our data do not address the etiology of the observed group differences.
It is unclear whether an abnormal amygdala response reflects a neurobiological
vulnerability to childhood emotional disorders, or whether the presence of
these disorders leads to the development of an abnormal amygdala response.
Imaging studies of the amygdala response before and after effective treatment
for anxiety or depression may help address whether the size and function of
this structure become more similar to the pattern in healthy children when
the symptoms are no longer present. Future studies will need to address several
limitations in this work. In particular, the specificity of the differential
amygdala responses must be addressed by including positive stimuli in addition
to other types of negative emotional stimuli, and by comparing more homogeneous
diagnostic groups with larger sample sizes and equal sex representation. Similarly,
the lack of online behavioral data regarding recognition and evaluation of
both the portrayed emotions as well as any emotion elicited in the child make
cognitive interpretations speculative. In future work, such behavioral data
may be useful in determining whether the exaggerated response observed in
anxious children correlates with a form of top-down processing of the emotion
or reflects a fairly automatic response.
CONCLUSIONS
Our results suggest that amygdala function is affected in both anxiety
and depression during childhood and adolescence. Children with anxiety disorders
showed an exaggerated amygdala response to fearful faces compared with healthy
children, whereas depressed children demonstrated a blunted amygdala response
to faces. This disruption appears to be specific to the child's own rating
of everyday anxiety.
AUTHOR INFORMATION
Accepted for publication June 26, 2001.
This work was supported in part by grant MH 41712, "The Psychobiology
of Anxiety and Depression in Children and Adolescents" (program directors:
Neal D. Ryan, MD, and Ronald E. Dahl, MD; project principal investigators:
B. J. Casey, PhD, and Ronald E. Dahl, MD), from the National Institute of
Mental Health, Bethesda, Md.
Preliminary data were presented at the annual meeting of the Cognitive
Neuroscience Society, San Francisco, Calif, April 9, 2000, and the Sixth International
Conference on Functional Mapping of the Human Brain, San Antonio, Tex, June
13, 2000.
We thank the children and adolescents who participated in this study.
We also thank David Perrett, PhD, for providing facial stimuli, and Laura
Trubnick and staff of the Child and Adolescent Sleep Lab, Western Psychiatric
Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh,
Pa, for help in data collection.
From the Sackler Institute for Developmental Psychobiology, Department
of Psychiatry, Weill Medical College of Cornell University, New York, NY (Drs
Thomas and Casey and Mr Eccard); the Mood and Anxiety Disorders Neuroimaging
Section, National Institute of Mental Health, Bethesda, Md (Dr Drevets); the
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pa (Drs Drevets,
Dahl, Ryan, Birmaher, and Axelson); and the Departments of Psychiatry and
Psychology, University of Wisconsin, Madison (Dr Whalen).
Corresponding author and reprints: Kathleen M. Thomas, PhD, Sackler
Institute for Developmental Psychobiology, Weill Medical College of Cornell
University, 1300 York Ave, Box 140, Suite F-1332, New York, NY 10021 (e-mail: kmt2001{at}med.cornell.edu).
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