Increased Amygdala Response to Positive Social
Feedback in Young People with Major Depressive
Christopher G. Davey, Nicholas B. Allen, Ben J. Harrison, and Murat Yücel
Background: Studies of depressed patients have demonstrated increased amygdala activation to negative affective stimuli. In this study,
we used a paradigm that employed personally relevant social stimuli, which are known to strongly activate the amygdala, to test whether
the amygdala demonstrated aberrant activity in depressed participants as they responded to stimuli with positive valence.
evaluated them. Voxelwise statistical parametric maps of brain response to positive social feedback and to a control feedback condition
were compared to test the hypothesis that differences in neural response between depressed and control participants would arise in the
.05, corrected). An exploratory analysis showed that depressed participants responded to faces from both feedback conditions with
(pregenual anterior cingulate cortex and anterior insular cortex; p ? .001, uncorrected).
hyperresponsivity in depression is not restricted to negatively-valenced stimuli. The heightened sensitivity of depressed participants to
social evaluation may help explain symptoms of depression such as social withdrawal.
Key Words: Adolescence, amygdala, fMRI, major depressive disor-
der, reward, social cognition
Depression has profound effects on a young person’s social func-
tioning, resulting in withdrawal from social activities and disen-
episodes of depression in young people are often “reactive” (as
opposed to melancholic) in the two senses of the term: they fre-
quently arise in response to precipitants such as relationship
breakup or social disappointment (4,5) and the mood state often
shows some responsivity to the social environment (6,7). Young
people with depression are, then, often responsive to the social
environment at the same time as they withdraw from it.
The amygdala, a medial temporal lobe structure that is highly
cated in the pathogenesis of depression, with functional magnetic
resonance imaging (fMRI) studies showing that it is hyperactive at
rest (8–10), in response to negative facial expressions (11–15) and
in response to other negative emotional stimuli (16–18). Recent
studies in adolescents with depression (19,20) and at risk for de-
pression (21) have confirmed that amygdala hyperresponsivity is
present in the early stages of illness. Although amygdala hyperre-
sponsivity is most often associated with negative stimuli, there is
ental illnesses are the “chronic illnesses of the young” (1)
and the mental illness that causes most disability in ado-
evidence that positive affective stimuli can also provoke an
amygdala response in healthy participants (22), particularly when
the stimuli have a social character (23,24).
The rewards associated with social events become more salient
during adolescence, driving an increase in sociability and the for-
mation of new peer and romantic relationships (25). This corre-
sponds with development of the “social brain” (26), in which brain
regions that are important for processing social information de-
velop rapidly during the adolescent period. Although such devel-
opment is necessary to allow successful navigation of the increas-
ingly complex social environment that adolescents encounter, it
may in fact contribute to the increased incidence of depression
during adolescence (27). The prefrontal, cortical-midline, and lim-
bic regions that are central components of the social brain are also
implicated in depression.
to be useful probes of depression in young people. A number of
aging literature that have attempted to address problems with
ecological validity (or “real worldness”) in the scanning environ-
ment by having the participants engage with stimuli with greater
verisimilitude, emphasizing personally meaningful social pro-
cesses. In the Cyberball task (28,29), for example, participants be-
lieved they were playing an online game with other participants,
and in other recent studies (30–32), the participants believed that
paradigm designs for these studies informed our study, in which a
probe the neural correlates of social processing in depression.
The aim of the study was to determine how young people with
depression, who had illnesses that were likely to be reactive to the
social environment, responded to social feedback. We were partic-
Neuropsychiatry Centre (CGD, BJH, MY) and Department of Psychologi-
cal Sciences (NBA), The University of Melbourne, Melbourne, Australia.
Youth Health Research Centre, The University of Melbourne, Parkville,
Victoria 3052, Australia; E-mail: email@example.com.
Received Sept 8, 2010; revised Dec 8, 2010; accepted Dec 8, 2010.
BIOL PSYCHIATRY 2011;xx:xxx
© 2011 Society of Biological Psychiatry
Specifically, we aimed to investigate whether depressed patients
and healthy control participants would demonstrate differences in
amygdala activation to positive social feedback. Further analysis
would determine whether there were differences between the de-
pressed and control participants in their processing of the faces
Methods and Materials
Depressed participants were recruited for the study from Ory-
gen Youth Health, a public youth mental health service in Mel-
had major depressive disorder determined by Structured Clinical
that extended from the middle teenage years to early adulthood,
is consistent with our current understanding of the continuities in
not meet criteria for psychotic disorder, substance dependence
disorder, pervasive developmental disorder, or intellectual disabil-
der or if they were taking antidepressant medication. The de-
pressed participants were successfully matched with a group of
control participants on age, gender, and full-scale IQ (Table 1). The
control participants were recruited via advertisement placed in a
ticipants (or their parents if they were younger than 18 years) pro-
approved by the local research and ethics committees. Imaging
data from one control participant and two depressed participants
ning (z axis translation ? 2 mm), resulting in a control group of 19
participants and a depressed group of 17 participants.
The illness characteristics of the depressed participants re-
mental health service that treats young people with relatively se-
depressed participants of 33.9 indicates that their illnesses were at
the severe end of the illness spectrum. Five of the participants had
comorbid anxiety disorders, including panic disorder (2 patients),
social anxiety disorder (1 patient), generalized anxiety disorder (1
patient), and combined panic disorder and generalized anxiety
treated with antidepressant medications, including fluoxetine (4
patients), citalopram (2 patients), and venlafaxine (3 patients). Us-
ing the categorization of dose-strengths outlined by Hansen and
six patients a medium dose, and one patient a high dose. The Beck
Depression Inventory scores for the medicated (32.5) and unmedi-
cated patients (35.6) were not significantly different (p ? .61).
The details of the experimental design have been reported pre-
viously (37). During an initial assessment approximately 1 week
before fMRI, participants were told that they were to be part of a
study that was investigating how people used first impressions to
decide whether they liked someone. Participants had their photo-
study participants who would assess how much they thought they
would like the participant on the basis of their appearance in the
photograph. The overt study design was, however, a ruse: the par-
ticipants’ photographs were deleted soon after they were taken,
and the photographs that they viewed, which they understood
were of other study participants, were in fact from a preexisting
ple whom they understood to have been enrolled in the study to
date; 20 females and 20 males, all with neutral facial expressions,
and selected from the larger face database on the basis that they
appeared to be of a similar age to the participants. On viewing the
photographs, the participants were asked to rate on a scale from 1
to 9 their answer to the question: “How much do you think you
would like this person if you were to meet them?”
On the day of fMRI, immediately before the scan, participants
scanner, participants viewed the “responses” from the people who
had rated them. The responses had been pseudo-randomly deter-
mined, ensuring balance between gender, and between faces that
the participants had given high and low ratings. These photo-
graphs made up the people who had apparently responded posi-
tively (henceforth referred to as “positive-feedback” faces) and
were presented during the scanning session on a green back-
ground. To provide a control condition, participants were told that
not all people could be contacted for a response; they are referred
to here as “control-feedback” faces and were presented on a white
background. People who had apparently made unfavorable re-
sponses were not shown, the investigation of social rejection not
being an aim of the study.
(16 positive-feedback faces and 16 control-feedback faces) were
presented three times over six blocks. The face blocks consisted of
12 min, 17 sec). Each photograph was displayed for 3 sec and was
interspersed with null events that had the effect of jittering the
interstimulus interval by between 1 and 7 sec (Figure 1), with the
timing and sequencing of stimulus presentation optimized by use
of the optseq2 software tool (http://surfer.nmr.mgh.harvard.edu/
optseq). Participants were not required to make a button-press
response because of concern that performance of a concomitant
affective processing, as shown by other studies (39,40). They were
instead instructed to pay attention to the faces, and after the scan-
Table 1. Demographic Variables of the Participants and Characteristics of
the Depressed Participants
First Episode of Depression
Median Length of Episode
Comorbid Anxiety Disorder
Median Length of
BDI, Beck Depression Inventory.
aMean (SD), % (n), or as indicated.
2 BIOL PSYCHIATRY 2011;xx:xxx
C.G. Davey et al.
which they were shown the 32 faces they had seen in the scanner
alongside 32 faces they had never seen (but from the same data-
base). They were also asked to rate, on a 9-point scale, how good
they felt to discover that each of the people in the photographs
liked them. Participants were then debriefed. A questionnaire was
used to probe how the participants experienced the paradigm.
ing feedback, how good they felt on receiving feedback (assessed
globally), and how difficult they found maintaining their attention
throughout the task. Following this they were invited to comment
on the paradigm, and their comments recorded. The deceptive
nature of the task was then discussed with the participants, and a
note made of their response to the deception.
A 3T Siemens Magnetom Trio magnetic resonance scanner (Er-
langen, Germany) was used to acquire whole-brain functional T2*-
weighted echo-planar images. Functional sequences consisted of
view of 210 mm, with a 64 ? 64 pixel matrix, and with a slice
thickness of 3 mm (no interslice gap). Thirty-six interleaved slices,
cover the whole brain for all functional sequences. The first four
(additional) images were discarded to allow the magnetization to
reach steady state. In addition, high-resolution T1-weighted ana-
tomic images were acquired to aid registration of the functional
images to standard space. During scanning, participants were pro-
vided with earphones to reduce scanner noise, and foam-rubber
Presentation software (Neurobehavioral Systems, Albany, Califor-
nia), and were projected onto a half-transparent viewing screen
using an LCD projector (Epson EMP-1810, Tokyo, Japan). Stimuli
Image Preprocessing and Analysis
Image analysis was carried out using tools from the FMRIB Soft-
ware Library (http://www.fmrib.ox.ac.uk/fsl). The images were re-
aligned to compensate for head movements, spatially smoothed
using a 6-mm full-width-half-maximum Gaussian kernel and tem-
porally filtered using a nonlinear high-pass filter with a 128-sec
cutoff period. The positive-feedback and control-feedback face
dynamic response functions, and parameter estimates were calcu-
tion (41). Temporal derivatives were included as covariates to
improve statistical sensitivity. The individual statistical maps were
registered with the participants’ high-resolution structural images
and then normalized to standard (Montreal Neurological Institute)
space using nonlinear transformations.
Mixed-effects analysis was performed at a second level, and
voxels were identified for each group that showed greater activa-
tion to the positive-feedback compared with control-feedback
faces by performing whole-brain analysis with a statistical thresh-
old of p ? .001 (uncorrected). Between-group analysis was con-
ducted using a two-stage process. In the first stage, group differ-
ences for the positive-feedback versus control-feedback contrast
ing at p ? .05 (family-wise error corrected for the small search
volume) (42). Regions were delineated using the Harvard–Oxford
probabilistic atlas in FSL (43).
The second stage of analysis of between-group differences in-
volved whole-brain analysis using a mixed-effects analysis of vari-
ance (ANOVA), with a between-group factor (depressed vs. control
participants) and within-group factor (positive- vs. control-feed-
back). Analysis determined whether any regions other than the
amygdala showed an interaction between group and feedback,
and a main-effects analysis was performed to identify regions that
showed a main effect of group (regions where depressed and con-
trol participants showed differential responses to the faces more
generally). Thresholding was performed at p ? .001 (uncorrected)
with minimum required cluster extents (KE) of eight contiguous
voxels. Although this ad hoc correction does not allow for formal
statistical control of Type I error, it is often adopted in exploratory
fMRI analyses in which there are no clear a priori hypotheses for
regional activations. Nonetheless, the interpretation of results that
use the correction should take the lack of formal statistical control
into account. Further protection against Type I error was provided
by ensuring that the peak voxel for each cluster was within a face-
responsive region for either group (within maps created by exam-
which also ensured that differences arose because one group
showed greater activation than the other and not because one
showed less deactivation than the other. Finally, the clusters iden-
tified in the preceding analyses were tested to determine whether
there were any effects of medication or presence of anxiety disor-
A two-factor ANOVA (group ? face gender) showed that there
were main effects of group on the face ratings [F(1,34) ? 7.7, p ?
.009; control participants rated the faces higher than depressed
participants] and of face gender [F(1,34) ? 37.2, p ? 6.3 ? 10?7;
of the faces at the first session compared with those at the second
session (mean intraclass correlation coefficient in control partici-
pants ? .68 [SD ? .19]; mean intraclass correlation coefficient in
depressed participants ? .71 [SD ? .19]; t34? .37, p ? .71).
Figure 1. Experimental task design. The facial stimuli were presented in
blocks of 16 faces over 96 sec (only a portion of the stimuli are illustrated
presented on a green background and control-feedback faces on a white
background. The faces were presented for 3 sec, and the inclusion of null
7 sec. Photographs reprinted with permission from the AR database Tech
C.G. Davey et al.
BIOL PSYCHIATRY 2011;xx:xxx 3
In the postscan session, there were no differences between the
groups in their response to the debriefing questionnaire (Table S1
in Supplement 1). None of the participants commented that they
believed they had been deceived, and all were noted as having
expressed surprise when the deception was revealed. Both groups
reliably discriminated the faces they had seen during the scanning
session from distractor faces, suggesting similar levels of attention
to the stimuli (control participants’ mean d’ ? 3.96 [SD ? 1.64];
depressed participants’ mean d’ ? 4.43 [SD ? 2.26]; t34? .60, p ?
.55). Correct identification of the positive- and control-feedback
faces was similar for both groups (Table S2 in Supplement 1). The
were liked by each of the people in the task as significantly less
.8] on a 9-point scale to the question, “How good did finding out
that they like you make you feel?”; t34? 2.10, p ? .04).
In a direct comparison of responses to the positive-feedback
regions (ventromedial prefrontal cortex [PFC], pregenual cingulate
ing regions; and in the amygdala (Table S3 in Supplement 1 and
terior midline regions (posterior cingulate cortex and precuneus);
positive-feedback contrast in either group.
Analysis of group differences for the positive-versus control-
the left amygdala (KE?18 voxels) showed greater activation in the
depressed participants for the positive-feedback versus control-
?16 ?4 ?18; peak Z score, 2.47; Figure 4).
two-factor ANOVA (group ? feedback) to identify voxels that
showed significant activation (p ? .001, uncorrected) for the inter-
Figure 3. Activations to the positive- and control-feed-
back conditions in the depressed and control partici-
back faces are depicted in orange and response to the
and displayed on the lateral and medial surfaces of the
right hemisphere using a population-averaged surface
representation that takes into account between-subject
variability in sulcal anatomy (60). The inset images show
the contrast between the positive- and control-feedback
conditions, displayed on a high-resolution (.5 mm isotro-
pic) version of the MNI152 (Montreal Neurological Insti-
tute) standard brain.
Figure 2. Analysis of the face ratings by group. Both the control and the
depressed participants rated the female faces more highly than the male
than the control participants.
4 BIOL PSYCHIATRY 2011;xx:xxx
C.G. Davey et al.
(essentially a between-group comparison of response to all faces
versus fixation). No additional activations (to those demonstrated
in the left amygdala) were identified by the group-by-feedback
sive to the main effect of group (listed in Table 2 and illustrated in
Figure 5). The depressed group showed greater activations to the
main effect of feedback (the positive- and control-feedback condi-
tions considered together) in regions including ventrolateral PFC
in visual association areas.
Statistical comparison was conducted between depressed pa-
tients who were taking medication and unmedicated depressed
patients in each of the regions that had shown differential activa-
tions between the groups (i.e., by performing region-of-interest
analyses in the activation clusters). Although the small number of
depressed participants in each group (nine patients were taking
analysis showed that medication had no significant effects, even at a
liberal threshold of p ? .10. Further analysis compared the unmedi-
cated participants with the control participants. In the amygdala, the
tion compared with control participants (t25? 2.15, p ? .04); in the
The experience of receiving positive social feedback proved to
be a salient experience for both the depressed and control partici-
pants. Compared with the control participants, the depressed par-
stimuli. The preponderance of findings showing that depressed
patients demonstrate amygdala hyperresponsivity to negative
stimuli may reflect the “negativity bias” that is inherent in the way
we respond to the environment (44): negative stimuli generally
have more salience than positive stimuli. The difference in
amygdala reactivity between depressed and control participants
literature on negativity bias suggests will more often be the case
when they have a negative character. Socially meaningful stimuli
that are personally relevant and thus highly salient, however, even
if positively valenced, have been demonstrated by this study to
drive a greater amygdala response in depressed participants.
It is not entirely clear how amygdala hyperresponsivity to posi-
tive social feedback may relate to the phenomenology of depres-
sion. One possibility is that greater amygdala response to positive
social feedback corresponds to a higher level of arousal in de-
pressed patients. Given that arousal is a potentially ambiguous
psychological signal (45), this may result in these events being
misinterpreted as aversive, which in turn motivates withdrawal
from even potentially positive social encounters. This is consistent
with previous studies that have found hyperresponsivity of
amygdala-related physiological measures (e.g., the startle reflex
potentiation) (46) to positive stimuli in depressed patients.
Figure 4. Comparison of depressed and control participants’ response to
the positive-feedback versus control-feedback contrast in the amygdala,
with a graph showing the blood oxygen level–dependent activations for
the control participants and the depressed participants, who have been
ipants were compared with the control participants (p ? .05).
Table 2. Significant Activations for the Main Effect of Group
Brain RegionBrodmann Area
No. of Voxels
in ClusterZ Score at Peak Voxel
MNI Coordinates of Peak Voxel
Depressed ? Control
Right inferior frontal cortex**
Right inferior parietal cortex*
Left occipital cortex*
Right pregenual ACC*
Left inferior frontal cortex*
Left pregenual ACC
Right superior frontal cortex*
Right middle temporal cortex
Control ? Depressed
Left lateral occipital cortex
Right fusiform cortex
Right lingual cortex*
**p ? .01.
ACC, anterior cingulate cortex; MNI, Montreal Neurological Institute.
C.G. Davey et al.
BIOL PSYCHIATRY 2011;xx:xxx 5
Response to the faces as a whole, irrespective of the condition
associated with them, was associated with greater activation in
depressed compared with control participants in the left inferior
represent an effort by the depressed participants to appraise and
downregulate their more ambivalent feelings about viewing the
affective stimuli—particularly where they are of ambiguous va-
lence (47)—and modulation of their emotional impact (48–50). In
depressed patients, the vlPFC has previously been reported to
response to negative words (52) and pain (53).
This study’s demonstration of increased activations in depressed
participants in right anterior insula and pregenual ACC suggests that
are coactivated by tasks that evoke felt emotion (54). The pregenual
ACC has previously been demonstrated to show increased activity in
depressed participants in the resting state (55) and decreased activa-
memories (58), and pain (53). Considered against these findings, the
function of the regions, and the phenomenology of depression, in-
creased activation in pregenual ACC and anterior insula in depressed
participants suggests that viewing the faces was affectively arousing.
Although the valence of the arousal is not clear, it is of note that the
behavioral data showed that receiving positive social feedback was
ing that depressed participants, who experience feelings of low self-
Generalization of the study results may be limited by a num-
ber of factors, including the characteristics of the participants
and the constructs that were assessed. The study included de-
pressed young people who were suffering from relatively severe
depression, and half were being treated with antidepressant
medication. Although analysis did not demonstrate that medi-
cation had significant effects on the reported results, the small
numbers in the medicated and nonmedicated groups limited
our ability to examine its effects. There are feasible mechanisms
through which antidepressant medications might influence the
results, with evidence, for example, that increased synaptic se-
rotonin has region-specific effects on the blood oxygen level–
dependent signal (59) (although for regions such as the PFC, in
the opposite direction to one that would affect our findings). A
further limitation to interpretation of the study results arose
and interpretation may have been more conclusive had we
gained more behavioral information on how the participants
responded to the feedback conditions.
Notwithstanding these limitations, the paradigm was able to
demonstrate how depression affects a young person’s engage-
ment with the social world. The results suggest that depressed
young people are, on the whole, sensitive to social evaluation.
The study showed that amygdala hyperresponsivity in depres-
sion is not limited to negatively valenced stimuli; it is also dem-
onstrated by the response of the participants to personally rele-
vant stimuli with positive valence, which may represent a
nonspecific arousal to social stimuli that are misinterpreted as
depression: social events are not anticipated with much plea-
sure, and social withdrawal is a common symptom. The study
results provide some explanation for the phenomenological ob-
servations. The paradigm demonstrates that although de-
pressed young people are “reactive” to the social environment,
Figure 5. Activations to the main effect of group from a
two-factor analysis of variance (group ? feedback). Re-
gions in which depressed participants showed greater
response to the all-faces versus fixation contrast are
shown in orange, including ventrolateral prefrontal cor-
Activations in selected clusters are illustrated graphically
(note that the activations for the right inferior parietal
blood oxygen level-dependent.
6 BIOL PSYCHIATRY 2011;xx:xxx
C.G. Davey et al.
tralia (Neuroscience Research Grant). Dr. Davey is supported by a Na-
tional Health and Medical Research Council (NHMRC) Training (Post-
a grant from the Colonial Foundation and Drs. Harrison (ID No.
628509) and Yücel (ID No. 509345) are supported by NHMRC Clinical
All authors reported no biomedical financial interests or potential
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