Subgenual anteriorcingulate responsesto peer rejection: A marker
of adolescents’ risk for depression
CARRIE L. MASTEN,aNAOMI I. EISENBERGER,aLARISSA A. BOROFSKY,bKRISTIN MCNEALY,c
JENNIFER H. PFEIFER,dAND MIRELLA DAPRETTOa
aUniversity of California, Los Angeles;bUniversity of Southern California;cDuke University; anddUniversity of Oregon
Extensive developmental research has linked peer rejection during adolescence with a host of psychopathological outcomes, including depression.Moreover,
recent neuroimaging research has suggested that increased activity in the subgenual region of the anterior cingulate cortex (subACC), which has been
hypothesis that adolescents’ subACC responses are predictive of their risk for future depression, by examining the relationship between subACC activity
during peer rejection and increases in depressive symptoms during the following year. During a functional magnetic resonance imaging scan, 20 13-year-
olds were ostensibly excluded by peers during an online social interaction. Participants’ depressive symptoms were assessed via parental reports at the
time of the scan and 1 year later. Region of interest and whole-brain analyses indicated that greater subACC activity during exclusion was associated with
increases in parent-reported depressive symptoms during the following year. These findings suggest that subACC responsivity to social exclusion may
and the increased risk of depression that occurs during adolescence.
As children transition into adolescence, they face a unique
1990) at the same time as peer rejection becomes more prev-
alent (Coie, Dodge, & Kupersmidt, 1990; Juvonen, Graham,
&Shuster, 2003). At this age there is awell-documented shift
from relying on parents for social support to relying on peer
relationships (Rubin, Bukowski, & Parker, 2006). Upon en-
tering adolescence, youth spend increased time with peers
(Csikszentmihalyi & Larson, 1984), seek out peers’ opinions
and place increased value on gaining their approval (Brown,
1990), and are generally more concerned with maintaining
peer acceptance (Parkhurst & Hopmeyer, 1998). However,
along with this heightened emphasis on social relationships
with peers comes increased risk for peer rejection, which is
a particularly prevalent form of negative treatment at this
age (Coie et al., 1990). Given adolescents’ reliance on peer
relationships and the degree to which they value peer accep-
tance, it is not surprising that this increase in peer rejection
has significant negative consequences for adolescents’ emo-
tional well-being and mental health.
increasingly predictive of depression (Hankin, Mermelstein, &
Roesch, 2007; Larson & Ham, 1993; Leadbeater, Kuperminc,
Blatt, & Hertzog, 1999; Nolan, Flynn, & Garber, 2003; Ru-
dolph, 2002; Rudolph et al., 2000; Rudolph & Hammen,
1999; Rudolph, Hammen, & Burge, 1994), and overall there
is a significant spike in the onset of depression (Pine, Cohen,
Gurley, Brook, & Ma, 1998; Pine, Cohen, Johnson, & Brook,
and conflict have been linked with increased rates of depression
Wilson, 2002; Nolan et al., 2003; Panak & Garber, 1992; Prin-
stein & Aikins, 2004; Rigby, 2003), increased internalizing and
externalizing symptoms over time (Carter, Garber, Ciesla, &
Cole, 2006), increased social withdrawal (Abecassis, Hartup,
Address correspondence and reprint requests to: Carrie L. Masten, c/o
Naomi I. Eisenberger, Department of Psychology, University of California,
Los Angeles, 1285 Franz Hall, Box 951563, Los Angeles, CA 90095-
1563; E-mail: email@example.com.
This work was supported by the Santa Fe Institute Consortium. Support was
also provided by an Elizabeth Munsterberg Koppitz Award and a Ruth
L. Kirschstein National Research Service Award (to C.M.). The authors are
grateful for the generous support from the Brain Mapping Medical Research
Organization, Brain Mapping Support Foundation, Pierson–Lovelace Foun-
dation, Ahmanson Foundation, Tamkin Foundation, Jennifer Jones–Simon
Foundation, Capital Group Companies Charitable Foundation, Robson Fam-
ily, William M. and Linda R. Dietel Philanthropic Fund at the Northern Pied-
tially supported by grants (RR12169, RR13642 and RR00865) from the
National Center for Research Resources, a component of the National Insti-
tutes of Health. Its contents are solely the responsibilityof the authors and do
not necessarily represent the official views of the National Center for Re-
search Resources or the National Institutes of Health. The funders had no
role in the study design, data collection and analysis, decision to publish,
or preparation of the manuscript. The authors thank Elliot Berkman for sta-
Development and Psychopathology 23 (2011), 283–292
#Cambridge University Press 2011
Haselager, Scholte, & Lieshout, 2002), and other adverse men-
tal health outcomes that persist across development (Lev-Wie-
sel, Nuttman-Shwartz, & Sternberg, 2006; Prinstein & Aikins,
2004; Prinstein, Sheah, & Guyer, 2005).
incidences of peer rejection and interpersonal stress lead to in-
creases in depression, rather than the converse possibility that
depressed individuals elicit more interpersonal stressors (Ham-
& Garber, 1992; Hankin et al., 2007; Nolan et al., 2003). Thus,
adolescents’ responses to social stressors in peer contexts may
precipitate increases in internalizing symptoms and depression
not only experience an increase in peer-related stressors that
likely contributes to these symptom increases but also are
more sensitive to these stressors (Hankin & Abramson, 2001;
Nelson, Leibenluft, McClure, & Pine, 2005; Rudolph, 2002).
dicted psychopathological outcomes, even after controlling for
hower, 2003). In other words, adolescents likely experience
more peer-related stress in adolescence because of both an in-
creased number of stressful events as well as heightened sensi-
tivity to these events, and individuals’ responses to negative
events like peer rejection are likely an important contributor to
adolescents’ heightened risk for depression.
Building on this literature, researchers have suggested that
manyofthechangesthatoccurduring adolescence, including
a reorientation toward peers and away from parents, height-
ened stress responses to peer rejection, and the increasing
onset of mood disorders, may partially reflect underlying
changes in neural responses to social events (Nelson et al.,
2005; Steinberg, 2008). The degree of neural activity that
adolescents display in brain regions responsible for affective
rectly relate to their emotional sensitivity to these events and
predict their likelihood of developing psychopathology (Nel-
son et al., 2005). This theory is consistent with the robust de-
velopmental literature indicating that heightened sensitivity
to social stressors during adolescence contributes to depres-
sion onset and suggests a parallel contribution of neural sen-
sitivity to adolescents’ risk for depression.
rejection contribute to adolescents’ risk for depression through
both behavioral and neural pathways, specific neurobiological
markers that might predict future outcomes remain unexplored
in adolescents. Fortunately, however, recent neuroimaging
studies of adult populations have begun to elucidate the brain
systems involved in depression, and they provide a framework
typical age of depression onset. These studies have focused
largely on the subgenual anterior cingulate cortex (subACC)
and its role in depressive symptomatology. For example, re-
search examining depressed populations has indicated that
the subACC is more responsive to negative emotional stimuli
among depressed patients (Chen et al., 2007; Davidson, Irwin,
ity is indicative of the severity of depressive symptoms (Saxena
et al., 2003), and responsiveness to clinical treatment (Brody
ity in predicting depressive symptoms during adolescence prior
to disorder onset is clearly warranted. Specifically, examining
may be useful in predicting adolescents’ risk for depression.
Itis interesting that thesubACC and several of its surround-
ing subcortical structures have already been implicated in ado-
lescents’ experiencesof peer rejectionaswellasotheraffective
experiences. A recent neuroimaging study examining 13-year-
olds’ neural responses to peer rejection found heightened sub-
compared to peer inclusion, and this activity was positively re-
lated to adolescents’ reported distress resulting from the exclu-
sion (Masten et al., 2009). This finding suggests that overlap-
ping neural systems are involved in both sensitivity to peer
rejection among adolescents and neural dysregulation among
depressed adults, and supports the possibility that heightened
subACC activity might be predictive of both sensitivity to
peer rejection and heightened risk for depression during
adolescence. Additional studies examining social processing
among adolescents have implicated other subcortical regions
in affective processing that are highly interconnected with the
subACC, including the ventral striatum, hypothalamus, amyg-
dala, orbitofrontal cortex, and anterior cingulate (Guyer et al.,
2008; Guyer, McClure-Tone, Shiffrin, Pine, & Nelson, 2009;
tant index of sensitivity to social stressors like peer rejection,
and that this subcortical activity might act as a marker of ado-
lescents’ risk for depression.
esis. One route via which peer-related stressors likely contrib-
ute to adolescents’ risk for depression isthrough altered neural
sensitivities (see Nelson et al., 2005), and the subACC has
been shown to index responses to one of the most pervasive
and stressful types of peer-related stressors, that is, peer rejec-
tion (Masten et al., 2009), as well as emotional processing
among depressed adults (Chen et al., 2007; Davidson, Irwin,
Anderle, & Kalin, 2003). Thus, our goal was to examine
whetherheightenedsubACC activity in response topeerrejec-
tion among adolescents was associated with increases in de-
pressivesymptomsover time. Toexamine this, healthyadoles-
cents were ostensibly excluded during a functional magnetic
resonance imaging (fMRI) scan in order to measure subACC
responses to peer rejection. These subACC responses were
then correlated with concurrent, and increases in, depressive
symptoms over the following year. We expected that adoles-
centsdisplayinggreater subACCactivity wouldbe morelikely
to develop depressive symptoms over time.
In this study we aimed to expand on previous research in
several ways. First, although research has examined neural
correlates of depression among adults, this is the first neuro-
C. L. Masten et al.
imaging study to examine antecedents of risk for depression
during adolescencewhen disorder onset has not yet occurred.
Our sample consisted of young adolescents who had recently
begun middle school—the period of development during
which peers relationships are highlysalient and peer rejection
is most prevalent (Brown, 1990; Coie et al., 1990; Juvonen
et al., 2003; Rubin et al., 2006). In addition, theseyoung ado-
lescents were all typically developing and within the normal
range of depressive symptomatology. Thus, we were able to
examine predictors of adolescents’ risk for depression prior
to any potential disorder onset, as well as developmental pro-
cesses relevant for understanding changing depressive symp-
toms across this period of development. Second, we used an
ecologically valid taskto examine emotional responsestoa sa-
lient, real-life, social stressor. Previous neuroimaging studies
examining depression in adults have typically relied on resting
state responses or simple emotion-processing tasks, whereas
previous behavioral studies examining adolescents have relied
largely on reports of past experiences or imagined vignettes.
ulate a real, highly relevant, social experience is much needed
(Nelson et al., 2005). Third, to our knowledge, no prior neuro-
imaging studies have examined predictive links between social
or emotional experiences and mental health-related outcomes
across time. Thus, we employed a longitudinal design in order
depression and to complement the many well-designed, longi-
tudinal, behavioral studies examining this topic.
Fourth, in the current study we also explored potential sex
differences, given that these differences have been well estab-
lished in both clinical and affective neuroimaging research on
social/emotional processing and depression. Specifically, re-
search has shown that the onset of depression is earlier and
more prevalent among females (Weissman & Klerman, 1977;
Wolk & Weissman, 1995), and that these differences in depres-
sion first reliably emerge in adolescence (Nolen-Hoeksema &
are more likely to develop depression as a result of certain de-
cerns (Rudolph & Conley, 2005), and both increased frequency
& Abramson, 1999; Wagner & Compas, 1990). Furthermore,
neuroimaging studies have also shown sex differences in affec-
tive and emotional processing in adolescents (e.g., Guyer et al.,
2009). Thus, although our sample size did not permit definitive
tests of sex differences, we explored potential differential pat-
terns in the links between subACC activity and development
of depressive symptoms among boys and girls.
A socioeconomically diverse sample of 20 adolescents (13
females), representing a range of ethnic backgrounds (45%
Caucasian, 30% Latino, 10% African American, 10% Asian,
and 5% Native American), were recruited from the greater
Los Angeles area through mass mailings, summer camps,
parents underwent extensive screening and participants
showed no self- or parent-reported evidence of any psychiat-
ric disorder, and were not taking any psychiatric medications
¼ 12.4–13.6 years, M ¼ 12.94 years), participants completed
an fMRI scan during which they experienced a simulated ex-
perience of peer rejection and subsequentlyself-reported their
distress, and their parents completeda measure assessing their
child’s depressive symptoms (see below). At the second time
is particularly relevant given prior research characterizing the
All participants and their parents provided assent/consent in
accordance with UCLA’s institutional review board.
fMRI-simulated peer exclusion task
In order to simulate peer rejection during the fMRI scan, ado-
lescents played two rounds of a computerized game called
“Cyberball” (Williams, Cheung, & Choi, 2000; Williams
et al., 2002), in which participants experienced simulated
peer exclusion. This simulation of exclusion was used as a
proxy for peer rejection based on research indicating that dur-
ing early adolescence, isolating peers from social groups is
one of the dominant methods used to reject peers (Coie
et al., 1990). Moreover, Cyberball has been used successfully
with adults (Eisenberger, Lieberman, & Williams, 2003) and
adolescents (Masten et al., 2009).
Duringthe instructionsfor theCyberball game,participants
Internet with two other adolescents in other scanners, in order
to examine coordinated neural activity. To increase ecological
validity, participants were given the first names, ages (which
matched that of the participant) and genders (one boy, one
girl) of these other players. Once in the scanner, the Cyberball
game was displayed on a computer screen through MR-com-
cartoon images representing the other players, as well as a car-
toon image of their own “hand” that they controlled using a
button box. Throughout the game the ball was thrown back
and forth among the three players, with the participant choos-
other two “players” determined by the preset program. Partici-
pants played two rounds of Cyberball during two sequential
fMRI scans: one round in which they were “included” through-
out the game, and one round in which they were “excluded” by
the other participants. Throughout the inclusion round the com-
puterizedplayers wereequallylikely to throw the ball tothepar-
Neural basis of adolescents’ risk for depression
the two computerized players stopped throwing the ball to the
participant after the participant had received a total of 10 throws
and threw the ball only to each other for the remainder of the
game. Upon leaving the scanner, participants self-reported their
distress resulting from the exclusion condition (see below) and
Measure of distress resulting from peer exclusion
Immediately following completion of the Cyberball task,
adolescents completed the Need–Threat Scale (NTS; Wil-
liams et al., 2000; Williams et al., 2002) in order to measure
distress associated with the exclusion condition. The NTS as-
cluded during the game, including ratings of self-esteem (“I
felt liked”), belongingness (“I felt rejected”), meaningfulness
(“I felt invisible”), and control (“I felt powerful”), on a scale
ranging from 1 (not at all) to 5 (very much).
Measures of depressive symptoms
Depressive symptoms were assessed at both time points
through parental reports on the withdrawn/depressed subscale
of the Childhood Behavior Checklist (CBCL; Achenbach &
toms and negative affect typical of depression and other mood
disorders. Participants were specifically recruited so as not to
meet clinical or subclinical criteria for any psychiatric condi-
tion including depression (Ts . 65). However, a range of
CBCL scores was reported on this subscale at both time points
(see behavioral results). Participants’ scores at Time 1 reflect
their concurrent depressive symptoms at the time of the
fMRI scan. Scores at Time 2, after controlling for Time 1, re-
flect increases (or decreases) in participants’ depressive symp-
toms during the year following the scan. To control for scores
at Time 1, residualized scores for Time 2 were calculated,
whereby thegroup-level variance in Time 2scoresthat was ex-
plained by Time 1 scores was removed. There were no sex dif-
ferences in depressive symptoms at either time point, and there
were no sex differences inthe amount of increaseindepressive
symptoms from Time 1 to Time 2.
fMRI data acquisition
Images were collected using a Siemens Allegra 3-Tesla MRI
crease motion, and head motion was restrained with foam pad-
ding. For each participant, an initial two-dimensional spin–
echo image (repetition time [TR] ¼ 4000 ms, echo time [TE]
¼ 40 ms, matrix size 256?256, 4-mm thickness, 1-mm gap)
a high-resolution structural scan (echo planar spin–spin relaxa-
tion time [T2] weighted spin–echo, TR ¼ 4000 ms, TE ¼ 54
ms, matrix size 128?128, field of view ¼ 20 cm, 36 slices,
1.56-mm in-plane resolution, 3-mm thickness) coplanar with
tion during fMRI analysis preprocessing. Each of the two
rounds of Cyberball was completed during a functional scan
lasting 2 min, 48 s (echo planar combined magnetic field inho-
mogeneities and spin–spin relaxation time [T2*] weighted gra-
matrix size 64?64, 36 axial slices, field of view ¼ 20 cm,
3-mm thickness, 1-mm skip).
fMRI data analysis
Neuroimaging data were preprocessed and analyzed using
statistical parametric mapping (SPM5; Wellcome Depart-
ment of Cognitive Neurology, Institute of Neurology, Lon-
don), and region of interest (ROI) extraction was performed
using the MARsBaR toolbox within SPM (Marseille boı ˆte
a ` re ´gion d’inte ´re ˆt; Brett, Anton, Valabregue & Poline,
2002). Preprocessing included image realignment to correct
for head motion, normalization into a standard stereotactic
space defined by the Montreal Neurological Institute and
the International Consortium for Brain Mapping, and spatial
smoothing using an 8-mm Gaussian kernel at full width at
half-maximum to increase the signal/noise ratio.
Modeling of contrasts. The Cyberball task was modeled as a
block design. Each round of Cyberball was modeled as a run
with each period of inclusion and exclusion modeled as
blocks within the run for a total of two inclusion blocks
(one during the first run and one during the short period of in-
clusion in the second run prior to exclusion) and one exclu-
sion block. After modeling the Cyberball paradigm, linear
contrasts were calculated for each planned condition compar-
ison for each participant. These individual contrast images
were then used in ROI and whole-brain, group-level, ran-
dom-effects analyses across all participants.
ROI analyses. Given our specific interest in the relationship
between subACC activity and adolescents’ risk for depres-
sion, we first performed ROI analyses to examine whether
subACC activity in response to peer rejection was associated
with either concurrent depressive symptoms or increases in
depressive symptoms during the following year. The ROI
was functionally defined (using the MARsBaR toolbox) as
the cluster in the subACC that was previously found to
show greater activation to peer exclusion compared to inclu-
sion, among a larger group of adolescents that included those
in the current study (see Masten et al., 2009; peak voxel [x y z
in millimeters (8 22 24)], t ¼ 4.06, p ¼ .0005, k ¼ 151 vox-
els). Mean parameter estimates for each participant (which
model the amplitude of the blood oxygen level-dependent re-
sponse during exclusion vs. inclusion) were then extracted
and averaged across all voxels in the ROI. Standard statistical
software (SPSS 16.0, Chicago) was used to conduct correla-
tions to determine whether these parameter estimates were
increases in (scores at Time 2, controlling for Time 1) depres-
C. L. Masten et al.
sive symptom scores. To examine whether activity in this
same region of the subACC correlated with participants’
ball, we examined whether these parameter estimates were
subACC activity would be associated specifically with
greater increases in depressive symptoms over time, as well
as greater self-reported distress, all tests were one tailed.
Whole-brain analyses. In order to supplement the ROI analy-
peer rejection and depressive symptoms, as well as self-re-
ported distress following exclusion, the following group-level
tests were run at each voxel across the entire brain volume:
that were associated with individuals’ concurrent depressive
symptoms (parent-reported scores at Time 1), (b) examination
of differences between exclusion and inclusion that were asso-
ciated with longitudinal increases in individuals’ depressive
symptoms (parent-reported scores at Time 2, controlling for
Time 1scores), and (c) examination of differences between ex-
clusion and inclusion that were associated with NTS scores.
Reported correlational findings reflect regions of the brain
identified using these whole-brain regressions, in which de-
All whole-brain, group-level regression analyses were thresh-
olded at p , .001 for magnitude, with a minimum cluster
size threshold of 10 voxels. All coordinates are reported in
Montreal Neurological Institute format.
Analyses of sex differences. Finally, given the established sex
differences in depression onset during adolescence (Nolen-
Hoeksema & Girgus, 1994; Peterson et al., 1993; Weissman
& Klerman, 1977; Wolk & Weissman, 1995), we also per-
formed exploratory ROI and whole-brain regressions to ex-
tivity and longitudinal increases in depressive symptoms.
For subjective distress reported immediately following the
Cyberball game, participants’ mean score was 2.90 (SD ¼
0.73) and ranged from 1.58 to 4.50 out of a possible 5; these
scores did not differ by sex. For parent-reported depression
symptoms, CBCL subscale scores ranged from T ¼ 50 to
57 at both time points. Scores were similar on average at
Time 1 (M ¼ 51.35, SD ¼ 2.35) and Time 2 (M ¼ 51.85,
SD ¼ 2.43), suggesting that across the whole sample there
was no overall increase in depressive symptoms. These sub-
was no sex difference in the amount of increase in depression
symptoms from Time 1 to Time 2. Finally, there were no sig-
nificant correlations between self-reported distress following
scores at Time 1 (r ¼ 2.02, ns) or Time 2 (r ¼ 2.12, ns), per-
of current neuroimaging studies.
ROI analyses revealed that activity during peer rejection in the
subACC was not associated with concurrent depressive symp-
toms (r ¼ .01, ns), but was significantly correlated with subse-
quent increases in depressive symptoms (r ¼ .39, p , .05; see
Figure 1). Therewas no sex difference in this effect (Z ¼ 0.24,
ns; girls: r ¼ .34, p ¼ .13; boys: r ¼ .46, p ¼ .15). In addition,
activity in this ROI was marginally correlated with self-re-
Figure 1. A scatterplot depicting the relationship between increases in depressive symptoms scores and mean parameter estimates extracted for
each individual from the subgenualanteriorcingulate cortex (subACC) region of interest (ROI;r ¼ .39; ROI is functionallydefined asthe region
that showed greater activity among adolescents experiencing peer exclusion compared to inclusion in a previous study; see Masten et al., 2009).
Neural basis of adolescents’ risk for depression
ported social distress following the exclusionepisode (r ¼ .32,
p ¼ .08).Thus, greater subACCactivityin response topeerre-
jection was associated with greater subsequent increases in de-
pressive symptoms among adolescents as well as greater self-
reported distress in response to rejection.
Consistent with the ROI analyses, whole-brain analyses indi-
cated that greater subACC activity during peer rejection was
not related to concurrent depressive symptoms (see Table 1).
However, activity in two regions of the subACC was signifi-
cantlyassociated with increases in depressive symptoms during
effects (Zs , 0.15,ns).1In addition, as reported previously (see
Mastenet al.,2009),whole-brain analysesalsorevealedthat ac-
tivity in a similar region of the subACC correlated significantly
with self-reported social distress following rejection (r ¼ .70, p
, .001 for the 20 participants included in the current sample).
regions—the dorsomedial prefrontal cortex (DMPFC; [14 44
44], t ¼ 5.14, r ¼ .80, p , .0001, k ¼ 60) and the middle tem-
was associated with a longitudinal increase in depressive symp-
activity and increases in depressive symptom scores.
Findings from this study indicate that healthy adolescents dis-
playing greater subACC activationinresponseto peer rejection
are more likely to exhibit an increase in depressive symptoms
during the following year. To our knowledge, this is the first
study to establish a neurobiological link between a social
of predictive links. Our findings provide promising support for
the hypothesis that subACC responsiveness may be predictive
of healthy adolescents’ risk for future depression, and extends
behavioral research that has consistently linked experiences of
peer rejection with depressive symptoms during adolescence
(French et al., 1995; Larson et al., 2002; Nolan et al., 2003; Pa-
nak & Garber, 1992; Prinstein & Aikins, 2004; Rigby, 2003).
Table 1. Anatomical regions activated during the exclusion condition versus the inclusion condition that correlated
significantly with concurrent depressive symptoms
Anat. Region BA
Positive Associations With Concurrent Depressive Symptoms
Negative Associations With Concurrent Depressive Symptoms
Note: BA, putative Brodmann area; L, R, respective left and right hemispheres; x, y, and z, Montreal Neurological Institute coordinates in respective left–right,
anterior–posterior, and interior–superior dimensions; t, t score at those coordinates (local maxima); r, correlation coefficient representing the strength of the
association between concurrent depression symptom scores and the difference between activity during exclusion and activity during inclusion in the specified
clusters; VLPFC, ventrolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; PCC, posterior cingulate cortex; IPL, inferior parietal lobe; DLPFC,
dorsolateral PFC; SMA, supplementary motor area; rACC, rostral anterior cingulate cortex; STG, superior temporal gyrus; dACC, dorsal ACC.
1. In addition, when whole-brain regression analyses were run separately for
participants in each group; p ¼ .05, minimum cluster ¼ 10 voxels), there
activity and increases in depressive symptom scores. For both girls and
boys, the subACC was related to increases in depressive symptoms: girls,
[12 36 210], t ¼ 6.39, r ¼ .89, p , .0001, k ¼ 589; boys, [6 30 210], t ¼
5.37, r ¼ .92, p , .005, k ¼ 332. Although our sample size was not large
enough to permit a definitive investigation of sex differences, these anal-
yses provide little evidence that the relationship between subACC activity
and increases in depressive symptoms varies in any meaningful way
C. L. Masten et al.
These findings also build on previous work with adults
linking subACC activity with functioning among depressed
patients (Brody et al., 1999; Chen et al., 2007; Davidson
et al., 2003; Mayberg et al., 1997; Saxena et al., 2003) in two
ways. First, these findings indicated that subACC activity is a
potentially important neural marker of depressive symptoms
that can be assessed prior to any diagnosis of depression. In
other words, subACC responses may be predictive of indi-
viduals’ risk for developing depression during late adolescence
Second, these previous studies of depression in adults relied on
resting state activity (Brody et al., 1999; Mayberg et al., 1997;
Saxena et al., 2003) or responses to simple emotional stimuli
(Chen et al., 2007; Davidson et al., 2003). The current findings
demonstrate a link between neural sensitivity during a real,
social experience with peers and depressive symptom ratings,
which is an extension of previous work that has been needed
for a long time (Nelson et al., 2005). Thus, our findings extend
previous work by demonstrating that subACC activity in re-
of subACC activity, may be indicative of future depression.
Given that subACC activity during peer rejection did not
relate to concurrent depressive symptoms, but rather was asso-
ciated with longitudinal increases in depressive symptoms,
heightened subACC activity during peer rejection may specifi-
toms over time. Thus, individuals who show greater subACC
responses to peer rejection early in adolescence may be more
likely to subsequentlyexperience increases in depressive symp-
toms, and may face a greater likelihood of eventually develop-
ing a clinical disorder. The absence of a link between subACC
vulnerability among certain individuals that is cumulative over
sitivity include increases in internalizing symptoms that could
ity could represent an early indication of which individuals will
their sensitivity to peer rejection. Of course, causality cannot be
determined from the correlational methods used in this study;
however, future research with adolescent participants should
continue to probe the relationships between subACC activity,
depressive symptoms, and eventual disorder onset.
Although understanding the mechanism responsible for the
rejection might actuallyalteradolescents’ subjective emotional
experiences and result in more acute emotional responses and
more negative interpretations of both current and future in-
stances of peer rejection. As a result, the peers of these adoles-
andpotentially reject them more frequentlyin the future. Thus,
over time, sensitivity at the neural level might actually elicit
more negative peer rejection experiences, from both the vic-
tim’s perspective and in terms of frequency, that put adoles-
cents at greater risk for psychopathology.
Second, in the current study we found some indication that
activity during peer rejection in regions other than the subACC,
including the DMPFC, posterior cingulate cortex, and precu-
neus, also related to depressive symptoms both concurrently
and over time. Based on prior research linking these areas
tives of others (Frith & Frith, 1999, 2003, 2006; Mitchell et al.,
Figure 2. The whole-brain regression analysis displaying activity in the subgenual anterior cingulate cortex (subACC) during peer exclusion
compared to inclusion that was associated with increases in depressive symptoms over the following year. The scatterplot is provided to illustrate
the relationship between increases in depressive symptoms and the mean parameter estimates extracted for each individual from the significant
subACC cluster. For display purposes only, activation shown here isthresholded at p ¼ .01 to better depict the location and nature of this activa-
tion. [A color version of this figure can be viewed online at journals.cambridge.org/dpp]
Neural basis of adolescents’ risk for depression
2005), one possibility is that adolescents displaying greater ac-
tivity in these regions are thinking more about the negative so-
cial interaction or worrying more about why they were rejected.
Over time, frequent mentalizing associated with negative peer
interactions could lead to chronic rumination and other depres-
Third, another possibility isthat greater responsivity in the
subACC during peer rejection reflects an inability to properly
regulate emotions resulting from such negative events.2One
previously proposed mechanism for depression is corticolim-
dysregulation of the subACC in particular has been impli-
cated in susceptibility for depression (Pezawas et al., 2005).
Moreover, the positive relationship found in the current find-
ings and in previous findings (Masten et al., 2009) between
subACC activity and adolescents’ distress following peer re-
jection further suggests that activity in this region is greater
among individuals who are less able to regulate negative
emotion. Examining the link between subcortical regions
and emotion regulation in the context of adolescents’ risk
for depression will be a fruitful avenue for future research.
The findings of the current study should be considered in
light of several limitations, which might also help direct future
studies. First, the adolescent participants did not meet clinical
criteria for depression; thus, the links found between subACC
do not necessarily reflect patterns representative of a depressed
adolescence, we believe the findings reported here contribute to
actual disorderonset.However,itwill becrucial forfuturestud-
ies to examine depressed adolescent populations with longitu-
dinal data that taps brain function spanning the period during
depression. Second, the measure of depressive symptoms em-
ployed was not ideal. Although the withdrawn/depressed sub-
scale of the CBCL is useful for measuring an array of internal-
izing symptoms typical of depressive disorders, future studies
should use more comprehensive diagnostic tests with multiple
reporters (e.g., self-reports in addition to parental reports) to
measure both depressive symptomatology among typically de-
ulations. Third, although the goal of the present investigation
would benefit from using other tasks that are known to engage
cortex, hypothalamus; Guyer et al., 2009; Monk et al., 2003;
Nelson et al., 2005), as well as areas implicated in the current
study that have been previously linked with cognitive control
and mentalizing processes (i.e., DMPFC, posterior cingulate
cortex, precuneus; Frith & Frith, 1999, 2003, 2006; Mitchell
will be invaluable for understanding causal links between ado-
lescents’ social experiences and the development of psychopa-
Fourth, future research should further explore potential sex
pressive symptoms. Although the current findings provide no
activity and increases in depressive symptoms over time, the
sample size for girls and particularly for boys was too small
in this investigation to permit conclusive results. Given the
well-established sex differences in frequencyof social stressors,
(Hankin & Abramson, 1999; Nolen-Hoeksema, Girgus, 1994;
Peterson, et al., 1993; Wagner & Compas, 1990), larger studies
could focus specifically on differences between boys and girls,
status and pubertal timing that might play a key role in produc-
ing sex differences in the development of depression.
These findings are the first to demonstrate a neural link be-
tween peer rejection and depressive symptoms during adoles-
cence and suggest that heightened subACC responsivity may
be a marker of adolescents’ risk for later depression. In addi-
tion, these findings contribute to the growing body of neuro-
psychiatric research implicating the subACC as a region that
depression, as well as its developmental course. Finally, this
work as a whole links the fields of adolescent peer relations
and clinical neuroscience, and contributes to our knowledge
about how risk for depression may develop in the context
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