The default mode network and self-referential
processes in depression
Yvette I. Shelinea,b,c,1, Deanna M. Barcha,b,d, Joseph L. Pricee, Melissa M. Rundleb, S. Neil Vaishnavib,
Abraham Z. Snyderb,c, Mark A. Mintuna,b, Suzhi Wanga, Rebecca S. Coalsonb,c, and Marcus E. Raichleb,c,2
Departments ofaPsychiatry,bRadiology,cNeurology,dPsychology, andeAnatomy and Neurobiology, Washington University, St. Louis, MO 63110
Contributed by Marcus E. Raichle, December 12, 2008 (sent for review August 26, 2008)
The recently discovered default mode network (DMN) is a group of
a self-referential nature. In normal individuals, activity in the DMN
is reduced during nonself-referential goal-directed tasks, in keep-
ing with the folk-psychological notion of losing one’s self in one’s
work. Imaging and anatomical studies in major depression have
found alterations in both the structure and function in some
regions that belong to the DMN, thus, suggesting a basis for the
disordered self-referential thought of depression. Here, we sought
to examine DMN functionality as a network in patients with major
depression, asking whether the ability to regulate its activity and,
hence, its role in self-referential processing, was impaired. To do
so, we asked patients and controls to examine negative pictures
passively and also to reappraise them actively. In widely distrib-
uted elements of the DMN [ventromedial prefrontal cortex pre-
cortex (BA 39), and lateral temporal cortex (BA 21)], depressed, but
not control subjects, exhibited a failure to reduce activity while
both looking at negative pictures and reappraising them. Further-
more, looking at negative pictures elicited a significantly greater
increase in activity in other DMN regions (amygdala, parahip-
pocampus, and hippocampus) in depressed than in control sub-
jects. These data suggest depression is characterized by both
stimulus-induced heightened activity and a failure to normally
down-regulate activity broadly within the DMN. These findings
provide a brain network framework within which to consider the
pathophysiology of depression.
cognitive reappraisal ? fMRI ? medial prefrontal network ?
emotional dysregulation ? activation differences
decrease their activity (1) when compared with a quiet resting
state (e.g., awake with eyes closed). The consistency with which
certain areas of the brain do so, regardless of the nature of the
goal-directed task, led to the notion of an organized default
mode of brain function (2) in which some regions are most active
when we are in a resting state. The areas of the brain most
consistently displaying such behavior regardless of task have
come to be known as the default mode network (DMN) (3, 4),
which consists of areas in dorsal and ventral medial prefrontal
cortices, medial and lateral parietal cortex, and parts of the
medial and lateral temporal cortices.
Recently summarized data (4) indicate that the DMN is
involved in the evaluation of potentially survival-salient infor-
mation from the body and the world: perspective taking of the
desires, beliefs, and intentions of others and in remembering the
past as well as planning the future (2–4). All of these putative
functions are self-referential in nature. Reduction of activity in
the DMN during effortful cognitive processing (1, 5) can be
interpreted as reflecting the need to attenuate the brain’s
self-referential activity as a means of more effectively focusing
on a task. A failure to do so might well lead to interference in
task performance from internal emotional states, as seen in
patients with depression.
hen we engage in almost any goal-directed behavior of a
nonself-referential nature, certain areas of the brain
Studies in patients with major depression have identified
structural and functional abnormalities in brain circuits involved
include the hippocampus, amygdala, anterior cingulate, ventro-
medial prefrontal cortex, and dorsal medial prefrontal cortex
and fall within the anterior portion of the DMN. Although
studies (6–9) have found depression-related abnormalities in
portions of the DMN, it is not clear whether certain regions or
the DMN as a whole is involved in the emotional dysregulation
of depression. Therefore, in the current study, we used fMRI to
measure changes in brain activity occurring within the entire
DMN in 20 individuals with major depression and 21 demo-
graphically similar control subjects during an affective reap-
praisal task (10). Our goal was to examine the role of the DMN
in emotional modulation in depression. To examine task-induced
activity differences within the entire DMN rather than simply in
selected regions, we used a DMN ‘‘mask’’ from an independent
for influencing the results by the content of the task (11).
Behavioral Data. We used a modification of the Ochsner et al. (10)
conditions: passively view neutral pictures (‘‘look neutral’’),
passively view negative picture (‘‘look negative’’), actively make
a negative picture more positive (‘‘make positive’’), and actively
were no significant differences between depressed and control
subjects in the ratings of pictures either during passive viewing
or explicit regulation (see SI Text for details).
the DMN boundaries (see Materials and Methods) to restrict
regions of interest (ROIs) in our data to areas falling within the
DMN. These boundaries correspond closely to published DMN
maps from PET and fMRI data (1, 2, 12) (Fig. 1). We conducted
2 voxelwise ANOVAs (group X picture type X time within trial
and group X regulate task X time within trial) to determine
group differences. In these analyses, ‘‘group’’ contrasted de-
pressed vs. control subjects, ‘‘look’’ (picture type) contrasted
looking at neutral vs. negative pictures, and ‘‘regulate task’’
contrasted passively looking at negative pictures vs. consciously
performed research; S.N.V. contributed new reagents/analytic tools; Y.I.S., D.M.B., J.L.P.,
M.M.R., S.N.V., A.Z.S., S.W., and R.S.C. analyzed data; and Y.I.S., D.M.B., J.L.P., and M.E.R.
wrote the paper.
The authors declare no conflict of interest.
Freely available online through the PNAS open access option.
1To whom correspondence may be addressed at: Washington University School of Medi-
cine, Department of Psychiatry, 660 South Euclid Avenue St. Louis, MO 63110. E-mail:
2To whom correspondence may be addressed. E-mail: email@example.com.
This article contains supporting information online at www.pnas.org/cgi/content/full/
© 2009 by The National Academy of Sciences of the USA
February 10, 2009 ?
vol. 106 ?
no. 6 www.pnas.org?cgi?doi?10.1073?pnas.0812686106
reframing the picture context as positive. Time within trial
referred to the variation across the frame estimates (1–8) for a
particular condition (see Materials and Methods for details of
default region selection and image analysis).
Regions with Task-Induced Activity Reductions. Passive viewing of
negative vs. neutral pictures (look condition). Group effects. There were
14 regions within the DMN that exhibited a group difference
between depressed and controls for the look condition. The
typical pattern of activity for controls was decreased activity
during the task, whereas depressed subjects failed to have a
decrease in activity. Compared with controls, depressed indi-
viduals demonstrated less of a task-related decrease in activity
(i.e., higher activity) in all 14 of these regions except L BA8 (see
Table 1 and Fig. 1 regions in red). Fig. 2 shows time–activity
curves for 8 representative ROIs of the 14 regions in Fig. 1 that
differed between depressed and controls.
neutral pictures in both depressed and controls or a greater
increase in activity for negative than neutral pictures. These
regions are shown in Fig. 1, with the colors indicating whether
the regions exhibited increased or decreased activity. These
regions are also shown in Table S1, and the time–activity curves
are shown in Fig. S1.
Regulation of emotional responses. Group effects. As shown in Table
1, there were 11 regions for which the depressed participants
failed to show the same amount of task-related decreased
activity during the make positive condition as controls, including
2 rostral anterior cingulate regions (Fig. 2 and Fig. S2), dorsal
anterior cingulate (Fig. S2), 2 ventromedial prefrontal cortex
BA8 (Fig. S2), lateral parietal cortex (BA 39) (Fig. S2), and 5
whereas the top right image shows the lateral surface left hemisphere. The bottom left shows the lateral surface right hemisphere whereas the bottom right
image shows the medial surface left hemisphere. All regions are shown in Table 1 (group differences) or Table S1 (regions without group difference effects).
As indicated by the legend, superimposed red colored regions show areas within the DMN where task-induced differences distinguished depressed and control
subjects. The remaining regions had no group differences but had activity decreases in the regulate condition only (yellow), in the look condition only (green),
in both the regulate and look conditions (brown), or had activity increases in both the regulate and look conditions (fuschia).
Task-induced activity in the default mode network. The DMN is shown in light blue. The top left image shows the medial surface right hemisphere
Sheline et al.
February 10, 2009 ?
vol. 106 ?
no. 6 ?
lateral temporal cortex (BA 21) regions (Fig. 2 and Fig. S2).
similar patterns of activity, and their time courses are shown in
In addition there were a number of regions that showed
decreased activity in both depressed and controls during the
regulate condition (see Fig. 1, Fig. S1, and Table S1).
Regions with Task-Induced Activity Increases. Passive viewing of neg-
ative vs. neutral pictures (look condition). Group effects. Three regions
showed more increase in activity in depressed subjects than in
controls, as shown in Table 1 and Fig. 2. In the left parahip-
pocampus, depressed subjects had significantly greater activity
than controls (across the entire time course) in response to
negative as compared with neutral pictures. Although there were
no group differences in the overall time courses (frames 1–8) in
amygdala and hippocampus, examination of the time courses
suggested that depressed patients may have shown enhanced ac-
tivity in the later part of the trial, after onset of the picture.
on the frames covering 10–17.5 s.
The left amygdala [F (1, 43) ? 6.47, P ? 0.01] and right
hippocampus [F (1, 43) ? 7.42, P ? 0.009] showed significantly
different patterns of responses to picture types in depressed vs.
control subjects (i.e., picture type X group interaction). As can
be seen in Fig. 2, controls did not show a significant difference in
responses to neutral vs. negative pictures, but the depressed indi-
viduals showed significantly greater activity to negative compared
with neutral pictures. In one region (left dorsal medial prefrontal
cortex BA8), controls had significantly greater activity in response
to negative pictures than depressed (Table 1 and Fig. S2).
Picture-type effects. Several regions showed increased activity
for negative pictures compared with neutral pictures in both
depressed and controls. These regions are shown in Fig. 1 and
Regulation of emotional responses. We used regulate task (look-
factors and diagnostic group as a between subject factor.
Group effects. As shown in Table 1, 2 regions showed group
differences that varied as a function of the task. In the left
parahippocampus and left dorsal medial prefrontal cortex, de-
pressed had greater activity than controls during the emotional
regulation (make positive) condition compared with passively
looking at negative pictures.
Picture-type effects. Several regions showed more increased
activity in the make positive condition compared with passive
viewing of negative pictures in both depressed and controls. By
using the regulate task (look-negative vs. make positive) and
picture task X time interactions that did not further interact with
group. (Fig. 1, Fig. S1, and Table S1).
Exploratory effects. To look for nonpredicted effects in regions
outside the a priori DMN ROI, we conducted a whole-brain
ANOVA to determine group main effects or interaction with
group. We identified 4 regions, all in the cerebellum, that met
threshold criteria. See SI Text for discussion.
The DMN (Fig. 1) is a constellation of brain areas defined
functionally on the basis of their coordinated behavior in the
human brain (2, 5). This behavior manifests itself in several ways.
First, the areas together typically exhibit activity decreases
during the performance of a wide range of goal-directed tasks
(1–5). Exceptions to this widespread decrease in activity, as in
associated with specific components of the DMN, such as that
attributed to the ventral medial prefrontal cortex.
Second, the areas comprising the DMN exhibit striking tem-
poral coherence in the resting state (resting quietly with eyes
closed). This resting state temporal coherence emerges from the
spontaneous fluctuations in the fMRI BOLD signal, a phenom-
enon first noted by Biswal and colleagues (13) in the somato-
motor system. It has since been extended to virtually all cortical
systems including the DMN (for recent review see ref. 11) and
subcortical structures (14).
Table 1. Regions showing significant group differences in activations in the analysis of passive viewing of neutral and negative
pictures (look) and regulation vs. passive viewing of negative pictures (regulate)
Region (X, Y, Z) No. of voxels Look effect (dep ? con), P value Regulate effect (dep ? con), P value
Ventromedial prefrontal cortex
Medial frontal BA10
Medial frontal BA10
Lateral temporal cortex
Lateral parietal cortex
Dorsal medial prefrontal cortex
?18, 18, 38
18, 19, 28
?4, 53, ?3
4, 54, ?8
?43, ?16, ?5
?44, ?15, ?5
?52, 1, ?27
?50, 1, ?27
?55, ?2, ?21
42, ?71, 13 61 0.004
?22, ?6, ?13
19, ?27, ?7
?22, ?31, ?18
?11, 14, 50 500.005†
*Time frame 5–8 s, see text.
†Dep ? con.
www.pnas.org?cgi?doi?10.1073?pnas.0812686106 Sheline et al.
Finally, the DMN follows a developmental trajectory in
humans in which interhemispheric coherence within the DMN
appears strong by age 6, but anterior–posterior coherence be-
tween parietal regions and medial prefrontal cortex is weak (15).
This longitudinal development of DMN coherence suggests an
important experiential component in sculpting the DMN. As
trauma that have been shown to cause a predisposition to the
development of depression (16), for example, through changes in
neurotrophic factors or other factors that could affect neuro-
plasticity and DMN connectivity (17). Aberrant regulation of
neuronal plasticity may result in maladaptive changes in neural
networks that underlie the development of major depressive
The results of the current study provide information about the
role of DMN in emotional activity and regulation in major
depression. We found very consistent evidence widely distrib-
uted within the DMN that depressed individuals differed from
controls during the performance of emotional tasks. Specifically,
there were group differences (differences in both the look and
regulate tasks) in multiple DMN regions. Furthermore, we
found clear evidence in controls, as well as depressed subjects,
that manipulation of negative emotional content of pictures and
the need to regulate emotion modulated activity in many DMN
(Fig. 1 and Table S1).
Our results confirm and extend the results of other studies
examining DMN in depression. One study (18) found increased
activity in some DMN, including amygdala and anteromedial
prefrontal cortex (BA 9/8) but found decreases in anterior
cingulate (BA 32). Grimm et al. (19) reported alterations in 2
midline DMN regions and found that these activity differences
correlated with depression severity and feelings of hopelessness.
Greicius et al. (20) found abnormally increased resting state
connectivity of subgenual anterior cingulate by using functional
connectivity MRI. Whereas other studies have examined cog-
nition or affect related processing in some DMN regions, our
study is unique in determining DMN differences from a focused
theoretical perspective, independently determining the DMN
from a separate resting state dataset and identifying any acti-
to regulation of emotion (regulate), and time within trial that reflected modulations of task-related activation (Lower). (A–C) As indicated, there was less of a
decrease in activity in depressed compared with control subjects in left ventromedial prefrontal cortex (BA10) (A), right rostral anterior cingulate (B), and left
difference (Lower) was only significant in the left parahippocampus.
Time–activity curves are shown for a subset of regions in Fig. 1. (A–F) Time–activity curves plot percent fMRI signal change (y axis) vs. time in seconds
areas in the current study (also shown in Fig. 1) in which depressed subjects
visceral control areas.
Anatomical connections of the medial prefrontal network in the
Sheline et al.
February 10, 2009 ?
vol. 106 ?
no. 6 ?
vation differences within the network as a whole. We found the
failure to decrease activity in the DMN in depression was not
specific to voluntary regulation of affect but appears instead to
be a more general pattern of response, suggesting that DMN
abnormalities might contribute to deficits in ‘‘automatic’’ and
controlled processing of affective stimuli. Automatic processing
occurred in the current experiment when subjects saw emotional
stimuli and had a subliminal or automatic brain response. We
suggest that dysregulation of automatic emotional processing indi-
cates the fundamental importance of the DMN in depression.
Our working hypothesis to explain the origin of increased
activity in DMN regions during emotional modulation tasks is
their extensive anatomical connections to regions involved in
emotion, internal inspection, and endocrine regulation (e.g.,
hypothalamus, amygdala, and periaquaductal gray of the brain-
stem) (Fig. 3). DMN regions have been thought to be involved
in self-inspection and monitoring of the internal and external
milieu (2, 4–5), which are activities that may also be overactive
in depression, especially in the form of ruminations (21).
An emerging point is that the DMN is composed of a group
of relatively large but widely separated areas that each have their
own unique anatomy, connections, and functionality. One of the
best understood areas resides in the medial prefrontal cortex,
which, along with its connections, as defined in monkeys, has
been dubbed the ‘‘medial prefrontal network’’ by Price and
colleagues (22). This anterior portion of the DMN, including the
anterior cingulate and ventromedial prefrontal cortex (BA 10),
is extensively interconnected and intimately tied to limbic and
other structures, such as the hypothalamus, that provide internal
visceral surveillance. Although the recognition of the DMN
arose from studies that identified common activity during func-
tional tasks, it is interesting that many of these regions are also
part of the medial prefrontal cortex or its connections. In the
current study, we found many DMN regions that differed
between depressed and controls that are anatomically connected
with the medial and dorsal prefrontal cortex network in ma-
caques (23). These anatomically connected regions include left
lateral temporal cortex (23) and limbic regions (24) (Fig. 3).
The parahippocampal area seen in this study theoretically
corresponds to the entorhinal and posterior parahippocampal
cortex in monkeys. The macaque rostral superior temporal gyrus
region may be homologous with rostral middle temporal gyrus
regions that have shifted ventrally because of differential en-
largement of the midportion of the temporal lobe in humans.
The same shift is seen in the movement of the visual association
areas from the ventrolateral to the ventral surface of the
temporal lobe (25).
Although we did not find evidence of differences between
depressed and control subjects in the posterior cingulate and
precuneus, which are part of the posterior DMN, these regions
did, nonetheless, show significant effects of both looking at
negative pictures and regulating emotion (picture type and
However, the lateral parietal cortex is a region that has not been
found to be anatomically connected to the medial and prefrontal
cortex, but it is an important part of the DMN and differed
significantly in emotion-mediated activity between depressed
and controls in the current study.
In depressed patients there was increased activity, relative to
controls, in response to negative pictures in the hippocampus,
parahippocampal cortex, and amygdala, consistent with other
studies (26–29). Although these structures are not as frequently
described as components of the DMN, there have been a number
during cognitive tasks (1). Studies have shown that decreases in
activity during focused attention reflect a dynamic interaction
between cognitive demands and the person’s emotional state
(30–34). In depression, it has been hypothesized that heightened
limbic responses to negative affect-eliciting stimuli may provide
a bottom up source of input that can serve to dysregulate
cognitive control systems that might normally suppress such
affective responses (30, 35, 36). This hypothesis is supported by
studies of cognitive task performance in depression that have
revealed a failure to reduce activity in medial prefrontal regions
in response to increased cognitive demand (37) or during an
emotional conflict task (38). As such, the failure of depressed
patients to appropriately decrease activity in medial prefrontal
regions suggests an impaired ability to suppress attention to
internal emotional states.
Although, like other studies (33, 39), we found increased
prefrontal activity in the dorsal and rostral cingulate (BA10 and
BA8, respectively) in depressed subjects, relative to controls,
during emotional regulation, we did not find clear evidence,
unlike other studies (10, 33, 39), that either controls or depressed
patients were able to modulate amygdala activity in response to
demands to down-regulate responses to negative stimuli. Nonethe-
less, we did see clear evidence for a left amygdala response to
negative pictures with left amygdala hyperactivity in depression.
Another somewhat surprising finding in the current study was
that depressed participants did not differ from controls in their
ratings of the picture stimuli. Such ratings are very susceptible to
demand characteristics, however, and it is possible that partic-
ipants responded in a way that they knew was expected of them
(e.g., less negative ratings of pictures in the regulation condi-
tion), highlighting the importance of objective measures of brain
function that may be less susceptible to such effects. Importantly,
the absence of behavioral differences between groups allowed us
to interpret the fMRI differences in depressed subjects without
correcting for behavioral differences. However, additional stud-
ies would be needed to show the importance of correlating fMRI
activity with clinical characteristics, such as rumination, to
further explore the functional significance of the neural findings.
In summary, we found differences between depressed and
control subjects in important regions within the DMN. Regions
in the DMN are part of a core system that is critical in
self-referential properties. In the face of emotional stimuli, the
DMN is overactive for both implicit and explicit emotional
modulation. We hypothesize that whether interrogating visceral
reactions, emotions, potential threats, or remembering the past,
to name a few functions of the DMN, there is an increase in the
degree of self-referential focus in depression. Thus, depression
can be thought of as an illness involving a pathological inability
of the DMN to regulate self-referential activity in a situationally
Materials and Methods
Participants. Participants were screened by the same criteria as described in
controls [M/F: 6/15, age: 35 (SD ? 7.3), education: 16 (SD 2)]. There were no
significant group differences in age (of 43 subjects, t ? .25, P ? 0.81), gender
0.79). Given the gender imbalance between depressed and control subjects in
the current study, we reanalyzed our data excluding 4 males from the de-
pressed group to result in a group of 20 depressed subjects. Our results
continued to reveal significant differences between the groups in all of the
of 4 weeks, were administered a 17-item Hamilton Depression Rating Scale
(HDRS) (41), and were excluded for acute physical illness, history of trauma
resulting in loss of consciousness, and lifetime psychiatric disorders. Depressed
participants were included with HDRS scores of ?18 (mean 21 ? 3.5). Control
participants had scores ?8 (mean 0 ? 0.4). All participants provided written
informed consent in accordance with Washington University Human Subjects
Committee criteria and were paid $25.00 per hour for their participation.
www.pnas.org?cgi?doi?10.1073?pnas.0812686106 Sheline et al.
Procedure. We used a modification of the Ochsner et al. (10) paradigm Download full-text
examining emotional regulation. We used 4 different task conditions: pas-
(look negative), actively make a negative picture more positive (make posi-
tive), and actively make a negative picture more negative (make negative).
The latter was included to ensure that subjects would reliably regulate their
emotions (i.e., had they been asked to only make pictures positive or look
the neutral pictures). Because we had no a priori hypothesis about the make
negative condition, it was not included in the data analysis.
In the make positive condition, participants were instructed to deperson-
alize the image such that it did not pertain to them, that the image was not
real, and that the outcome of the scene portrayed was positive. In the make
pertinent to themselves or a loved one and that the outcome was negative.
Before entering the scanner, participants received instruction on how to
attenuate emotional response and spent ?15 min practicing (with 10 addi-
tonal minutes of practice in the scanner).
Stimulus Presentation. Stimuli from the International Affective Picture Series
(42) were counterbalanced for picture type (see SI Text).
fMRI Image Acquisition, Processing, and Analysis. All fMRI data were obtained
on the same Siemens 3T Allegra MRI scanner and processed as described (30)
(see SI Text).
DMN for ROI Identification. To test our hypotheses, we identified a priori the
DMN boundaries to determine ROIs in our data falling within the DMN by
using standard methods (12) (see SI Text).
Statistical Analysis. To test our hypotheses, we used a priori defined ROIs,
consisting of the DMN as defined above and in the SI Text. Voxel clusters
within the a priori defined default connectivity map showing effects of
interest were identified by using a 3-stage process. (i) We required voxels to
show significant effects at P ? 0.001 and to belong to clusters of at least 14
contiguous voxels. (ii) We required that the activity peak of a given voxel
We then conducted analyses by using the clusters identified in the previous
step and (to protect against Type I error) required results to show post hoc
effects at P ? 0.01.
Exploratory Effects. To look for nonpredicted effects in regions outside the
a priori DMN ROI, we conducted a whole-brain ANOVA to determine group
main effects or interaction with the group. We identified 4 regions, all
in the cerebellum, that met threshold criteria. See SI Text for further
ACKNOWLEDGMENTS. We thank Tony Durbin for his assistance in subject
recruitment and fMRI scanning. This work was supported by National Insti-
tutes of Health Grants R01 MH64821, K24 MHO79510 (to Y.I.S.), and
P50NS06833 (to M.E.R.).
1. Shulman G, et al. (1997) Common blood flow changes across visual tasks II: Decreases
in cerebral cortex. J Cogn Neurosci 9:648–663.
2. Raichle M, et al. (2001) A default mode of brain function. Proc Natl Acad Sci USA
3. Raichle ME, Snyder AZ (2007) A default mode of brain function: A brief history of an
evolving idea. Neuroimage 37:1083–1099.
function, and relevance to disease. Ann NY Acad Sci 1124:1–38.
5. Gusnard D, Akbudak E, Shulman G, Raichle M (2001) Medial prefrontal cortex and
Acad Sci USA 98:4259–4264.
6. Ressler K, Mayberg H (2007) Targeting abnormal neural circuits in mood and anxiety
disorders: From the laboratory to the clinic. Nat Neurosci 10:1116–1124.
7. Sheline, Y (2003) Neuroimaging studies of mood disorder effects on the brain. Bio-
logical Psychiatry 54: 338–352.
8. Davidson R, Pizzagalli D, Nitschke J, Putnam K (2002) Depression: Perspectives from
affective neuroscience. Annu Rev Psychol 53:545–574.
structures in major depression. Prog Brain Res 126:413–431.
cognitive regulation of emotion. J Cog Neurosci 14:1215–1229.
11. Fox M, Raichle M (2007) Spontaneous fluctuations in brain activity observed with
functional magnetic resonance imaging. Nat Rev Neurosci 8:700–711.
12. Fox M, et al. (2005) The human brain is intrinsically organized into dynamic, anticor-
related functional networks. Proc Natl Acad Sci USA 102:9673–9678.
13. Biswal B, Yetkin F, Haughton V, Hyde J (1995) Functional connectivity in the motor
cortex of resting human brain using echo-planar MRI. Magn Reson Med 34:537–541.
thalamus. J Neurophysiol 100:1740–1748.
Acad Sci USA 41:45–57.
16. Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB (2008) The link between
childhood trauma and depression: Insights from HPA axis studies in humans. Psycho-
17. Uys J, et al. (2006) Developmental trauma is associated with behavioral hyperarousal,
altered HPA axis activity and decreased hippocampal neurotrophin expression in the
adult rat. Ann NY Acad Sci 1071:542–546.
18. Anand A, et al. (2005) Activity and connectivity of brain mood regulating circuit in
depression: A functional magnetic resonance study. Biol Psych 57:1079–1088.
19. Grimm S, et al. (2008) Altered negative BOLD responses in the default-mode network
during emotion processing in depressed subjects. Neuropsychopharmacology,
20. Greicius M, et al. (2007) Resting-state functional connectivity in major depression:
Abnormally increased contributions from subgenual cingulate cortex and thalamus.
Biol Psychiatry 62: 429–437.
21. Ray R, et al. (2005) Individual differences in trait rumination modulate neural systems
22. Ongu ¨r D, Price J (2000) The organization of networks within the orbital and medial
prefrontal cortex of rats, monkeys and humans. Cereb Cortex 10:206–219.
23. Saleem K, Kondo H, Price J (2008) Complementary circuits connecting the orbital and
medial prefrontal networks with the temporal, insular, and opercular cortex in the
macaque monkey. J Comp Neurol 506:659–693.
24. Carmichael S, Price J (1996) Connectional networks within the orbital and medial
prefrontal cortex of macaque monkeys. J Comp Neurol 371:179–207.
25. Orban GA, Van Essen D, Vanduffel W (2004) Comparative mapping of higher visual
areas in monkeys and humans. Trends Cogn Sci 8:315–324.
26. Sheline Y, et al. (2001) Increased amygdala response to masked emotional faces in
depressed subjects resolves with antidepressant treatment: An fMRI study. Biol Psych
27. Davidson R, Irwin W, Anderle M, Kalin N (2003) The neural substrates of affective
processing in depressed patients treated with venlafaxine. Am J Psych 160:64–75.
28. Fu C, et al. (2004) Attenuation of the neural response to sad faces in major depression
by antidepressant treatment: A prospective, event related functional magnetic reso-
nance imaging study. Arch Gen Psych 61:877–889.
independent features. Biol Psych 61:198–209.
30. Drevets W, Raichle M (1998) Reciprocal suppression of regional cerebral blood flow
during emotional versus higher cognitive processes: Implication for interactions be-
tween emotion and cognition. Cognit Emot 12:353–385.
31. Simpson J, et al. (2000) The emotional modulation of cognitive processing An fMRI
study. J Cognit Neurosci 12:157–170.
32. Bush G, Luu P, Posner MI (2000) Cognitive and emotional influences in anterior
cingulate cortex. Trends Cognit Sci 4:215–222.
33. Ochsner K, Gross J (2005) The cognitive control of emotion. Trends Cognit Sci 9:242–249.
34. Dolcos F, McCarthy G (2006) Brain systems mediating cognitive interference by emo-
tional distraction. J Neurosci 26:2072–2079.
35. Mayberg H (1997) Limbic-cortical dysregulation: A proposed model of depression.
J Neuropsychiatr and Clin Neurosci 9:471–481.
during the processing of emotional stimuli: A meta-analysis of 385 PET and fMRI
studies. Brain Res Rev 58:57–70.
37. Wagner G, et al. (2006) Cortical inefficiency in patients with unipolar depression: An
event related MRI study with the Stroop task, 126. Biol Psych 59:958–965.
38. Fales C, et al. (2008) Altered emotional interference processing in affective and
cognitive-control brain circuitry in major depression. Biol Psych 63:377–384.
39. Phan K, et al. (2005) Neural substrates for voluntary suppression of negative affect: A
functional magnetic resonance imaging study. Biol Psych 57:210–219.
40. American Psychiatric Association (2000) DSM-IV-R: Diagnostic and Statistical Manual
of Mental Disorders (American Psychiatric Association, Washington, DC), 4th Ed.
41. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry
42. Lang P, Bradley M, Cuthbert, B (1999) International Affective Picture System (IAPS):
Technical Manual and Affective Ratings (NIMH CSEA, Gainsville, FL).
Sheline et al.
February 10, 2009 ?
vol. 106 ?
no. 6 ?