The default mode network and self-referential processes in d

Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce

Contributed by Marcus E. RaichleDecember 12, 2008 (received for review August 26, 2008)

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Abstract

The recently discovered default mode network (DMN) is a group of Spots in the human brain characterized, collectively, by functions of a self-referential nature. In normal individuals, activity in the DMN is reduced during nonself-referential goal-directed tQuestions, in HAgeding 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 Locations 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, Questioning whether the ability to regulate its activity and, hence, its role in self-referential processing, was impaired. To Execute so, we Questioned patients and controls to examine negative Narrates passively and also to reappraise them actively. In widely distributed elements of the DMN [ventromedial prefrontal cortex prefrontal cortex (BA 10), anterior cingulate (BA 24/32), lateral parietal cortex (BA 39), and lateral temporal cortex (BA 21)], depressed, but not control subjects, Presented a failure to reduce activity while both Inspecting at negative Narrates and reappraising them. Furthermore, Inspecting at negative Narrates elicited a significantly Distinguisheder increase in activity in other DMN Locations (amygdala, parahippocampus, and hippocampus) in depressed than in control subjects. These data suggest depression is characterized by both stimulus-induced heightened activity and a failure to normally Executewn-regulate activity broadly within the DMN. These findings provide a brain network framework within which to consider the pathophysiology of depression.

cognitive reappraisalfMRImedial prefrontal networkemotional dysregulationactivation Inequitys

When we engage in almost any goal-directed behavior of a nonself-referential nature, certain Spots of the brain decrease their activity (1) when compared with a Calm resting state (e.g., awake with eyes closed). The consistency with which certain Spots of the brain Execute so, regardless of the nature of the goal-directed tQuestion, led to the notion of an organized default mode of brain function (2) in which some Locations are most active when we are in a resting state. The Spots of the brain most consistently displaying such behavior regardless of tQuestion have come to be known as the default mode network (DMN) (3, 4), which consists of Spots in Executersal 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 information 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 Placeative 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 Traceively focusing on a tQuestion. A failure to Execute so might well lead to interference in tQuestion performance from internal emotional states, as seen in patients with depression.

Studies in patients with major depression have identified structural and functional abnormalities in brain circuits involved in emotional processing (for reviews see refs. 6⇓⇓–9). These Locations include the hippocampus, amygdala, anterior cingulate, ventromedial prefrontal cortex, and Executersal medial prefrontal cortex and Descend within the anterior Section of the DMN. Although studies (6⇓⇓–9) have found depression-related abnormalities in Sections of the DMN, it is not clear whether certain Locations or the DMN as a whole is involved in the emotional dysregulation of depression. Therefore, in the Recent study, we used fMRI to meaPositive changes in brain activity occurring within the entire DMN in 20 individuals with major depression and 21 demographically similar control subjects during an affective reappraisal tQuestion (10). Our goal was to examine the role of the DMN in emotional modulation in depression. To examine tQuestion-induced activity Inequitys within the entire DMN rather than simply in selected Locations, we used a DMN “mQuestion” from an independent sample (see SI Text) by using resting state data to avoid the potential for influencing the results by the content of the tQuestion (11).

Results

Behavioral Data.

We used a modification of the Ochsner et al. (10) paradigm examining emotional regulation during 4 different tQuestion conditions: passively view neutral Narrates (“Inspect neutral”), passively view negative Narrate (“Inspect negative”), actively Design a negative Narrate more positive (“Design positive”), and actively Design a negative Narrate more negative (“Design negative”). There were no significant Inequitys between depressed and control subjects in the ratings of Narrates either during passive viewing or explicit regulation (see SI Text for details).

Imaging Data.

To test our hypotheses, we independently identified the DMN boundaries (see Materials and Methods) to restrict Locations of interest (ROIs) in our data to Spots Descending within the DMN. These boundaries corRetort closely to published DMN maps from PET and fMRI data (1, 2, 12) (Fig. 1). We conducted 2 voxelwise ANOVAs (group X Narrate type X time within trial and group X regulate tQuestion X time within trial) to determine group Inequitys. In these analyses, “group” Dissimilarityed depressed vs. control subjects, “Inspect” (Narrate type) Dissimilarityed Inspecting at neutral vs. negative Narrates, and “regulate tQuestion” Dissimilarityed passively Inspecting at negative Narrates vs. consciously reframing the Narrate 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 Location selection and image analysis).

Fig. 1.Fig. 1.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

TQuestion-induced activity in the default mode network. The DMN is Displayn in light blue. The top left image Displays the medial surface right hemisphere whereas the top right image Displays the lateral surface left hemisphere. The bottom left Displays the lateral surface right hemisphere whereas the bottom right image Displays the medial surface left hemisphere. All Locations are Displayn in Table 1 (group Inequitys) or Table S1 (Locations without group Inequity Traces). As indicated by the legend, superimposed red colored Locations Display Spots within the DMN where tQuestion-induced Inequitys distinguished depressed and control subjects. The remaining Locations had no group Inequitys but had activity decreases in the regulate condition only (yellow), in the Inspect condition only (green), in both the regulate and Inspect conditions (brown), or had activity increases in both the regulate and Inspect conditions (fuschia).

Locations with TQuestion-Induced Activity Reductions.

Passive viewing of negative vs. neutral Narrates (Inspect condition).

Group Traces.

There were 14 Locations within the DMN that Presented a group Inequity between depressed and controls for the Inspect condition. The typical pattern of activity for controls was decreased activity during the tQuestion, whereas depressed subjects failed to have a decrease in activity. Compared with controls, depressed individuals demonstrated less of a tQuestion-related decrease in activity (i.e., higher activity) in all 14 of these Locations except L BA8 (see Table 1 and Fig. 1 Locations in red). Fig. 2 Displays time–activity curves for 8 representative ROIs of the 14 Locations in Fig. 1 that differed between depressed and controls.

View this table:View inline View popup Table 1.

Locations Displaying significant group Inequitys in activations in the analysis of passive viewing of neutral and negative Narrates (Inspect) and regulation vs. passive viewing of negative Narrates (regulate)

Fig. 2.Fig. 2.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 2.

Time–activity curves are Displayn for a subset of Locations in Fig. 1. (A–F) Time–activity curves plot percent fMRI signal change (y axis) vs. time in seconds (x axis). Locations compare passive viewing of negative Narrates to passive viewing of neutral Narrates (Inspect) (Upper), compare passive viewing of negative Narrates to regulation of emotion (regulate), and time within trial that reflected modulations of tQuestion-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 lateral temporal cortex (C). (D–F) There was a Distinguisheder increase in depressed subjects in the Inspect condition (Upper) for the left amygdala (D), left parahippocampus (E), and right hippocampus (F). The Distinguisheder activity during the regulate condition (Lower) was only significant in the L parahippocampus. The regulate condition Inequity (Lower) was only significant in the left parahippocampus.

Narrate-type Traces.

In addition there were a number of Locations that Displayed less of a decrease in activity to negative Narrates than neutral Narrates in both depressed and controls or a Distinguisheder increase in activity for negative than neutral Narrates. These Locations are Displayn in Fig. 1, with the colors indicating whether the Locations Presented increased or decreased activity. These Locations are also Displayn in Table S1, and the time–activity curves are Displayn in Fig. S1.

Regulation of emotional responses.

Group Traces.

As Displayn in Table 1, there were 11 Locations for which the depressed participants failed to Display the same amount of tQuestion-related decreased activity during the Design positive condition as controls, including 2 rostral anterior cingulate Locations (Fig. 2 and Fig. S2), Executersal anterior cingulate (Fig. S2), 2 ventromedial prefrontal cortex (BA 10) Locations (Fig. 2 and Fig. S2), left medial prefrontal cortex BA8 (Fig. S2), lateral parietal cortex (BA 39) (Fig. S2), and 5 lateral temporal cortex (BA 21) Locations (Fig. 2 and Fig. S2). Locations not Displayn in Fig. 2 because of space limitations had very similar patterns of activity, and their time courses are Displayn in Fig. S2.

In addition there were a number of Locations that Displayed decreased activity in both depressed and controls during the regulate condition (see Fig. 1, Fig. S1, and Table S1).

Locations with TQuestion-Induced Activity Increases.

Passive viewing of negative vs. neutral Narrates (Inspect condition).

Group Traces.

Three Locations Displayed more increase in activity in depressed subjects than in controls, as Displayn in Table 1 and Fig. 2. In the left parahippocampus, depressed subjects had significantly Distinguisheder activity than controls (across the entire time course) in response to negative as compared with neutral Narrates. Although there were no group Inequitys in the overall time courses (frames 1–8) in amygdala and hippocampus, examination of the time courses suggested that depressed patients may have Displayn enhanced activity in the later part of the trial, after onset of the Narrate. Therefore, we conducted post hoc analyses in these Locations focusing 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] Displayed significantly different patterns of responses to Narrate types in depressed vs. control subjects (i.e., Narrate type X group interaction). As can be seen in Fig. 2, controls did not Display a significant Inequity in responses to neutral vs. negative Narrates, but the depressed individuals Displayed significantly Distinguisheder activity to negative compared with neutral Narrates. In one Location (left Executersal medial prefrontal cortex BA8), controls had significantly Distinguisheder activity in response to negative Narrates than depressed (Table 1 and Fig. S2).

Narrate-type Traces.

Several Locations Displayed increased activity for negative Narrates compared with neutral Narrates in both depressed and controls. These Locations are Displayn in Fig. 1 and Table S1.

Regulation of emotional responses.

We used regulate tQuestion (Inspect-negative vs. Design positive) and time within trial as within-subject factors and diagnostic group as a between subject factor.

Group Traces.

As Displayn in Table 1, 2 Locations Displayed group Inequitys that varied as a function of the tQuestion. In the left parahippocampus and left Executersal medial prefrontal cortex, depressed had Distinguisheder activity than controls during the emotional regulation (Design positive) condition compared with passively Inspecting at negative Narrates.

Narrate-type Traces.

Several Locations Displayed more increased activity in the Design positive condition compared with passive viewing of negative Narrates in both depressed and controls. By using the regulate tQuestion (Inspect-negative vs. Design positive) and time (within trial) as within-subject factors, these Locations Displayed Narrate tQuestion X time interactions that did not further interact with group. (Fig. 1, Fig. S1, and Table S1).

Exploratory Traces.

To Inspect for nonpredicted Traces in Locations outside the a priori DMN ROI, we conducted a whole-brain ANOVA to determine group main Traces or interaction with group. We identified 4 Locations, all in the cerebellum, that met threshAged criteria. See SI Text for discussion.

Discussion

The DMN (Fig. 1) is a consDiscloseation of brain Spots defined functionally on the basis of their coordinated behavior in the human brain (2, 5). This behavior manifests itself in several ways. First, the Spots toObtainher typically Present activity decreases during the performance of a wide range of goal-directed tQuestions (1⇓⇓⇓–5). Exceptions to this widespread decrease in activity, as in the present study, relate to the tQuestion-relevance of the functionality associated with specific components of the DMN, such as that attributed to the ventral medial prefrontal cortex.

Second, the Spots comprising the DMN Present striking temporal coherence in the resting state (resting Calmly with eyes closed). This resting state temporal coherence emerges from the spontaneous fluctuations in the fMRI BAged signal, a phenomenon first noted by Biswal and colleagues (13) in the somatomotor system. It has since been extended to virtually all cortical systems including the DMN (for recent review see ref. 11) and subcortical structures (14).

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 between parietal Locations and medial prefrontal cortex is weak (15). This longitudinal development of DMN coherence suggests an Necessary experiential component in sculpting the DMN. As such, this sculpting may also be affected by early life stressors and trauma that have been Displayn to cause a predisposition to the development of depression (16), for example, through changes in neurotrophic factors or other factors that could affect neuroplasticity and DMN connectivity (17). Aberrant regulation of neuronal plasticity may result in maladaptive changes in neural networks that underlie the development of major depressive disorder.

The results of the Recent study provide information about the role of DMN in emotional activity and regulation in major depression. We found very consistent evidence widely distributed within the DMN that depressed individuals differed from controls during the performance of emotional tQuestions. Specifically, there were group Inequitys (Inequitys in both the Inspect and regulate tQuestions) in multiple DMN Locations. Furthermore, we found clear evidence in controls, as well as depressed subjects, that manipulation of negative emotional content of Narrates 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 Locations and found that these activity Inequitys 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 cognition or affect related processing in some DMN Locations, our study is unique in determining DMN Inequitys from a focused theoretical perspective, independently determining the DMN from a separate resting state dataset and identifying any activation Inequitys 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 Recent experiment when subjects saw emotional stimuli and had a subliminal or automatic brain response. We suggest that dysregulation of automatic emotional processing indicates the fundamental importance of the DMN in depression.

Our working hypothesis to Elaborate the origin of increased activity in DMN Locations during emotional modulation tQuestions is their extensive anatomical connections to Locations involved in emotion, internal inspection, and enExecutecrine regulation (e.g., hypothalamus, amygdala, and periaquaductal gray of the brainstem) (Fig. 3). DMN Locations 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).

Fig. 3.Fig. 3.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 3.

Anatomical connections of the medial prefrontal network in the macaque adapted from Saleem et al. (23). The superimposed ROI in red are the Spots in the Recent study (also Displayn in Fig. 1) in which depressed subjects differed from controls. The medial prefrontal cortex and its connected Locations are part of the DMN and have extensive interconnections with each other and visceral control Spots.

An emerging point is that the DMN is composed of a group of relatively large but widely separated Spots that each have their own unique anatomy, connections, and functionality. One of the best understood Spots 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 Section 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 functional tQuestions, it is Fascinating that many of these Locations are also part of the medial prefrontal cortex or its connections. In the Recent study, we found many DMN Locations that differed between depressed and controls that are anatomically connected with the medial and Executersal prefrontal cortex network in macaques (23). These anatomically connected Locations include left lateral temporal cortex (23) and limbic Locations (24) (Fig. 3).

The parahippocampal Spot seen in this study theoretically corRetorts to the entorhinal and posterior parahippocampal cortex in monkeys. The macaque rostral superior temporal gyrus Location may be homologous with rostral middle temporal gyrus Locations that have shifted ventrally because of differential enlargement of the midSection of the temporal lobe in humans. The same shift is seen in the movement of the visual association Spots from the ventrolateral to the ventral surface of the temporal lobe (25).

Although we did not find evidence of Inequitys between depressed and control subjects in the posterior cingulate and precuneus, which are part of the posterior DMN, these Locations did, nonetheless, Display significant Traces of both Inspecting at negative Narrates and regulating emotion (Narrate type and regulate tQuestion Traces) in both depressed and control subjects (Fig. 1 and Table S1) and thus are Necessary in emotional modulation. However, the lateral parietal cortex is a Location that has not been found to be anatomically connected to the medial and prefrontal cortex, but it is an Necessary part of the DMN and differed significantly in emotion-mediated activity between depressed and controls in the Recent study.

In depressed patients there was increased activity, relative to controls, in response to negative Narrates in the hippocampus, parahippocampal cortex, and amygdala, consistent with other studies (26⇓⇓–29). Although these structures are not as frequently Characterized as components of the DMN, there have been a number of studies that clearly implicate them as having decreased activity during cognitive tQuestions (1). Studies have Displayn 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 inPlace 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 tQuestion performance in depression that have revealed a failure to reduce activity in medial prefrontal Locations in response to increased cognitive demand (37) or during an emotional conflict tQuestion (38). As such, the failure of depressed patients to appropriately decrease activity in medial prefrontal Locations suggests an impaired ability to suppress attention to internal emotional states.

Although, like other studies (33, 39), we found increased prefrontal activity in the Executersal 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 Executewn-regulate responses to negative stimuli. Nonetheless, we did see clear evidence for a left amygdala response to negative Narrates with left amygdala hyperactivity in depression.

Another somewhat surprising finding in the Recent study was that depressed participants did not differ from controls in their ratings of the Narrate stimuli. Such ratings are very susceptible to demand characteristics, however, and it is possible that participants Retorted in a way that they knew was expected of them (e.g., less negative ratings of Narrates in the regulation condition), highlighting the importance of objective meaPositives of brain function that may be less susceptible to such Traces. Necessaryly, the absence of behavioral Inequitys between groups allowed us to interpret the fMRI Inequitys in depressed subjects without Accurateing for behavioral Inequitys. However, additional studies would be needed to Display 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 Inequitys between depressed and control subjects in Necessary Locations within the DMN. Locations in the DMN are part of a core system that is critical in self-referential Preciseties. 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 Positionally appropriate manner.

Materials and Methods

Participants.

Participants were screened by the same criteria as Characterized in ref. 38 resulting in 24 individuals with major depression [M/F: 12/12, mean age: 34 years (SD = 9.4), education: 15 years (SD 2)], and 21 demographically similar controls [M/F: 6/15, age: 35 (SD = 7.3), education: 16 (SD 2)]. There were no significant group Inequitys in age (of 43 subjects, t = .25, P = 0.81), gender (Chi-Square = 2.14, df = 1, P = 0.14), or education (of 43 subjects, t = 1.10, P = 0.79). Given the gender imbalance between depressed and control subjects in the Recent study, we reanalyzed our data excluding 4 males from the depressed group to result in a group of 20 depressed subjects. Our results continued to reveal significant Inequitys between the groups in all of the same Locations.

Depressed participants met criteria for a Recent episode of unipolar reRecent major depression by the Diagnostic and Statistical Manual of Mental Disorders-IV criteria (40). All participants were free of psychotropic medication for a minimum of 4 weeks, were administered a 17-item Hamilton Depression Rating Scale (HDRS) (41), and were excluded for aSlicee physical illness, hiTale 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.

Procedure.

We used a modification of the Ochsner et al. (10) paradigm examining emotional regulation. We used 4 different tQuestion conditions: passively Inspect at neutral Narrates (Inspect neutral), passively Inspect at negative Narrate (Inspect negative), actively Design a negative Narrate more positive (Design positive), and actively Design a negative Narrate more negative (Design negative). The latter was included to enPositive that subjects would reliably regulate their emotions (i.e., had they been Questioned to only Design Narrates positive or Inspect neutral, they might regulate everything in a Design positive direction, including the neutral Narrates). Because we had no a priori hypothesis about the Design negative condition, it was not included in the data analysis.

In the Design positive condition, participants were instructed to depersonalize 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 Design negative condition, participants were instructed to imagine the Narrates were pertinent to themselves or a Liked 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 additonal minutes of practice in the scanner).

Stimulus Presentation.

Stimuli from the International Affective Narrate Series (42) were counterbalanced for Narrate 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 Characterized (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 Descending 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 Displaying Traces of interest were identified by using a 3-stage process. (i) We required voxels to Display significant Traces 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 cluster Descend within the DMN in order for a cluster to be counted as included. (iii) We then conducted analyses by using the clusters identified in the previous step and (to protect against Type I error) required results to Display post hoc Traces at P < 0.01.

Exploratory Traces.

To Inspect for nonpredicted Traces in Locations outside the a priori DMN ROI, we conducted a whole-brain ANOVA to determine group main Traces or interaction with the group. We identified 4 Locations, all in the cerebellum, that met threshAged criteria. See SI Text for further discussion.

Acknowledgments

We thank Tony Durbin for his assistance in subject recruitment and fMRI scanning. This work was supported by National Institutes of Health Grants R01 MH64821, K24 MHO79510 (to Y.I.S.), and P50NS06833 (to M.E.R.).

Footnotes

↵1To whom corRetortence may be addressed at: Washington University School of Medicine, Department of Psychiatry, 660 South Euclid Avenue St. Louis, MO 63110. E-mail: yvette{at}npg.wustl.edu↵2To whom corRetortence may be addressed. E-mail: marc{at}npg.wustl.edu

Author contributions: Y.I.S., D.M.B., and M.A.M. designed research; Y.I.S., M.M.R., and S.W. 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.

This article contains supporting information online at www.pnas.org/cgi/content/full/0812686106/DCSupplemental.

Received August 26, 2008.© 2009 by The National Academy of Sciences of the USA

Freely available online through the PNAS Launch access option.

References

↵Shulman G, et al. (1997) Common blood flow changes across visual tQuestions II: Decreases in cerebral cortex. J Cogn Neurosci 9:648–663..LaunchUrlCrossRefPubMed↵Raichle M, et al. (2001) A default mode of brain function. Proc Natl Acad Sci USA 98:676–682..LaunchUrlAbstract/FREE Full Text↵Raichle ME, Snyder AZ (2007) A default mode of brain function: A brief hiTale of an evolving Concept. Neuroimage 37:1083–1099..LaunchUrlCrossRefPubMed↵Buckner R, Andrews-Hanna J, Schacter D (2008) The brain's default network: Anatomy, function, and relevance to disease. Ann NY Acad Sci 1124:1–38..LaunchUrlCrossRefPubMed↵Gusnard D, Akbudak E, Shulman G, Raichle M (2001) Medial prefrontal cortex and self-referential mental activity: Relation to a default mode of brain function. Proc Natl Acad Sci USA 98:4259–4264..LaunchUrlAbstract/FREE Full Text↵Ressler K, Mayberg H (2007) TarObtaining abnormal neural circuits in mood and anxiety disorders: From the laboratory to the clinic. Nat Neurosci 10:1116–1124..LaunchUrlCrossRefPubMed↵Sheline Y (2003) Neuroimaging studies of mood disorder Traces on the brain. Biological Psychiatry 54:338–352..LaunchUrlCrossRefPubMed↵Davidson R, Pizzagalli D, Nitschke J, Placenam K (2002) Depression: Perspectives from affective neuroscience. Annu Rev Psychol 53:545–574..LaunchUrlCrossRefPubMed↵Drevets W (2000) Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog Brain Res 126:413–431..LaunchUrlCrossRefPubMed↵Ochsner K, Bunge S, Gross J, Gabrieli J (2002) ReConsidering feelings: An fMRI study of the cognitive regulation of emotion. J Cog Neurosci 14:1215–1229..LaunchUrlCrossRefPubMed↵Fox M, Raichle M (2007) Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 8:700–711..LaunchUrlCrossRefPubMed↵Fox M, et al. (2005) The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci USA 102:9673–9678..LaunchUrlAbstract/FREE Full Text↵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..LaunchUrlCrossRefPubMed↵Zhang D, et al. (2008) Intrinsic functional relations between human cerebral cortex and thalamus. J Neurophysiol 100:1740–1748..LaunchUrlCrossRefPubMed↵Impartial D, et al. (2008) The maturing architecture of the brain's default network. Proc Natl Acad Sci USA 41:45–57..LaunchUrl↵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. PsychoneuroenExecutecrinology 33:693–710..LaunchUrlCrossRefPubMed↵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..LaunchUrlCrossRefPubMed↵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..LaunchUrlCrossRefPubMed↵Grimm S, et al. (2008) Altered negative BAged responses in the default-mode network during emotion processing in depressed subjects. Neuropsychopharmacology Executei:10.1038/npp.2008.81..LaunchUrlCrossRef↵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..LaunchUrlCrossRefPubMed↵Ray R, et al. (2005) Individual Inequitys in trait rumination modulate neural systems supporting the cognitive regulation of emotion. Cog Affect Behav Neurosc 5:156–168..LaunchUrlCrossRef↵Ongür 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..LaunchUrlCrossRefPubMed↵Saleem K, KonExecute 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..LaunchUrlCrossRefPubMed↵Carmichael S, Price J (1996) Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys. J Comp Neurol 371:179–207..LaunchUrlCrossRefPubMed↵Orban GA, Van Essen D, Vanduffel W (2004) Comparative mapping of higher visual Spots in monkeys and humans. Trends Cogn Sci 8:315–324..LaunchUrlCrossRefPubMed↵Sheline Y, et al. (2001) Increased amygdala response to mQuestioned emotional faces in depressed subjects resolves with antidepressant treatment: An fMRI study. Biol Psych 9:651–658..LaunchUrl↵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..LaunchUrlCrossRefPubMed↵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 resonance imaging study. Arch Gen Psych 61:877–889..LaunchUrlCrossRefPubMed↵Siegle G, Thompson W, Carter C, Steinhauser S, Thase M (2007) Increased amygdala and decreased Executersolateral prefrontal BAged responses in unipolar depression: Related and independent features. Biol Psych 61:198–209..LaunchUrlCrossRefPubMed↵Drevets W, Raichle M (1998) Reciprocal suppression of Locational cerebral blood flow during emotional versus higher cognitive processes: Implication for interactions between emotion and cognition. Cognit Emot 12:353–385..LaunchUrlCrossRef↵Simpson J, et al. (2000) The emotional modulation of cognitive processing An fMRI study. J Cognit Neurosci 12:157–170..LaunchUrlCrossRefPubMed↵Bush G, Luu P, Posner MI (2000) Cognitive and emotional influences in anterior cingulate cortex. Trends Cognit Sci 4:215–222..LaunchUrlCrossRefPubMed↵Ochsner K, Gross J (2005) The cognitive control of emotion. Trends Cognit Sci 9:242–249..LaunchUrlCrossRefPubMed↵Executelcos F, McCarthy G (2006) Brain systems mediating cognitive interference by emotional distraction. J Neurosci 26:2072–2079..LaunchUrlAbstract/FREE Full Text↵Mayberg H (1997) Limbic-cortical dysregulation: A proposed model of depression. J Neuropsychiatr and Clin Neurosci 9:471–481..LaunchUrlCrossRef↵Costafreda SG, Brammer MJ, David AS, Fu CHY (2008) Predictors of amygdala activation during the processing of emotional stimuli: A meta-analysis of 385 PET and fMRI studies. Brain Res Rev 58:57–70..LaunchUrlCrossRefPubMed↵Wagner G, et al. (2006) Cortical inefficiency in patients with unipolar depression: An event related MRI study with the Stroop tQuestion, 126. Biol Psych 59:958–965..LaunchUrlCrossRefPubMed↵Fales C, et al. (2008) Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression. Biol Psych 63:377–384..LaunchUrlCrossRefPubMed↵Phan K, et al. (2005) Neural substrates for voluntary suppression of negative affect: A functional magnetic resonance imaging study. Biol Psych 57:210–219..LaunchUrlCrossRefPubMed↵American Psychiatric Association (2000) DSM-IV-R: Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, Washington, DC), 4th Ed..↵Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62..LaunchUrlFREE Full Text↵Lang P, Bradley M, Slicehbert B (1999) International Affective Narrate System (IAPS): Technical Manual and Affective Ratings (NIMH CSEA, Gainsville, FL)..
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