The default mode network and self-referential processes in depression
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The recently discovered default mode network (DMN) is a group of areas 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 tasks, in keeping 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 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, exhibited a failure to reduce activity while both looking at negative pictures and reappraising them. Furthermore, looking at negative pictures elicited a significantly greater increase in activity in other DMN regions (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 down-regulate activity broadly within the DMN. These findings provide a brain network framework within which to consider the pathophysiology of depression.
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Negatively biased self-generated thoughts and heightened activity of the DMN have been associated with depression.
“For example, negatively biased self-generated thoughts and heightened activity of the DMN have been associated with depression (20, 21, 54, 56–58), as well as maladaptive rumination (55).”
From SSRI Treatment Response Prediction in Depression Based on Brain Activation by Emotional Stimuli (2020) · cites this paper as [58]
The Discussion reports overactive DMN regions in depressed subjects during emotional tasks and hypothesizes increased self-referential focus in depression. It does not establish that the subjects’ self-generated thoughts were negatively biased; the negative material in the study was presented as pictures. (LLM, conf=0.82)
Experimental — accuracy not yet measuredBlunted dlPFC activation has been accompanied by exaggerated amygdalar activation when viewing and reappraising negative pictures.
“Thus, blunted dlPFC activation has been accompanied by exaggerated amygdalar activation when (1) viewing and reappraising negative pictures [167], (2) processing subliminal negative stimuli [168, 169] (Fig. 4d) and negative words”
From Prefrontal cortex and depression (2022) · cites this paper as [167]
The Imaging Data section reports greater left-amygdala responses to negative pictures in depressed participants and lower activation in the left dorsal medial prefrontal cortex during viewing. It does not report blunted dorsolateral prefrontal (dlPFC) activation. Figure 2 and the Discussion indicate that the amygdala group difference was found during viewing, not reappraisal. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHigher activity in DMN regions during perception of negative stimuli in patients with MDD is a known alteration.
“Higher activity in DMN regions during perception of negative stimuli in patients with MDD is a known alteration (58).”
From SSRI Treatment Response Prediction in Depression Based on Brain Activation by Emotional Stimuli (2020) · cites this paper as [58]
Mood disorders including major depressive disorder and bipolar disorder are associated with enhanced activity and connectivity of default network structures with key regions of the limbic and/or salience networks.
“For example, mood disorders including major depressive disorder and bipolar disorder are associated with enhanced activity and connectivity of DN structures with key regions of the limbic and/or salience networks.147,148,215–219”
From The default network and self-generated thought: component processes, dynamic control, and clinical relevance (2014) · cites this paper as [216]
MDD resting-state data show vmPFC and limbic hyperactivity and greater connectivity between medial prefrontal regions and an affective network including amygdala.
“Resting-state data from samples with major depressive disorders demonstrate hyperactivity in the vmPFC and limbic structures (e.g., amygdala, bed nucleus of the stria terminalis [BNST])25, as well as increased connectivity between medial prefrontal regions (including the vmPFC) and other networks including an affective network to which the amygdala is interconnected26.”
From Developmental pathways to amygdala–prefrontal function and internalizing symptoms in adolescence (2012) · cites this paper as [26]
The depression-related connectivity results differ from the anxiety results and align with prior reports of greater connectivity between medial prefrontal and emotion circuits.
“Our findings on relations between amygdala-vmPFC resting-state fcMRI and depression stand in marked contrast to those for anxiety and they are consistent with recent findings that show increased connectivity between medial prefrontal and emotion circuits26.”
From Developmental pathways to amygdala–prefrontal function and internalizing symptoms in adolescence (2012) · cites this paper as [26]
Depression involves a failure to regulate activity in DMN-associated neural structures such as the amygdala, parahippocampus, and hippocampus.
“In a recent study examining the default mode network in depression comparing resting conditions (looking at negative and positive pictures) with an active reappraisal condition has shown that depression is characterized by a failure to regulate activity in neural structures (amygdala, parahippocampus, hippocampus), associated with the DMN (Sheline, Barch, Price, Rundle, Vaishnavi, Snyder, et al. 2”
From Understanding depressive rumination from a cognitive science perspective: The impaired disengagement hypothesis (2011) · cites this paper as Sheline et al., 2009
The behavioral effects of oxytocin were associated with reduced dorsomedial and ventromedial prefrontal cortex responses and functional connectivity between them and other cortical midline regions.
“These behavioral effects of OXT were associated with reduced dmPFC and vmPFC responses and functional connectivity between them and other cortical midline regions (vmPFC-precuneus/PCC, dmPFC-ACC/ hippocampus) important for self-vs.other processing”
From Oxytocin blurs the self-other distinction during trait judgments and reduces medial prefrontal cortex responses: Oxytocin Blurs Self-Other Distinction (2016) · cites this paper as Sheline et al., 2009
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Self-citation
- Authors
- Sheline, Y. I., Barch, D. M., Price, J. L., Rundle, M. M., Vaishnavi, S. N., Snyder, A. Z., Mintun, M. A., Wang, S., Coalson, R. S., & Raichle, M. E.
- Affiliations
- Neurology, Inc (US)
- Washington University in St. Louis (US)
- Radiology
- Departments of aPsychiatry
- Corresponding author
- Sheline, Yvette I.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-02-10
- Volume
- 106
- Issue
- 6
- Pages
- 1942-1947
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2631078
- OpenAlex
- W2158327608
- Cited by
- 1,480
- References
- 41
- Citations by year
- 2026: 87 · 2025: 89 · 2024: 83 · 2023: 80 · 2022: 116 · 2021: 131 · 2020: 100 · 2019: 88 · 2018: 98 · 2017: 80 · 2016: 104 · 2015: 95 · 2014: 78 · 2013: 79 · 2012: 65
- FWCI
- 27.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (K24MHO79510)
- National Institute of Mental Health (R01 MH64821, R01MH064821, K24MH079510)
- National Institute of Neurological Disorders and Stroke (P50NS006833, P50 NS06833)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Mind wandering and attention
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- default mode network, major depressive disorder, self-referential processing, cognitive reappraisal, negative pictures, ventromedial prefrontal cortex, anterior cingulate cortex, parahippocampal cortex, amygdala, hippocampus, depression pathophysiology
- MeSH terms
- Adult, Behavior, Brain Mapping, Cerebral Cortex, Major Depressive Disorder, Ego, Emotions, Female, Humans, Limbic System, Male, Visual Perception, Case-Control Studies, Prefrontal Cortex, Young Adult
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