Relationship Between Amygdala Responses to Masked Faces and Mood State and Treatment in Major Depressive Disorder
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CONTEXT: Major depressive disorder (MDD) is associated with behavioral and neurophysiological evidence of mood-congruent processing biases toward explicitly presented, emotionally valenced stimuli. However, few studies have investigated such biases toward implicitly presented stimuli. OBJECTIVE: To investigate differential amygdala responses to sad, happy, and neutral faces presented below the level of explicit conscious awareness using a backward masking task in unmedicated participants with MDD and healthy controls (HCs). DESIGN: Initial cross-sectional design followed by a longitudinal treatment trial using functional magnetic resonance imaging. SETTING: Psychiatric outpatient clinic at the National Institute of Mental Health. PARTICIPANTS: We studied 22 unmedicated, currently depressed people with MDD (dMDD), 16 unmedicated individuals with MDD in full remission (rMDD), and 25 HCs. INTERVENTION: Ten dMDD participants underwent 8 weeks of antidepressant treatment with the selective serotonin reuptake inhibitor sertraline hydrochloride. MAIN OUTCOME MEASURES: Amygdala region-of-interest and whole-brain analyses evaluated the hemodynamic response during exposure to masked sad vs masked happy faces, to masked sad vs neutral faces, and to masked happy vs neutral faces. RESULTS: The dMDD participants showed greater amygdala responses than HCs to masked sad faces, whereas HCs showed greater amygdala responses to masked happy faces. The bias toward sad faces also was evident in rMDD participants relative to HCs and did not differ between dMDD and rMDD participants. This processing bias reversed toward the normative pattern in dMDD participants after sertraline treatment. CONCLUSIONS: Emotional-processing biases occur in amygdala responses to sad faces presented below the level of conscious awareness in dMDD or rMDD individuals and to happy faces in HCs. By influencing the salience of social stimuli, mood-congruent processing biases in the amygdala may contribute to dysfunction in conscious perceptions and social interactions in MDD. Our data suggest, however, that the negative bias resolves and a positive bias develops in patients with MDD during selective serotonin reuptake inhibitor treatment.
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Blunted dlPFC activation has been accompanied by exaggerated amygdalar activation when processing subliminal negative stimuli.
“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 [168]
The Results (fMRI Results; page not provided) report greater amygdala responses to masked-sad faces in depressed participants than in healthy controls, supporting the subliminal-stimulus portion of the claim. They do not report blunted dlPFC activation accompanying that response; the reported frontal difference concerns unmasked faces. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAmygdalar hyperactivity to negative stimuli emerged in fully remitted adults with past MDD.
“emerged in fully remitted adults with past MDD [168]”
From Prefrontal cortex and depression (2022) · cites this paper as [168]
The Discussion reports greater amygdala activity in fully remitted, unmedicated MDD subjects than in controls for masked-sad versus masked-happy faces. The claim omits that restriction: the same section reports no group difference for explicitly presented emotional faces, so the finding does not establish hyperactivity to negative stimuli generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAntidepressants facilitate positive emotional stimuli processing in MDD patients and reduce the activity of negative emotions, concomitant with a normalization of amygdala activity.
“Indeed, several meta-analyses concluded that antidepressants facilitate positive emotional stimuli processing in MDD patients and reduce the activity of negative emotions (Delaveau et al. 2011), concomitant with a normalization of amygdala activity (Chen et al. 2014; Victor et al. 2010).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Victor et al. 2010
Acutely depressed patients consistently show enhanced recognition of sad facial expressions.
“Enhanced recognition of sad facial expressions has also been consistently reported in acutely depressed patients.73,[143][144][145][146][147][148]”
From Systematic review of the neural basis of social cognition in patients with mood disorders (2012) · cites this paper as [73]
Victor and colleagues found that remitted MDD patients had exaggerated amygdala responses to masked sad faces and no amygdala response to masked happy faces compared with controls.
“A recent study by Victor and colleagues, 73 however, found that remitted patients with MDD showed exaggerated responses in the amygdala to masked sad faces and a lack of amygdalar response to masked happy faces compared with controls.”
From Systematic review of the neural basis of social cognition in patients with mood disorders (2012) · cites this paper as [73]
Victor and colleagues found that exaggerated amygdala response to masked sad faces and reduced amygdala activity to masked happy faces were reversed after 4 weeks of sertraline.
“Similarly, Victor and colleagues 73 found that an exaggerated response in the amygdala to masked sad faces and reduced amygdala activity to masked happy faces were reversed following administration of a 4-week treatment regimen of sertraline.”
From Systematic review of the neural basis of social cognition in patients with mood disorders (2012) · cites this paper as [73]
Antidepressant treatment normalizes hyperactive amygdala responses following 7 days or longer treatment with an SSRI.
“Antidepressant treatment modifies this, and hyperactive responses in the amygdala are normalised following 7 days'46 or longer44,45 treatment with an SSRI.”
From The effects of drugs on human models of emotional processing: an account of antidepressant drug treatment (2015) · cites this paper as [45]
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- Authors
- Victor, T. A., Furey, M. L., Fromm, S. J., Öhman, A., & Drevets, W. C.
- Affiliations
- National Institutes of Health (US)
- Karolinska Institutet (SE)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2010-11-01
- Volume
- 67
- Issue
- 11
- Pages
- 1128
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC3253452
- OpenAlex
- W2060926272
- Cited by
- 400
- References
- 59
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 23 · 2023: 11 · 2022: 14 · 2021: 48 · 2020: 18 · 2019: 19 · 2018: 21 · 2017: 26 · 2016: 26 · 2015: 41 · 2014: 30 · 2013: 39 · 2012: 36
- FWCI
- 42.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- John D. and Catherine T. MacArthur Foundation
- National Institutes of Health (Z99 MH999999)
- National Institute of Mental Health (Z01MH002792)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- major depressive disorder, amygdala, masked faces, backward masking, implicit emotional processing, sertraline, selective serotonin reuptake inhibitors, remitted depression, antidepressant response
- MeSH terms
- Adult, Affect, Amygdala, Awareness, Brain Mapping, Major Depressive Disorder, Emotions, Facial Expression, Female, Form Perception, Happiness, Humans, Magnetic Resonance Imaging, Male, Perceptual Masking, Social Perception, Wechsler Scales, Selective Serotonin Reuptake Inhibitors, Sertraline
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