Altered Emotional Interference Processing in Affective and Cognitive-Control Brain Circuitry in Major Depression
Open accessAbstract
Background Major depression is characterized by a negativity bias: an enhanced responsiveness to, and memory for, affectively negative stimuli. However, it is not yet clear whether this bias represents 1) impaired top-down cognitive control over affective responses, potentially linked to deficits in dorsolateral prefrontal cortex function; or 2) enhanced bottom-up responses to affectively laden stimuli that dysregulate cognitive control mechanisms, potentially linked to deficits in amygdala and anterior cingulate function.Methods We used an attentional interference task using emotional distracters to test for top-down versus bottom-up dysfunction in the interaction of cognitive-control circuitry and emotion-processing circuitry. A total of 27 patients with major depression and 24 control participants was tested. Event-related functional magnetic resonance imaging was carried out as participants directly attended to, or attempted to ignore, fear-related stimuli.Results Compared with control subjects, patients with depression showed an enhanced amygdala response to unattended fear-related stimuli (relative to unattended neutral). By contrast, control participants showed increased activity in right dorsolateral prefrontal cortex (Brodmann areas 46/9) when ignoring fear stimuli (relative to neutral), which the patients with depression did not show. In addition, the depressed participants failed to show evidence of error-related cognitive adjustments (increased activity in bilateral dorsolateral prefrontal cortex on posterror trials), but the control group did show them.Conclusions These results suggest multiple sources of dysregulation in emotional and cognitive control circuitry in depression, implicating both top-down and bottom-up dysfunction.
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Selective attention, interference processing, and working memory are cognitive domains all impacted in depression.
“cognitive domains that are all impacted in depression [93–96]”
From Personalized machine learning guided intervention for optimizing lifestyle behaviors in depression: a pilot study (2026) · cites this paper as [95]
The Discussion (page unavailable) reports altered responses to unattended fearful stimuli and impaired cognitive control over emotional distractors in patients with major depression, supporting the selective-attention and interference-processing parts of the claim. The paper does not establish that working memory is impacted; its references to memory concern negative emotional stimuli, not working-memory performance. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMDD is associated with reduced recruitment of dlPFC and dACC in contexts requiring ignoring task-irrelevant negative cues or behavioral adjustments after errors.
“MDD was associated with reduced recruitment of the dlPFC [160, 161, 170, 244-246] and dACC [160,161,246] in contexts requiring task-irrelevant negative cues to be ignored or behavioral adjustments after errors.”
From Prefrontal cortex and depression (2022) · cites this paper as [161]
The Effects of Attended and Unattended Fear section reports reduced right DLPFC recruitment when patients ignored fearful faces and lower activation in a region extending into the lower dorsal ACC. The Posterror Analysis reports that patients failed to increase DLPFC activation after errors. It does not show impaired error-related recruitment of the dorsal ACC: the Error Analysis found that its response to errors did not differ by group. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThis deficit in inhibitory regulation by the anterior cingulate and prefrontal results in an overactive amygdala as well as biases in memory towards negative stimuli and away from positive stimuli.
“This deficit in inhibitory regulation by the anterior cingulate and prefrontal results in an overactive amygdala as well as biases in memory towards negative stimuli and away from positive stimuli [57–60].”
From Association between time perspective and metacognition among Lebanese adults: the mediating role of mindfulness (2023) · cites this paper as [59]
The Abstract (page not provided) describes enhanced memory for negative stimuli in depression, and the Discussion reports increased amygdala activity alongside reduced DLPFC recruitment when patients ignored fearful faces. But the Discussion suggests that amygdala overactivity influenced DLPFC activity from the bottom up, rather than establishing that impaired prefrontal or cingulate inhibition caused the amygdala response. The study did not test memory for positive stimuli. (LLM, conf=0.87)
Experimental — accuracy not yet measuredRelative to healthy controls, individuals with MDD showed reduced dlPFC activation during tasks involving matching negative facial expressions, presenting negative stimuli, requiring to ignore negative faces, or inducing emotional interference.
“Relative to healthy controls, individuals with MDD showed reduced dlPFC activation during tasks involving matching negative facial expressions [159], presenting negative stimuli [156, 160], requiring to ignore negative faces [161], or inducing emotional interference [162].”
From Prefrontal cortex and depression (2022) · cites this paper as [161]
The right DLPFC has been shown to be less active in individuals with depression than in healthy controls during observation of threat-related facial expressions and of fearful faces, even if these were not explicitly attended to.
“the right DLPFC has been shown to be less active in individuals with depression than in healthy controls during observation of threat-related facial expressions (Mingtian et al., 2012) and of fearful faces, even if these were not explicitly attended to (Fales et al., 2008).”
From Social functioning in major depressive disorder (2016) · cites this paper as Fales et al., 2008
Actively depressed patients show increased neural responses to positive and negative facial expressions in the subgenual anterior cingulate cortex.
“Actively depressed patients also show increased neural responses to positive and negative facial expressions in the subgenual portion of the anterior cingulate cortex, a region involved in the physiologic response of emotional processing.45,46,52,63”
From Systematic review of the neural basis of social cognition in patients with mood disorders (2012) · cites this paper as [52]
These findings may be interpreted as deficits in the cognitive control of emotion during processing of emotionally salient stimuli such as faces.
“These findings may be interpreted as deficits in the cognitive control of emotion during the processing of emotionally salient stimuli (faces).”
From Systematic review of the neural basis of social cognition in patients with mood disorders (2012) · cites this paper as [52]
Elevated activity and altered connectivity of the amygdala and ventromedial regions such as the subgenual cingulate may result in the negative processing bias inherent in MDD.
“Elevated activity and altered connectivity of the amgydala and ventromedial regions, such as the subgenual cingulate, may result in the negative processing bias inherent in the disorder.”
From Systematic review of the neural basis of social cognition in patients with mood disorders (2012) · cites this paper as [52]
When patients with major depressive disorder are asked to ignore negative stimuli, they fail to recruit the dorsolateral prefrontal cortex, which is correlated with amygdala hyperactivity.
“Conversely, when patients with MDD were asked to ignore negative stimuli, they failed to recruit the DLPFC which was correlated with amygdala hyperactivity48.”
From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [48]
MDD patients show prefrontal hypoactivation during tasks that require ignoring negative-valence distracters.
“Hypoactivation of these regions is observed in MDD patients when performing tasks that require ignoring negative valence distracters [183].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [183]
DlPFC in depression typically demonstrates hypoactivation.
“DlPFC in particular has been previously linked with neural changes in depression, typically demonstrating hypoactivation (Fales et al., 2008; Siegle et al., 2007)”
From Neural correlates of emotional processing in depression: Changes with cognitive behavioral therapy and predictors of treatment response (2011) · cites this paper as Fales et al., 2008
Past studies have found impairments in cognitive control in individuals with depression when they are confronted with emotional information.
“Past studies have found impairments in cognitive control in individuals with depression when confronted with emotional information (Beevers et al. 2010; Ditcher et al. 2009; Fales et al. 2008).”
From Executive Function Deficits in Daily Life Prospectively Predict Increases in Depressive Symptoms (2014) · cites this paper as Fales et al. 2008
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“…in both bipolar disorder and unipolar depression, and are consistent with neuroimaging studies reporting abnormal activity in these regions during emotion regulation tasks in both bipolar depressed (Deckersbach et al., 2008) and unipolar depressed adults (Fales et al., 2008; Siegle et al., 2002).”
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- Authors
- Fales, C. L., Barch, D. M., Rundle, M. M., Mintun, M. A., Snyder, A. Z., Cohen, J. D., Mathews, J., & Sheline, Y. I.
- Affiliations
- Washington University in St. Louis (US)
- Princeton University (US)
- Corresponding author
- Sheline, Yvette I.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 63
- Issue
- 4
- Pages
- 377-384
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC2268639
- OpenAlex
- W2161710337
- Cited by
- 517
- References
- 55
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 32 · 2023: 20 · 2022: 21 · 2021: 57 · 2020: 27 · 2019: 22 · 2018: 15 · 2017: 30 · 2016: 35 · 2015: 35 · 2014: 34 · 2013: 27 · 2012: 38
- FWCI
- 11.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH066031, R01 MH06603101, R01 MH64821, R01MH064821)
- National Center for Research Resources (K24 RR18192, K24RR018192)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- major depressive disorder, negativity bias, emotional interference, attentional interference, top-down cognitive control, amygdala, dorsolateral prefrontal cortex, anterior cingulate cortex, emotional distracters, event-related fMRI
- MeSH terms
- Adult, Affect, Amygdala, Attention, Cognition, Cognition Disorders, Depressive Disorder, Major, Major Depressive Disorder, Face, Fear, Female, Gyrus Cinguli, Humans, Magnetic Resonance Imaging, Male, Nerve Net, Neuropsychological Tests, Surveys and Questionnaires, Visual Perception
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