Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder
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OBJECTIVE: Clinical data suggest that abnormalities in the regulation of emotional processing contribute to the pathophysiology of generalized anxiety disorder, yet these abnormalities remain poorly understood at the neurobiological level. The authors recently reported that in healthy volunteers the pregenual anterior cingulate regulates emotional conflict on a trial-by-trial basis by dampening activity in the amygdala. The authors also showed that this process is specific to the regulation of emotional, compared to nonemotional, conflict. Here the authors examined whether this form of noninstructed emotion regulation is perturbed in generalized anxiety disorder. METHOD: Seventeen patients with generalized anxiety disorder and 24 healthy comparison subjects underwent functional MRI while performing an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect label words. Behavioral and neural measures were used to compare trial-by-trial changes in conflict regulation. RESULTS: Comparison subjects effectively regulated emotional conflict from trial to trial, even though they were unaware of having done so. By contrast, patients with generalized anxiety disorder were completely unable to regulate emotional conflict and failed to engage the pregenual anterior cingulate in ways that would dampen amygdalar activity. Moreover, performance and brain activation were correlated with symptoms and could be used to accurately classify the two groups. CONCLUSIONS: These data demonstrate that patients with generalized anxiety disorder show significant deficits in the noninstructed and spontaneous regulation of emotional processing. Conceptualization of anxiety as importantly involving abnormalities in emotion regulation, particularly a type occurring outside of awareness, may open up avenues for novel treatments, such as by targeting the medial prefrontal cortex.
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A functional perspective of worry has been supported in studies using neurobiological, psychophysiological, behavioral, and self-report measurement.
“A functional perspective of worry has been supported in studies utilizing neurobiological11, psychophysiological12–14, behavioral15, and self-report16–17 measurement.”
From AN OPEN TRIAL OF EMOTION REGULATION THERAPY FOR GENERALIZED ANXIETY DISORDER AND COOCCURRING DEPRESSION. (2015) · cites this paper as [11]
Citation 11 is attached to the neurobiological-measurement part of the sentence. The Introduction and Discussion report neural findings in generalized anxiety disorder that are consistent with a regulatory role for worry, but the Discussion explicitly presents worry’s compensatory function as speculation; the study did not directly test that function. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIndividuals with GAD may respond poorly to motivational conflict, demonstrating deficits in attentional and cognitive elaborative regulation strategies.
“these individuals may respond poorly to this motivational conflict, demonstrating deficits in different systems of regulation30 encompassing attentional (e.g., attentional flexibility in processing both interoceptive and exteroceptive emotional stimuli31–33, 11) and more cognitive elaborative strategies (e.g., meta-cognitive awareness, cognitive reappraisal34, 35).”
From AN OPEN TRIAL OF EMOTION REGULATION THERAPY FOR GENERALIZED ANXIETY DISORDER AND COOCCURRING DEPRESSION. (2015) · cites this paper as [11]
The Discussion reports that patients with GAD could not adapt to emotional conflict and had a deficit in implicit emotional regulation. It does not establish deficits across different regulatory systems, including the attentional flexibility or cognitive elaborative strategies named in the citing sentence; those examples carry separate citations. (LLM, conf=0.85)
Experimental — accuracy not yet measuredEvidence from neurobiological, psychophysiological, behavioral, and self-report studies supports the functional account of worry.
“Considerable evidence supports this functional view of worry at neurobiological (Etkin, Prater, Hoeft, Menon, & Schatzberg, 2010), psychophysiological (Oathes, Siegel, & Ray, 2011; Weinberg, Klein, & Hajcak, 2012), behavioral (Cooper, Miranda, & Mennin, 2013), and self-report”
From A Pilot Study of Emotion Regulation Therapy for Generalized Anxiety and Depression: Findings From a Diverse Sample of Young Adults. (2018) · cites this paper as Etkin et al., 2010
Individuals with distress disorders often fail to enhance or diminish emotional experiences in a manner appropriate to a particular environmental context.
“Rather than processing emotion information and utilizing its motivational value, individuals with distress disorders often fail to enhance or diminish emotional experiences in a manner appropriate to a particular environmental context.”
From Emotion Regulation Therapy: A Mechanism-Targeted Treatment for Disorders of Distress (2017) · cites this paper as Etkin et al., 2010
GAD with and without MDD is characterized by a failure to spontaneously regulate emotional conflict by shifting attention in response to a motivationally salient emotional stimulus in a conflict adaptation task.
“For example, GAD with and without MDD is characterized by a failure to spontaneously regulate emotional conflict by shifting attention in response to a motivationally salient emotional stimulus in conflict adaptation task (Etkin et al., 2010; Etkin and Schatzberg, 2011).”
From Emotion Regulation Therapy: A Mechanism-Targeted Treatment for Disorders of Distress (2017) · cites this paper as Etkin et al., 2010
Emotion regulation deficits commonly occur in GAD and MDD.
“Emotion regulation deficits commonly occur in GAD (Mennin et al., 2007; Etkin et al., 2010; Etkin and Schatzberg, 2011), and MDD (Johnstone et al., 2007).”
From Emotion Regulation Therapy: A Mechanism-Targeted Treatment for Disorders of Distress (2017) · cites this paper as Etkin et al., 2010
Clients administered a conflict adaptation task evidenced pre- to mid-treatment improvements in their ability to shift attention in the face of emotional conflict (pre to mid d = 0.74) to levels comparable to healthy controls.
“One promising preliminary finding is related to emotional conflict adaptation (Etkin et al., 2010; Etkin and Schatzberg, 2011) wherein clients were administered a conflict adaptation task and evidenced pre- to mid-treatment improvements in their ability to shift their attention in the face of emotional conflict (pre to mid d = 0.74) to levels comparable to healthy controls (Etkin et al., 2010).”
From Emotion Regulation Therapy: A Mechanism-Targeted Treatment for Disorders of Distress (2017) · cites this paper as Etkin et al., 2010
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- Authors
- Etkin, A., Prater, K. E., Hoeft, F., Menon, V., & Schatzberg, A. F.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Etkin, Amit
- Venue
- American Journal of Psychiatry
- Published
- 2010-05-01
- Volume
- 167
- Issue
- 5
- Pages
- 545-554
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC4367202
- OpenAlex
- W2123350238
- Cited by
- 550
- References
- 60
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 20 · 2023: 20 · 2022: 21 · 2021: 35 · 2020: 46 · 2019: 40 · 2018: 39 · 2017: 44 · 2016: 43 · 2015: 51 · 2014: 48 · 2013: 44 · 2012: 36
- FWCI
- 47.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS058899, R21NS058899)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD047520, R01HD047520, K23HD054720)
- 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 › Psychiatry and Mental health › Psychosomatic Disorders and Their Treatments
- Keywords
- generalized anxiety disorder, emotion regulation, implicit emotion regulation, pregenual anterior cingulate cortex, amygdala, emotional conflict, medial prefrontal cortex, functional connectivity, symptom classification
- MeSH terms
- Adaptation, Psychological, Adult, Amygdala, Anxiety Disorders, Conflict, Psychological, Emotions, Female, Gyrus Cinguli, Humans, Magnetic Resonance Imaging, Male, Neural Pathways, Psychiatric Status Rating Scales, Case-Control Studies
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