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Frontocingulate Dysfunction in Depression: Toward Biomarkers of Treatment Response
Open accessAbstract
Increased rostral anterior cingulate cortex (rACC) activity has emerged as a promising predictor of treatment response in depression, but neither the reliability of this relationship nor the mechanisms supporting it have been thoroughly investigated. This review takes a three-pronged approach to these issues. First, I present a meta-analysis demonstrating that the relationship between resting rACC activity and treatment response is robust. Second, I propose that the rACC plays a key role in treatment outcome because of its 'hub' position in the default network. Specifically, I hypothesize that elevated resting rACC activity confers better treatment outcomes by fostering adaptive self-referential processing and by helping to recalibrate relationships between the default network and a 'task-positive network' that comprises dorsolateral prefrontal and dorsal cingulate regions implicated in cognitive control. Third, I support this hypothesis by reviewing neuropsychological, electrophysiological, and neuroimaging data on frontocingulate dysfunction in depression. The review ends with a discussion of the limitations of current work and future directions.
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“In a coordinate-based meta-analysis [69], increased rsFC in the pgACC predicted response to a variety of treatments (e.g., repetitive transcranial magnetic stimulation (rTMS), pharmacotherapy, cognitive behavior therapy, electroconvulsive therapy (ECT)) (see also [16]).”
From Prefrontal cortex and depression (2022) · cites this paper as [16]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The association between higher baseline anterior cingulate activity and better treatment response has been found by a more diverse set of studies, and has been meta-analytically confirmed (13, 40).”
From SSRI Treatment Response Prediction in Depression Based on Brain Activation by Emotional Stimuli (2020) · cites this paper as [40]
The cited source says what the claim attributes to it.
In the citing paper
“Of note, deficient recruitment of PFC (particularly, dlPFC) regions has been coupled with hyperactivity in paralimbic (e.g., pgACC, sgACC) and limbic (e.g., amygdala) regions critically implicated in automatic processing of emotional cues (for review, see [16,157]).”
From Prefrontal cortex and depression (2022) · cites this paper as [16]
The cited source says what the claim attributes to it.
In the citing paper
“Similarly, hyperactivation of, or a failure to deactivate, the pgACC has been reported in MDD across disparate affective tasks [16,179], including (1) affective evaluation and cognitive reappraisal of negative stimuli; (2) self-referential processing of negative attributes; (3) inhibition of negative words; and in response to (4) sad words and commission errors.”
From Prefrontal cortex and depression (2022) · cites this paper as [16]
The cited source says what the claim attributes to it.
In the citing paper
“in studies in which MDD subjects performed at the same level as controls, MDD has been linked to potentiated pgACC, dACC and left dlPFC [16,237,238] and pgACC hyperactivation persisted after remission [239].”
From Prefrontal cortex and depression (2022) · cites this paper as [16]
In the citing paper
“For now, an increased activity of pregenual ACC seems to be the most consistent general marker of good response to a variety of treatments, as supported by meta-analyses and shown in subsequent studies (Pizzagalli, 2011, Fu et al. 2013, Godlewska et al. 2016).”
From Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment (2021) · cites this paper as Pizzagalli, 2011
In the citing paper
“This was in line with other studies showing that increased reactivity of pgACC was perhaps the most reliable general predictor of clinical response to pharmacotherapy and psychotherapy alike (Pizzagalli 2011, Fu et al., 2013, Godlewska et al. 2016).”
From Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment (2021) · cites this paper as Pizzagalli 2011
In the citing paper
“Infliximab is a promising TNF antagonist that binds to soluble and transmembrane domains of TNF-α, thus preventing the binding of TNF-α to its receptors.74,75”
From Cognitive Impairment in Major Depressive Disorder (2019) · cites this paper as [74]
In the citing paper
“Among the most consistently identified proinflammatory cytokine disturbances in MDD is tumor necrosis factor alpha (TNF-α).17,74”
From Cognitive Impairment in Major Depressive Disorder (2019) · cites this paper as [74]
In the citing paper
“Finally, cognitive control has been reliably linked to the dlPFC and dACC (Pizzagalli, 2011; Ridderinkhof et al, 2004).”
From Neural Correlates of Three Promising Endophenotypes of Depression: Evidence from the EMBARC Study (2016) · cites this paper as Pizzagalli, 2011
In the citing paper
“The dlPFC has been strongly implicated in cognitive control (Pizzagalli, 2011; Ridderinkhof et al, 2004)”
From Neural Correlates of Three Promising Endophenotypes of Depression: Evidence from the EMBARC Study (2016) · cites this paper as Pizzagalli, 2011
In the citing paper
“Notably, the extent to which these biases can be modulated by pharmacological therapies in patients has been found to be indicative of treatment response (Sheline et al. 2001; Pizzagalli 2010)”
From Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers (2015) · cites this paper as Pizzagalli 2010
In the citing paper
“This region is involved in both emotional processing and regulation and has been linked to self-referential processing and cognitive and attentional control with strong connections to both limbic and prefrontal brain regions (Pizzagalli, 2011).”
From Meta-analyses of the neural mechanisms and predictors of response to psychotherapy in depression and anxiety (2018) · cites this paper as Pizzagalli, 2011
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Metadata
- Authors
- Pizzagalli, D. A.
- Affiliations
- Harvard University (US)
- Corresponding author
- Pizzagalli, Diego A
- ORCID
- Pizzagalli, Diego A
- Venue
- Neuropsychopharmacology
- Published
- 2010-09-22
- Volume
- 36
- Issue
- 1
- Pages
- 183-206
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3036952
- OpenAlex
- W2162541816
- Cited by
- 945
- References
- 294
- Citations by year
- 2026: 49 · 2025: 63 · 2024: 51 · 2023: 42 · 2022: 45 · 2021: 87 · 2020: 58 · 2019: 60 · 2018: 55 · 2017: 61 · 2016: 71 · 2015: 83 · 2014: 73 · 2013: 74 · 2012: 45
- FWCI
- 5.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institute of Mental Health (R01MH068376, R21MH078979, R01 MH68376)
- National Center for Complementary and Integrative Health (R21AT002974)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- depression, rostral anterior cingulate cortex, treatment response prediction, biomarkers, resting-state brain activity, default mode network, task-positive network, self-referential processing, cognitive control, dorsolateral prefrontal cortex
- MeSH terms
- Antidepressive Agents, Cognition, Major Depressive Disorder, Gyrus Cinguli, Humans, Nerve Net, Outcome Assessment, Health Care, Prefrontal Cortex, Biomarkers, Pharmacological
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