The DOI matches its Crossref record; 290 of the 290 references it cites were found in a registry or an index; 194 of the 286 sources its claims cite were checked for support.
Prefrontal cortex and depression
Open accessAbstract
The prefrontal cortex (PFC) has emerged as one of the regions most consistently impaired in major depressive disorder (MDD). Although functional and structural PFC abnormalities have been reported in both individuals with current MDD as well as those at increased vulnerability to MDD, this information has not translated into better treatment and prevention strategies. Here, we argue that dissecting depressive phenotypes into biologically more tractable dimensions - negative processing biases, anhedonia, despair-like behavior (learned helplessness) - affords unique opportunities for integrating clinical findings with mechanistic evidence emerging from preclinical models relevant to depression, and thereby promises to improve our understanding of MDD. To this end, we review and integrate clinical and preclinical literature pertinent to these core phenotypes, while emphasizing a systems-level approach, treatment effects, and whether specific PFC abnormalities are causes or consequences of MDD. In addition, we discuss several key issues linked to cross-species translation, including functional brain homology across species, the importance of dissecting neural pathways underlying specific functional domains that can be fruitfully probed across species, and the experimental approaches that best ensure translatability. Future directions and clinical implications of this burgeoning literature are discussed.
Overview
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TL;DR
This review argues that prefrontal cortex (PFC) dysfunction in major depressive disorder (MDD) is heterogeneous and context-dependent, and that parsing depression into anhedonia, negative processing biases, and learned helplessness/despair can better align clinical and preclinical evidence. It synthesizes human imaging findings with rodent and non-human primate work, emphasizing cross-species translation and treatment effects.
Key findings
- Across reward-processing tasks, MDD is generally linked to blunted ventral/dorsal striatal, pgACC/dACC, and central/medial OFC responses, but hyperactivation in mPFC/vmPFC/sgACC, dlPFC, and lateral OFC to non-rewards; many markers correlate with anhedonia and predict later symptoms. Examples include a voxel-wise meta-analysis comparing 1,399 MDD with 1,332 controls showing increased medial OFC/pgACC ALFF, and the largest structural MRI study (1,902 MDD vs. 7,658 controls) showing thinner ACC and OFC/vmPFC gray matter. In IMAGEN (N = 1,877 at age 14; N = 1,140 at age 19), higher depression severity related to reduced central OFC reward sensitivity and potentiated lateral OFC non-reward responses; in a youth sample (N = 1,576), blunted ventral striatal reward response predicted depression 2 years later, and in children (N = 637), reward-pathway resting connectivity predicted onset 3 years later.
- Negative processing biases in MDD and vulnerability are associated with dlPFC/dACC hypoactivation and pgACC/sgACC/amygdala hyperactivation, plus altered vmPFC–amygdala and dmPFC–amygdala coupling. A meta-analysis of 44 fMRI studies found reduced left dlPFC activation to negative stimuli in MDD, and a meta-analysis of 60 treatment studies found antidepressants decreased middle frontal gyrus/pgACC responses to negative stimuli while increasing rostral vmPFC, dlPFC, and pgACC responses to positive stimuli.
- Learned helplessness/despair has fewer human studies, but PFC regions are implicated in controllability and stressor effects. Rodent work suggests prelimbic cortex promotes active coping while infralimbic cortex promotes passive coping, with ketamine’s delayed effects requiring an intact infralimbic cortex; marmoset studies show area 25 overactivation blunts anticipatory/motivational arousal and increases threat reactivity, while area 14 inactivation increases appetitive arousal, and systemic ketamine can ameliorate area 25-induced reductions.
- Executive dysfunction in MDD involves reduced dACC/dlPFC recruitment and failure to deactivate pgACC/default-mode regions; greater deactivation of anteromedial PFC during working memory predicts better escitalopram response, and greater dmPFC deactivation before ketamine predicts greater cognitive symptom reduction.
Methods
- Narrative, integrative review rather than a systematic review or meta-analysis; the authors synthesize clinical and preclinical literature relevant to selected depressive phenotypes and PFC subregions.
- Human evidence includes fMRI, resting-state functional connectivity, structural MRI, meta-analyses, and large cohorts such as ENIGMA, IMAGEN, and UK Biobank, plus high-risk and remitted samples.
- Preclinical evidence includes rodent chronic stress models and selective PFC/OFC interventions, and non-human primate studies using lesions, inactivations, microstimulation, and ketamine; the main analysis is qualitative cross-species comparison.
Limitations
- The paper states that cross-species translation is limited by uncertain functional homology/analogy, especially for dl/vlPFC regions with no clear rodent counterpart, inconsistent prefrontal nomenclature, symptom complexity, and the difficulty of modeling chronic MDD with acute interventions. It also cautions that forced swim and tail suspension tests may reflect coping or anxiety rather than despair, and that chronic stress models vary in etiology and treatment response.
- The authors state that the review presents a selected summary due to space limitations, not an exhaustive account.
- Evident from the text: as a narrative review, it does not use formal systematic search, risk-of-bias assessment, or quantitative pooling; causal claims rely mainly on animal interventions, while many human findings are correlational.
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Claims the paper makes
73 Own interpretation · 70 Partly supported · 66 Supported · 41 No full text of the sources · 23 No basis given · 15 Sources not found · 7 Not supported · 5 Supported so far · 4 Not checked yet · 3 Mixed support · 3 Couldn’t confirm · accuracy not yet measured
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“studies of the neurobiology of reward processing have highlighted the variety of distinct pathways involved in its different aspects resulting in the recognition of separate subtypes of anhedonia, including consummatory, anticipatory, motivational and decisional [20,21].”
§ Prefrontal cortex and depression > Symptom complexity
What the sources say
- Partly supportedcites [20] Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011;35:537–55. sourceExperimental — accuracy not yet measured
The Research Highlights (section 6; page unavailable) propose motivational and consummatory anhedonia and introduce decisional anhedonia. Section 2.2 discusses anticipatory pleasure but says it is unclear whether that is the same construct as reward motivation; the paper does not establish anticipatory anhedonia as a fourth separate subtype. (LLM, conf=0.88)
- Disputedcites [21] Der-Avakian A, Markou A. The neurobiology of anhedonia and other reward-related deficits. Trends Neurosci. 2012;35:68–77. sourceExperimental — accuracy not yet measured
The Concluding Remarks distinguish consummatory and anticipatory anhedonia, but recommend limiting the term “anhedonia” to deficits in hedonic capacity. They treat motivation and decision-making as other reward-related processes, not as additional subtypes of anhedonia. (LLM, conf=0.87)
Checked by a reasoning model — may be wrong.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“An early meta-analysis (64 structural MRI studies) reported that frontal regions showed the largest volumetric reductions in MDD [78], particularly in the ACC and bilateral OFC, although distinct subregions were not investigated (see also [79]).”
§ Prefrontal cortex and depression > MDD AND CHRONIC STRESS MODELS IN RODENTS Resting state (task-free) functional connectivity findings in MDD
What the sources say
- Supportedcites [78] Koolschijn PC, van Haren NE, Lensvelt-Mulders GJ, Hulshoff Pol HE, Kahn RS. Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Hum Brain Mapp. 2009;30:3719–35. source
The Abstract describes a meta-analysis of 64 MRI studies and reports large volume reductions in frontal regions, especially the anterior cingulate and orbitofrontal cortex. Table II in “Areas in the Frontal Lobe” reports reduced orbitofrontal volume on both the left and right; that section identifies the anterior cingulate as having the largest effect. Page numbers are not available in our copy. (LLM, conf=0.94)
- Disputedcites [79] Gray JP, Müller VI, Eickhoff SB, Fox PT. Multimodal abnormalities of brain structure and function in major depressive disorder: a meta-analysis of neuroimaging studies. Am J Psychiatry. 2020;177:422–34. sourceExperimental — accuracy not yet measured
The Results report 97 studies, not 64 structural MRI studies. The Results section on all patients says the gray-matter-volume analysis found no significant region of convergent abnormality, rather than the largest reductions occurring in frontal regions. The Discussion identifies a subgenual anterior cingulate abnormality in the multimodal analysis, but does not report the claimed bilateral orbitofrontal volumetric reductions. Page numbers were not available in our copy. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Similarly, adolescents with MDD (N = 213) had lower cortical thickness in the medial OFC/vmPFC and superior frontal gyrus than adolescents without MDD history (N = 294) [81].”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
What the sources say
- Disputedcites [81] Schmaal L, Hibar DP, Sämann PG, Hall GB, Baune BT, Jahanshad N, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry. 2017;22:900–9. sourceExperimental — accuracy not yet measured
The Results (Adolescents) report the stated sample sizes and reduced surface area in the left medial OFC and right superior frontal gyrus, but explicitly say no cortical thickness differences were detected between adolescent patients and controls. The claim incorrectly describes the surface-area finding as a cortical-thickness finding. (LLM, conf=0.94)
Checked by a reasoning model — may be wrong.
plaincorrelationaln = 213- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Whereas amygdalar hyper-activation to negative faces was reported in a similar offspring sample (mean age: 14 years) [186], the PFC findings contrast with reports of blunted dlPFC activation (and normative amygdalar responses) to fearful faces [187] and a sad mood induction [188] among asymptomatic offspring of MDD patients (16-21 years old and 9-14 years old, respectively).”
§ Prefrontal cortex and depression > Micro-stimulation
What the sources say
- Disputedcites [188] Joormann J, Cooney RE, Henry ML, Gotlib IH. Neural correlates of automatic mood regulation in girls at high risk for depression. J Abnorm Psychol. 2012;121:61–72. sourceExperimental — accuracy not yet measured
The Abstract and Discussion (page not available in our copy) report greater, not normative, amygdala activation in high-risk girls after sad mood induction. They report lower dlPFC activation during the subsequent mood-regulation task, not during induction. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Among MDD subjects, a failure to deactivate the pgACC (and adjacent dmPFC) during cognitive or emotional processing tasks correlated with more depression severity and feelings of hopelessness [181, 182].”
§ Prefrontal cortex and depression > NEGATIVE PROCESSING BIASES Major depressive disorder
What the sources say
- Disputedcites [181] Korgaonkar MS, Grieve SM, Etkin A, Koslow SH, Williams LM. Using standardized fMRI protocols to identify patterns of prefrontal circuit dysregulation that are common and specific to cognitive and emotional tasks in major depressive disorder: first wave results from the iSPOT-D study. Neuropsychopharmacology. 2013;38:863–71. sourceExperimental — accuracy not yet measured
The Results section, “Correlation of fMRI With Symptom Severity, Behavioral Data and Across Tasks” (page unavailable), explicitly reports that dmPFC activation patterns did not correlate significantly with current depression severity. The Discussion describes possible failure to deactivate the ACC during cognitive tasks, but the claimed severity correlation is contrary to the reported result; the cited passages do not establish a correlation with hopelessness. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
- Not checked — no full text of the sourcecites [182] Grimm S, Boesiger P, Beck J, Schuepbach D, Bermpohl F, Walter M, et al. Altered negative BOLD responses in the default-mode network during emotion processing in depressed subjects. Neuropsychopharmacology. 2009;34:843–932. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“in a task that manipulated the perception of control over monetary rewards or losses, unlike controls, depressed individuals failed to show greater striatal activation to self-attributed vs. externally attributed monetary gains [210].”
§ Prefrontal cortex and depression > LEARNED HELPLESSNESS Major depressive disorder
What the sources say
- Disputedcites [210] Späti J, Chumbley J, Doerig N, Brakowski J, Grosse Holtforth M, Seifritz E, et al. Valence and agency influence striatal response to feedback in patients with major depressive disorder. J Psychiatry Neurosci. 2015;40:394–400. sourceExperimental — accuracy not yet measured
The Discussion (p. 5) says the altered putamen response in patients concerned self-attributed versus externally attributed losses, and explicitly reports no evidence of an altered ventral striatal response to gains. The simple-effects analysis (p. 5) likewise found no between-group effect for the gains contrast, contrary to the claimed difference from controls for monetary gains. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Specifically, ketamine infusion reduced (1) hyperactivation in the sgACC (BA25) to positive feedback [121], (2) FC between the pgACC and dACC [199], and (3) FC between the sgACC and limbic regions (e.g., hippocampus) [121].”
§ Prefrontal cortex and depression > Micro-stimulation
What the sources say
- Disputedcites [121] Morris LS, Costi S, Tan A, Stern ER, Charney DS, Murrough JW. Ketamine normalizes subgenual cingulate cortex hyper-activity in depression. Neuropsychopharmacology. 2020;45:975–81. sourceExperimental — accuracy not yet measured
The Effects of ketamine section explicitly reports no significant change in hippocampus–sgACC connectivity before versus after ketamine (p > 0.05). The Discussion mentions reduced connectivity in a previous study of healthy men, but that is not the finding of this paper’s ketamine cohort. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“one study employing acute restraint stress to induce a negative bias revealed that the effectiveness of systemic ketamine to reduce such a bias in the ambiguous cue test was dependent upon the mPFC [45]”
§ Prefrontal cortex and depression > Preclinical studies in animals
What the sources say
- Disputedcites [45] Hales CA, Robinson ESJ, Houghton CJ. Diffusion modelling reveals the decision making processes underlying negative judgement bias in rats. PLoS One. 2016;11:e0152592. sourceExperimental — accuracy not yet measured
The Results (Behavioural results, Fig. 2; page unavailable) report that acute restraint stress did not induce a negative judgement bias: it had no effect on any behavioural measure. The paper tested FG7142 as its acute drug manipulation, not systemic ketamine, and the retrieved passages do not report an mPFC-dependent ketamine effect. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Compared to controls, individuals with MDD showed increased ALFF in a region spanning the medial orbitofrontal cortex (OFC) and perigenual ACC (pgACC).”
§ Prefrontal cortex and depression > MDD AND CHRONIC STRESS MODELS IN RODENTS Resting state (task-free) functional connectivity findings in MDD
What the sources say
- Partly supportedcites [70] Gong J, Wang J, Qiu S, Chen P, Luo Z, Wang J, et al. Common and distinct patterns of intrinsic brain activity alterations in major depression and bipolar disorder: voxel-based meta-analysis. Transl Psychiatry. 2020;10:353. https://doi.org/10.1038/s41398-020-01036-5. sourceExperimental — accuracy not yet measured
The Results (ALFF differences of the main meta-analysis; page unavailable) report increased ALFF in MDD versus healthy controls in a cluster including the medial orbitofrontal cortex and anterior cingulate cortex. Table 1 places anterior cingulate/paracingulate areas in that cluster, but the paper does not identify them specifically as perigenual ACC. (LLM, conf=0.83)
plaincorrelationaln = 1,399- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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]).”
§ Prefrontal cortex and depression > MDD AND CHRONIC STRESS MODELS IN RODENTS Resting state (task-free) functional connectivity findings in MDD
What the sources say
- Not checked — no full text of the sourcecites [69] Long Z, Du L, Zhao J, Wu S, Zheng Q, Lei X. Prediction on treatment improvement in depression with resting state connectivity: a coordinate-based meta-analysis. J Affect Disord. 2020;276:62–68. source
- Partly supportedcites [16] Pizzagalli DA. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology. 2011;36:183–206. sourceExperimental — accuracy not yet measured
The meta-analysis Results report that higher pretreatment rostral ACC activity predicted better response across several treatments, including drugs and rTMS. They do not establish that increased resting-state functional connectivity predicted response; the paper discusses connectivity as a treatment-associated change instead. The Results also explicitly except ECT from the positive prediction finding and report no pretreatment rACC difference between CBT responders and nonresponders in the cited CBT study. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 103
- Probably not a substantial claim. 14
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“In tasks probing consummatory anhedonia (e.g., receipt of secondary rewards such as money), MDD has been associated with reduced activation in ventral (nucleus accumbens) and dorsal (caudate, putamen) striatum, ACC (rostral, dorsal), and OFC but hyperactivation in the mPFC, vmPFC (including sgACC) and dlPFC [100, 102, 104].”
§ Prefrontal cortex and depression > Consummatory anhedonia.
What the sources say
- Disputedcites [100] Zhang B, Lin P, Shi H, Öngür D, Auerbach RP, Wang X, et al. Mapping anhedonia-specific dysfunction in a transdiagnostic approach: an ALE meta-analysis. Brain Imaging Behav. 2016;10:920–39. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
- Partly supportedcites [102] Borsini A, Wallis ASJ, Zunszain P, Pariante CM, Kempton MJ. Characterizing anhedonia: a systematic review of neuroimaging across the subtypes of reward processing deficits in depression. Cogn Affect Behav Neurosci. 2020;20:816–41. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [104] O’Callaghan G, Stringaris A. Reward processing in adolescent depression across neuroimaging modalities: a review. Z Kinder Jugendpsychiatr Psychother. 2019;47:535–41. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Both forms of inflexibility have been reported following chronic stress but only stress-induced attentional set-shifting deficits were prevented by localized infusions of a cocktail of alpha 1, beta 1 and beta 2 adrenergic receptor agonists into the mPFC before each stress session of the chronic treatment period [257], whilst stress-induced reversal learning deficits remain.”
§ Prefrontal cortex and depression > Preclinical animal studies
What the sources say
- Disputedcites [257] Jett JD, Morilak DA. Too much of a good thing: blocking noradrenergic facilitation in medial prefrontal cortex prevents the detrimental effects of chronic stress on cognition. Neuropsychopharmacology. 2013;38:585–95. sourceExperimental — accuracy not yet measured
The Discussion reports that chronic stress impaired both ED set-shifting and reversal learning, and that the mPFC treatment prevented only the set-shifting deficit. But the Figure 4 caption and Experiment 2 identify the infused drugs as α1-, β1-, and β2-adrenergic receptor antagonists, not agonists. The claim reverses the identity of the intervention responsible for the reported effect. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Alternative accounts suggest instead that these tests measure adaptive learned responses to acute stress and reflect a natural shift from active to passive coping strategies [53,54] as distinct from behavioral despair.”
§ Prefrontal cortex and depression > Box 1. Cross-species prefrontal nomenclature
What the sources say
- Partly supportedcites [53] De Kloet ER, Molendijk ML. Coping with the forced swim stressor: towards understanding an adaptive mechanism. Neural Plast. 2016;2016:6503162. https://doi.org/10.1155/2016/6503162. sourceExperimental — accuracy not yet measured
The Introduction describes the forced swim test’s shift from active to passive behavior as an adaptive learning process, and §2.1 distinguishes that account from behavioral despair. The paper mentions tail suspension in §2.2, but does not extend its adaptive-learning account to that test. Page numbers were not provided in our copy. (LLM, conf=0.88)
- Partly supportedcites [54] Commons KG, Cholanians AB, Babb JA, Ehlinger DG. The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci. 2017;8:955–60. sourceExperimental — accuracy not yet measured
The Introduction describes the forced swim test’s normal shift from active to passive coping as potentially adaptive rather than a coping failure, and says the tail suspension test likewise measures active or passive coping rather than depression-like behavior directly (page not available). It does not establish that the responses measured by both tests are learned, so that part of the claim is unsupported. (LLM, conf=0.85)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In a sample of 421 individuals with MDD and 488 healthy controls, reduced rsFC emerged in MDD between the central OFC (BA13) and memory-related regions (e.g., parahippocampal gyrus), with increasingly weaker rsFC correlating with higher depression severity [71].”
§ Prefrontal cortex and depression > MDD AND CHRONIC STRESS MODELS IN RODENTS Resting state (task-free) functional connectivity findings in MDD
What the sources say
- Supportedcites [71] Cheng W, Rolls ET, Qiu J, Liu W, Tang Y, Huang CC, et al. Medial reward and lateral non-reward orbitofrontal cortex circuits change in opposite directions in depression. Brain. 2016;139:3296–309. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelationaln = 421- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In a similar study [77], TRD was characterized by higher pre-treatment resting state activity in a region between the pgACC and sgACC, and a course of ECT treatment normalized activity in this region and its connectivity with the vmPFC; moreover, higher pretreatment sgACC activity predicted better response to ECT.”
§ Prefrontal cortex and depression > MDD AND CHRONIC STRESS MODELS IN RODENTS Resting state (task-free) functional connectivity findings in MDD
What the sources say
- Partly supportedcites [77] Argyelan M, Lencz T, Kaliora S, Sarpal DK, Weissman N, Kingsley PB, et al. Subgenual cingulate cortical activity predicts the efficacy of electroconvulsive therapy. Transl Psychiatry. 2016;6:e789. https://doi.org/10.1038/tp.2016.54. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Thus, structural abnormalities spanning the sgACC and OFC emerge early in MDD and affect regions playing a key role in the regulation of negative emotion, value representation, and self-referential processing [17].”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
What the sources say
- Partly supportedcites [17] Hiser J, Koenigs M. The multifaceted role of the ventromedial prefrontal cortex in emotion, decision making, social cognition, and psychopathology. Biol Psychiatry. 2018;83:638–47. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Finally, although some abnormalities persist after remission (e.g., OFC hypo-responses to rewards [107], inability to sustain ventral striatal responses to positive cues [108]), acute striatal responses to rewards appear to normalize in individuals with past MDD [109].”
§ Prefrontal cortex and depression > Consummatory anhedonia.
What the sources say
- Supportedcites [107] Dichter GS, Kozink RV, McClernon FJ, Smoski MJ. Remitted major depression is characterized by reward network hyperactivation during reward anticipation and hypoactivation during reward outcomes. J Affect Disord. 2012;136:1126–34. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Supportedcites [108] Admon R, Pizzagalli DA. Corticostriatal pathways contribute to the natural time course of positive mood. Nat Commun. 2015;6:10065. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Supportedcites [109] Geugies H, Mocking RJT, Figueroa CA, Groot PFC, Marsman JBC, Servaas MN, et al. Impaired reward-related learning signals in remitted unmedicated patients with recurrent depression. Brain. 2019;142:2510–22. source
The Discussion reports no group differences in basic ventral striatal reward processing between remitted patients and controls. It proposes that reduced ventral striatal activation during reward delivery in depression likely recovers after remission. The OFC and sustained-response examples have separate citations and are not attributed to this source. (LLM, conf=0.93)
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“First, among patients with TRD, a single ketamine infusion rapidly reduced anhedonic symptoms, and reduction in anhedonia correlated with decreased metabolism in the right lateral OFC (as well as increased glucose metabolism in dACC) [116].”
§ Prefrontal cortex and depression > Anticipatory anhedonia.
What the sources say
- Supportedcites [116] Lally N, Nugent AC, Luckenbaugh DA, Niciu MJ, Roiser JP, Zarate CA. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J Psychopharmacol. 2015;29:596–607. source
The Discussion reports that anhedonia fell within 40 minutes after a single ketamine infusion in patients with treatment-refractory MDD. The Results (PET imaging) link reduced anhedonia to decreased metabolism in the right OFC and increased glucose metabolism in the dACC; the Discussion specifies the OFC finding as anterolateral. The authors caution that these findings are tentative because ketamine had no placebo-controlled comparison. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Changes in the dACC emerged only in treatment responders, and early increases in dACC cortical thickness 48 h after the second ECT administration predicted eventual clinical response.”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
What the sources say
- Partly supportedcites [89] Pirnia T, Joshi SH, Leaver AM, Vasavada M, Njau S, Woods RP, et al. Electroconvulsive therapy and structural neuroplasticity in neocortical, limbic and paralimbic cortex. Transl Psychiatry. 2016;6:e832. https://doi.org/10.1038/tp.2016.102. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In tasks probing reward anticipation, MDD has been linked to decreased activation in ventral and dorsal striatum as well as middle frontal gyrus (BA8), but hyperactivation in the dlPFC and mPFC including pgACC and caudal vmPFC [3,102,113].”
§ Prefrontal cortex and depression > Anticipatory anhedonia.
What the sources say
- Partly supportedcites [3] Pizzagalli DA. Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu Rev Clin Psychol. 2014;10:393–423. sourceExperimental — accuracy not yet measured
The Introduction reports reduced activation in the nucleus accumbens, caudate, and putamen in MDD during reward processing, including anticipation and responses to reward-predicting cues. It does not report decreased middle frontal gyrus (BA8) activation or reward-anticipation hyperactivation in the dlPFC, pgACC, or caudal vmPFC. (LLM, conf=0.87)
- Partly supportedcites [102] Borsini A, Wallis ASJ, Zunszain P, Pariante CM, Kempton MJ. Characterizing anhedonia: a systematic review of neuroimaging across the subtypes of reward processing deficits in depression. Cogn Affect Behav Neurosci. 2020;20:816–41. sourceExperimental — accuracy not yet measured
The Discussion’s “Summary of findings” (Reward wanting, anticipatory phase; page unavailable) reports striatal hypoactivation and a trend toward mPFC and dlPFC hyperactivation. But it reports a trend toward middle frontal gyrus hyperactivation, not the claimed decrease. The Results (Reward wanting; page unavailable) do not establish the specified BA8, pgACC, or caudal vmPFC locations; the reported mPFC and dlPFC finding was in adolescents with MDD. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [113] Zhang WN, Chang SH, Guo LY, Zhang KL, Wang J. The neural correlates of reward-related processing in major depressive disorder: a meta-analysis of functional magnetic resonance imaging studies. J Affect Disord. 2013;151:531–9. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The latter includes response and attentional inflexibility [95], spatial working memory (WM) deficits [96] and insensitivity of goal-directed actions to action-outcome contingency and outcome value [93], although these may vary depending on the nature of the stressor.”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
What the sources say
- Partly supportedcites [95] Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006;26:7870–4. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [96] Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Chui DH, Tabira T. Chronic stress induces impairment of spatial working memory because of prefrontal dopaminergic dysfunction. J Neurosci. 2000;20:1568–74. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [93] Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science. 2009;325:621–5. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Critically, depressive symptoms at ages 16 and 19 could be predicted by potentiated lateral OFC activation to nonrewards, but not central OFC activation to rewards, at age 14.”
§ Prefrontal cortex and depression > Anticipatory anhedonia.
What the sources say
- Partly supportedcites [114] Xie C, Jia T, Rolls ET, Robbins TW, Sahakian BJ, Zhang J, et al. Reward versus nonreward sensitivity of the medial versus lateral orbitofrontal cortex relates to the severity of depressive symptoms. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020;6:259–69. sourceExperimental — accuracy not yet measured
The Longitudinal Approach section reports that lateral OFC activation to no win versus large win at age 14 was associated with depressive symptom scores at ages 16 and 19. It also reports that medial OFC activation at age 14 did not predict scores at either age. The claim says “central OFC,” whereas the paper identifies this reward-responsive region as medial OFC; it does not establish that the two labels refer to the same region. (LLM, conf=0.85)
hedgedcorrelationaln = 1,877- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In the IMAGEN study (N = 1877 at age 14, N = 1140 at age 19), during reward anticipation, individuals with higher depression severity had reduced sensitivity to differing reward values in the central regions of OFC (areas 11 and 13) but higher lateral OFC (area 12) activation to non-rewards (no-win outcome) at both age 14 and 19 (Fig. 5) [114]”
§ Prefrontal cortex and depression > Anticipatory anhedonia.
What the sources say
- Partly supportedcites [114] Xie C, Jia T, Rolls ET, Robbins TW, Sahakian BJ, Zhang J, et al. Reward versus nonreward sensitivity of the medial versus lateral orbitofrontal cortex relates to the severity of depressive symptoms. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020;6:259–69. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In a subclinical sample, adolescents with elevated depressive symptoms showed blunted pgACC and rostral vmPFC activation during reward consumption, with the former correlating with higher anhedonia [110].”
§ Prefrontal cortex and depression > Consummatory anhedonia.
What the sources say
- Supportedcites [110] Rzepa E, Fisk J, McCabe C. Blunted neural response to anticipation, effort and consummation of reward and aversion in adolescents with depression symptomatology. J Psychopharmacol. 2017;31:303–11. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“study, GMV in the right dACC and right inferior frontal gyrus contributed to disease trajectory predictions; specifically, larger volume in these areas predicted better clinical outcome and lower depressive symptoms over 5 years [83].”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
What the sources say
- Partly supportedcites [83] Serra-Blasco M, de Diego-Adeliño J, Vives-Gilabert Y, Trujols J, Puigdemont D, Carceller-Sindreu M, et al. Naturalistic course of major depressive disorder predicted by clinical and structural neuroimaging data: a 5-year follow-up. Depress Anxiety. 2016;33:1055–64. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Moreover, at age 19, blunted reward-related central OFC activation correlated with more anhedonic symptoms, whereas potentiated non-reward lateral OFC activation correlated with sadness.”
§ Prefrontal cortex and depression > Anticipatory anhedonia.
What the sources say
- Partly supportedcites [114] Xie C, Jia T, Rolls ET, Robbins TW, Sahakian BJ, Zhang J, et al. Reward versus nonreward sensitivity of the medial versus lateral orbitofrontal cortex relates to the severity of depressive symptoms. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020;6:259–69. sourceExperimental — accuracy not yet measured
The age-19 association analyses report that lateral OFC activation correlated with symptoms including feeling overwhelmed by sadness, while medial OFC activation had a nominally significant negative association with anhedonia. The discussion likewise links reduced medial OFC reward sensitivity to anhedonia and increased lateral OFC nonreward sensitivity to negative feelings. The claim calls the reward-related region “central” rather than medial OFC and omits the nominal significance qualifier for the anhedonia association. (LLM, conf=0.84)
plaincorrelationaln = 1,140- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In rodents, the most abundant and consistent changes are in the mPFC (anterior cingulate, prelimbic and infralimbic) with somewhat more variable, mixed direction effects in the OFC (Fig. 3, top left-hand panel).”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
What the sources say
- Partly supportedcites [98] McEwen BS, Morrison JH. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron. 2013;79:16–29. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [99] McEwen BS, Nasca C, Gray JD. Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology. 2016;41:3–23. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Evidence of disrupted frontostriatal activation during reward consumption has been reported also in children with MDD, suggesting that such dysfunctions emerge early.”
§ Prefrontal cortex and depression > Consummatory anhedonia.
What the sources say
- Supportedcites [104] O’Callaghan G, Stringaris A. Reward processing in adolescent depression across neuroimaging modalities: a review. Z Kinder Jugendpsychiatr Psychother. 2019;47:535–41. source
The Functional MRI Findings section reports reduced caudate activation in children and adolescents with MDD aged 8–17 during reward outcomes, compared with matched controls. It also reports altered prefrontal activity during reward outcomes in depressed adolescents, supporting the description of early frontostriatal dysfunction. (LLM, conf=0.90)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These findings replicated prior results showing that left dlPFC rTMS treatment increased GMV in the pgACC (Fig. 4c) and such volumetric increases correlated with symptom reduction [91].”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
What the sources say
- Partly supportedcites [91] Lan MJ, Chhetry BT, Liston C, Mann JJ, Dubin M. Transcranial magnetic stimulation of left dorsolateral prefrontal cortex induces brain morphological changes in regions associated with a treatment resistant major depressive episode: an exploratory analysis. Brain Stimul. 2016;9:577–83. sourceExperimental — accuracy not yet measured
The Results (Imaging Results; page unavailable) report increased anterior cingulate gray matter volume after TMS and a correlation between that change and reduced depression severity. Our copy identifies the region as the left anterior cingulate, not specifically the perigenual ACC; it also notes that the correlation was not corrected for multiple comparisons. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For example, increasing the excitability of ILc by blockade of the glutamate transporter (GLT1) had an anhedonia-like effect, including an increase in the latency to drink sucrose and an increased threshold for intracranial self-stimulation [140].”
§ Prefrontal cortex and depression > Interim summary.
What the sources say
- Partly supportedcites [140] John CS, Smith KL, Van’T Veer A, Gompf HS, Carlezon WA, Cohen BM, et al. Blockade of astrocytic glutamate uptake in the prefrontal cortex induces anhedonia. Neuropsychopharmacology. 2012;37:2467–75. sourceExperimental — accuracy not yet measured
The Discussion reports that intra-PFC GLT-1 blockade increased ICSS thresholds and latency to begin drinking sucrose, consistent with an anhedonic-like effect. Figure 1 places the injections in the infralimbic PFC. The paper suggests that increased infralimbic activity could produce such effects, but it does not establish that the blockade increased ILc excitability. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“These findings fit recent evidence that a single-dose of ketamine reduced sgACC hyper-activity and improved an autonomic measure of anhedonia (anticipatory arousal to receipt of a primary reinforcer in marmosets (see below) [61]).”
§ Prefrontal cortex and depression > Anticipatory anhedonia.
What the sources say
- Supportedcites [61] Alexander L, Gaskin PLR, Sawiak SJ, Fryer TD, Hong YT, Cockcroft GJ, et al. Fractionating blunted reward processing characteristic of anhedonia by over-activating primate subgenual anterior cingulate cortex. Neuron. 2019;101:307–320.e6. source
The Discussion section, under “Ketamine as an Efficacious Treatment,” reports that a single ketamine administration reversed blunted anticipatory cardiovascular arousal in marmosets at 1 and 7 days. It also reports reduced DHK-induced metabolic uptake in sgACC/25 at 1 day. The Results specify that the sgACC/25 reduction was found using a region-of-interest analysis, not the voxel-based analysis. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In a large youth sample (N = 1576; mean age: ~14 years), blunted reward-related ventral striatum correlated with anhedonia (but not low mood) and predicted transition to subthreshold or clinical depression 2 years later among previously healthy youths ([119]; see also [120]).”
§ Prefrontal cortex and depression > Anticipatory anhedonia.
What the sources say
- Supportedcites [119] Stringaris A, Belil PVR, Artiges E, Lemaitre H, Gollier-Briant F, Wolke S, et al. The brain s response to reward anticipation and depression in adolescence: Dimensionality, specificity, and longitudinal predictions in a community-based sample. Am J Psychiatry. 2015;172:1215–23. source
The Method (Participants) reports 1,576 adolescents recruited around age 14. The Abstract (Results) states that low ventral striatum activation during reward anticipation was associated with anhedonia but not low mood, and predicted transition to subthreshold or clinical depression in previously healthy adolescents at 2-year follow-up. Page numbers are unavailable in our copy. (LLM, conf=0.94)
- Partly supportedcites [120] Morgan JK, Olino TM, McMakin DL, Ryan ND, Forbes EE. Neural response to reward as a predictor of increases in depressive symptoms in adolescence. Neurobiol Dis. 2013;52:66–74. sourceExperimental — accuracy not yet measured
The Discussion reports that lower striatal response during reward anticipation was associated with rising depressive symptoms over two years, particularly in adolescents in mid-to-late puberty. But Participants and Procedure describes a final sample of 72 youths aged 11–13, not 1,576 youths with a mean age near 14. The paper reports changes in depressive-symptom scores, not transitions to subthreshold or clinical depression, and does not establish the claimed anhedonia-versus-low-mood distinction. (LLM, conf=0.90)
plaincorrelationaln = 1,576- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, although fully remitted individuals showed normative ventral striatum RPE, they had greater RPE in the VTA [109], suggesting that some reward-related learning abnormalities do not normalize after recovery.”
§ Prefrontal cortex and depression > Reward learning.
What the sources say
- Supportedcites [109] Geugies H, Mocking RJT, Figueroa CA, Groot PFC, Marsman JBC, Servaas MN, et al. Impaired reward-related learning signals in remitted unmedicated patients with recurrent depression. Brain. 2019;142:2510–22. source
The Discussion reports significantly increased reward-learning activation in the VTA in remitted patients compared with healthy controls, with no observed group difference in the ventral striatum. The Results table likewise shows a significant VTA difference but no significant ventral-striatum difference for the total temporal-difference signal. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In a study using a card-guessing task, depressed adolescents had potentiated mPFC (BA10) activation (coupled with blunted ventral striatal activation) to rewards [111].”
§ Prefrontal cortex and depression > Reward learning.
What the sources say
- Partly supportedcites [111] Forbes EE, Hariri AR, Martin SL, Silk JS, Moyles DL, Fisher PM, et al. Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder. Am J Psychiatry. 2009;166:64–73. sourceExperimental — accuracy not yet measured
The Method (Measures) describes a card-guessing reward task, and the Results (Depression-Related Differences in Neural Response to Reward) report greater medial BA10 activation during reward outcome alongside reduced caudate activation in depressed adolescents. The paper identifies the reduced-response region as the caudate, not specifically the ventral striatum; the Methods say the striatal region of interest encompassed both ventral striatum and adjacent caudate. Page numbers were not available in our copy. (LLM, conf=0.85)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In studies using a “wheel-offortune” task, which involves making choices about varying amounts of monetary rewards with varying levels of risk, adults with MDD showed greater left OFC activation but reduced pgACC activation during the selection phase relative to controls; in addition, they showed greater activation to wins in the left inferior frontal gyrus (BA9/45) than controls [132].”
§ Prefrontal cortex and depression > Reward learning.
What the sources say
- Partly supportedcites [132] Smoski MJ, Felder J, Bizzell J, Green SR, Ernst M, Lynch TR, et al. fMRI of alterations in reward selection, anticipation, and feedback in major depressive disorder. J Affect Disord. 2009;118:69–78. sourceExperimental — accuracy not yet measured
The Results (Imaging Data, Reward Selection; page not provided) report greater left orbitofrontal activation in adults with MDD and greater paracingulate-gyrus activation in controls during the Wheel of Fortune task. The copy does not identify the latter region as pgACC, so it does not establish that more specific anatomical claim. (LLM, conf=0.83)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Moreover, optogenetic stimulation of ILc reduced the BOLD response to optogenetic-induced dopamine stimulation and blocked DA-stimulation-induced place preference [62].”
§ Prefrontal cortex and depression > Interim summary.
What the sources say
- Partly supportedcites [62] Ferenczi EA, Zalocusky KA, Liston C, Grosenick L, Warden MR, Amatya D, et al. Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior. Science. 2016;351:aac9698. sourceExperimental — accuracy not yet measured
The Results section, “Elevated mPFC excitability suppresses striatal responses to dopamine” (page unavailable), reports that optogenetic mPFC activation suppressed the striatal BOLD response to dopamine-neuron stimulation and eliminated the stimulation-associated place preference while activation was on. The cited passage identifies the stimulated region as mPFC, not specifically ILc, so the claim’s anatomical specificity is not established by our copy. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, they showed reduced approach-related activation in the dlPFC and, surprisingly, reduced avoidance-related pgACC activation.”
§ Prefrontal cortex and depression > Reward learning.
What the sources say
- Supportedcites [42] Ironside M, Amemori KI, McGrath CL, Pedersen ML, Kang MS, Amemori S, et al. Approach-avoidance conflict in major depressive disorder: congruent neural findings in humans and nonhuman primates. Biol Psychiatry. 2020;87:399–408. source
The Discussion reports reduced bilateral DLPFC approach-related activation in MDD and reduced pACC activation during avoidance relative to healthy controls. The Methods identify the MDD participants as unmedicated adult women; the claim does not imply that men were studied. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In a sample tested with the same paradigm, adolescents with MDD had higher left OFC and dACC activation but lower right lateral OFC during high-risk trials (trials with only 25% chance of winning a higher amount) relative to controls [133].”
§ Prefrontal cortex and depression > Reward learning.
What the sources say
- Supportedcites [133] Shad MU, Bidesi AP, Chen LA, Ernst M, Rao U. Neurobiology of decision making in depressed adolescents: a functional magnetic resonance imaging study. J Am Acad Child Adolesc Psychiatry. 2011;50:612–.e2. source
The Results section reports greater left dorsal OFC and right caudal ACC activation in depressed adolescents than in controls, and greater right ventrolateral OFC activation in controls. These findings are specifically for the high-risk (25%) versus equal-risk (50/50) choice contrast, rather than high-risk choices in isolation. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Importantly, both patternsreduced dmPFCamygdala FC but potentiated vmPFC-amygdala FC to negative faceshave been reported in adults with current MDD [176,190,191].”
§ Prefrontal cortex and depression > Micro-stimulation
What the sources say
- Not checked — no full text of the sourcecites [176] Matthews SC, Strigo IA, Simmons AN, Yang TT, Paulus MP. Decreased functional coupling of the amygdala and supragenual cingulate is related to increased depression in unmedicated individuals with current major depressive disorder. J Affect Disord. 2008;111:13–20. source
- Partly supportedcites [190] De Almeida JRC, Kronhaus DM, Sibille EL, Langenecker SA, Versace A, LaBarbara EJ, et al. Abnormal left-sided orbitomedial prefrontal cortical-amygdala connectivity during happy and fear face processing: a potential neural mechanism of female MDD. Front Psychiatry. 2011;2:69. https://doi.org/10.3389/fpsyt.2011.00069. eCollection 2011 sourceExperimental — accuracy not yet measured
In Results > Dynamic causal modeling (Table 4; page not provided), females with a current MDD episode showed greater left vmPFC–amygdala connectivity to fearful faces than healthy females (p = 0.03), but this comparison did not survive correction for multiple tests. The paper does not report reduced dmPFC–amygdala connectivity, and its vmPFC finding is limited to females rather than adults with MDD generally. (LLM, conf=0.87)
- Partly supportedcites [191] Wackerhagen C, Veer IM, Erk S, Mohnke S, Lett TA, Wüstenberg T, et al. Amygdala functional connectivity in major depression-disentangling markers of pathology, risk and resilience. Psychol Med. 2020;50:2740–50. sourceExperimental — accuracy not yet measured
The Task-related amygdala functional connectivity and Conclusion sections (pages unavailable) report reduced amygdala connectivity with a frontal region during face matching in MDD patients, broadly supporting the reduced-connectivity part, though they do not identify the region as dmPFC. They do not report potentiated vmPFC–amygdala connectivity in patients; the Pathology section instead describes increased amygdala–pgACC connectivity in unaffected relatives compared with patients and controls. (LLM, conf=0.84)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In summary, detailed parcellation studies in macaques have shown the importance of central regions of OFC in updating the valuations of expected outcomes on the basis of an animal's current state (area 13) and translating that information into goals for action selection (area 11).”
§ Prefrontal cortex and depression > Interim summary.
What the sources say
- Supportedcites [115] Murray EA, Rudebeck PH. Specializations for reward-guided decision-making in the primate ventral prefrontal cortex. Nat Rev Neurosci. 2018;19:404–17. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [150] Zhou J, Gardner MP, Schoenbaum G. Is the core function of orbitofrontal cortex to signal values or make predictions?. Curr Opin Behav Sci. 2021;41:1–9. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“It also reduced basal heart rate variability and increased sympathetic activity [144], consistent with sympathetically-driven alterations in cardiovascular activity in MDD [148, 149].”
§ Prefrontal cortex and depression > Interim summary.
What the sources say
- Supportedcites [144] Alexander L, Wood CM, Gaskin PLR, Sawiak SJ, Fryer TD, Hong YT, et al. Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioral and neural responses to threat. Nat Commun 2020;11:1–14. source
The Results section on basal cardiovascular function reports that sgACC/area 25 over-activation reduced heart rate variability in seven marmosets and increased the cardiac sympathetic index, shifting the balance toward sympathetic predominance. These findings support both parts of the claim. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Specifically, area 25 overactivation reduced the cardiovascular and behavioral Pavlovian conditioned arousal in anticipation of marshmallow reward and also decreased the number of responses an animal was willing to perform for reward on a progressive ratio task [61].”
§ Prefrontal cortex and depression > Interim summary.
What the sources say
- Supportedcites [61] Alexander L, Gaskin PLR, Sawiak SJ, Fryer TD, Hong YT, Cockcroft GJ, et al. Fractionating blunted reward processing characteristic of anhedonia by over-activating primate subgenual anterior cingulate cortex. Neuron. 2019;101:307–320.e6. source
The Results (Figure 2; page unavailable) report that sgACC/area 25 overactivation reduced both cardiovascular and behavioral responses to the cue predicting marshmallow reward. The Results (Figure 3; page unavailable) also report fewer responses before breakpoint on the progressive-ratio task. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Using an analogous task in rats, a similar pathway projecting from PLc to the striatal striosomes has been implicated in approach-avoidance decision making, with its inactivation increasing approach [203].”
§ Prefrontal cortex and depression > Preclinical studies in animals
What the sources say
- Supportedcites [203] Friedman A, Homma D, Gibb LG, Amemori K, Rubin SJ, Hood AS, et al. A corticostriatal path targeting striosomes controls decision-making under conflict. Cell. 2015;161:1320–33. source
The Introduction identifies the rat prelimbic cortex (PFC-PL) projection as preferentially targeting striosomes. The Discussion section “Motivational Conflict Activates the PFC-PL Pathway Preferentially Targeting Striosomes” reports that inhibiting this pathway increased approach to high-cost options during an approach-avoidance conflict task. Our copy provides no page numbers for these passages. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“If these same regions also process action-outcome information in the punishment domain as suggested by [39], at least for pgACC, then altered action-outcome learning and expression could likely play an important role in modulating one's actions in response to varying reward and punishment in an approach-avoidance task, and hence underlie the reported negative biases.”
§ Prefrontal cortex and depression > Preclinical studies in animals
What the sources say
- Supportedcites [39] Amemori K, Graybiel AM. Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making. Nat Neurosci. 2012;15:776–85. source
The citation supports the sentence’s conditional premise about pgACC processing action-outcome information in the punishment domain. In Results (Neural activity during the decision-making tasks), the paper examines pgACC activity associated with choices and their chosen airpuff outcomes; the Discussion describes units representing anticipation of each outcome. The proposed role of altered learning in the reported biases is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Functional homology exists between PFC regions in rodents/monkeys and humans such that findings in animals can inform MDD.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“overactivation of area 25 in marmosets enhanced the avoidance of punishment [41], alongside the already described blunting of anticipatory and motivational appetitive arousal and increased responsivity to uncertain threat and Pavlovian conditioned, certain threat.”
§ Prefrontal cortex and depression > Preclinical studies in animals
What the sources say
- Supportedcites [41] Wallis CU, Cockcroft GJ, Cardinal RN, Roberts AC, Clarke HF. Hippocampal interaction with area 25, but not area 32, regulates marmoset approach-avoidance behavior. Cereb Cortex. 2019;29:4818–30. source
The citation is attached to the claim that area 25 overactivation enhanced punishment avoidance in marmosets. The Results (Figure 3 caption and accompanying text) report exactly that; the other effects are presented as already described, not as findings attributed to this citation. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Additionally, higher levels of perceived helplessness and PINV magnitude correlated with rumination.”
§ Prefrontal cortex and depression > LEARNED HELPLESSNESS Major depressive disorder
What the sources say
- Partly supportedcites [208] Diener C, Kuehner C, Brusniak W, Struve M, Flor H. Effects of stressor controllability on psychophysiological, cognitive and behavioural responses in patients with major depression and dysthymia. Psychol Med. 2009;39:77–86. sourceExperimental — accuracy not yet measured
The Results section (page not provided) reports that higher rumination scores correlated with larger frontal PINV magnitudes during restitution of control in the depressed subsample. It reports elevated perceived helplessness in depressed participants, but does not establish a correlation between helplessness and rumination; the claim’s helplessness component is therefore unsupported. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“studies in healthy controls have shown that personally chosen vs. passively received rewards elicit stronger activation in the striatum (ventral and dorsal) and PFC (inferior frontal gyrus) [212-215], which is inversely related to depressive symptoms [212].”
§ Prefrontal cortex and depression > LEARNED HELPLESSNESS Major depressive disorder
What the sources say
- Partly supportedcites [212] Romaniuk L, Sandu AL, Waiter GD, McNeil CJ, Xueyi S, Harris MA, et al. The neurobiology of personal control during reward learning and its relationship to mood. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019;4:190–9. sourceExperimental — accuracy not yet measured
The Discussion sections “Personally Earned Versus Passively Received Rewards” and “Anticipating Choice” distinguish two findings: personally chosen outcomes enhanced inferior frontal gyrus activation, while ventral striatal activation occurred during anticipation of choice and was lower in participants with more depressive symptoms. The paper does not establish stronger ventral and dorsal striatal responses to personally chosen versus passively received rewards, or link that outcome contrast to depressive symptoms. (LLM, conf=0.88)
- Partly supportedcites [213] Leotti LA, Delgado MR. The inherent reward of choice. Psychol Sci. 2011;22:1310–8. sourceExperimental — accuracy not yet measured
The Results (Neuroimaging Results; page unavailable) report greater ventral-striatal activity for Choice than No-choice cues, and main effects of cue type in dorsal striatum and right inferior frontal cortex. The study measured anticipation of an opportunity to choose, not activation elicited by receipt of personally chosen rewards. Our copy does not report an inverse relationship with depressive symptoms. (LLM, conf=0.88)
- Partly supportedcites [214] Leotti LA, Delgado MR. The value of exercising control over monetary gains and losses. Psychol Sci. 2014;25:596–604. sourceExperimental — accuracy not yet measured
The Experiment 1 Neuroimaging Results report greater ventral-striatal activity for choice cues than no-choice cues when participants anticipated potential monetary gains. This supports a choice-related striatal effect, but the comparison concerns anticipation of a choice opportunity, not personally chosen versus passively received rewards. The cited results do not establish dorsal-striatal or inferior-frontal-gyrus activation, or an inverse relationship with depressive symptoms. Page numbers were not provided in our copy. (LLM, conf=0.88)
- Partly supportedcites [215] Wang KS, Delgado MR. Corticostriatal circuits encode the subjective value of perceived control. Cereb Cortex. 2019;29:5049–60. sourceExperimental — accuracy not yet measured
The ‘Neural Correlates Underlying the Opportunity for Control’ section (page unavailable) reports greater ventral-striatal activation for controllable SELF-choices than uncontrollable COMP-choices. It does not report this contrast for dorsal striatum or inferior frontal gyrus, nor does it link activation to depressive symptoms; the reported negative correlation is with locus-of-control scores, not depression. (LLM, conf=0.89)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“response and attentional inflexibility [95], spatial WM disruption [96] and insensitivity of goal-directed actions to action-outcome contingency and outcome value [93] have been induced by chronic stress exposure.”
§ Prefrontal cortex and depression > Preclinical animal studies
What the sources say
- Partly supportedcites [95] Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006;26:7870–4. sourceExperimental — accuracy not yet measured
Citation [95] attaches to response and attentional inflexibility, not the separately cited working-memory and goal-directed-action claims. The Results section ('Effects of stress on attentional set shifting,' pp. 7870–7874) reports impaired attentional shifting after repeated restraint stress in rats, but no impairment in reversal learning; it does not establish response inflexibility. (LLM, conf=0.86)
- Supportedcites [96] Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Chui DH, Tabira T. Chronic stress induces impairment of spatial working memory because of prefrontal dopaminergic dysfunction. J Neurosci. 2000;20:1568–74. source
The citation to this paper [96] is attached specifically to spatial working-memory disruption, not to the other effects in the sentence. In the section “Chronic stress induces working memory impairment via a D1 receptor-mediated hypodopaminergic mechanism in the PFC,” the authors report that chronic stress impaired spatial working memory in rats on a delayed-alternation task. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [93] Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science. 2009;325:621–5. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Altered performance on FST and TST are also associated with abnormal activity within the OFC including promotion of passive coping behavior following inhibition of histone acetylation in ventrolateral regions [229], activation of the OFC-amygdala pathway [230] and weekly infusions of a 5-HT2a agonist into lateral OFC [141].”
§ Prefrontal cortex and depression > Preclinical animal studies
What the sources say
- Partly supportedcites [229] Zhao Y, Xing B, Dang Y, Qu C, Zhu F, Yan C. Microinjection of valproic acid into the ventrolateral orbital cortex enhances stress-related memory formation. PLoS One. 2013;8:e52698. sourceExperimental — accuracy not yet measured
The Results (page unavailable) report increased FST immobility after valproic acid was infused into the ventrolateral orbital cortex before the first swim. But the paper identifies valproic acid as a histone deacetylase inhibitor, not an inhibitor of histone acetylation. The OFC–amygdala and 5-HT2a clauses carry other citations and are not attributed to this source. (LLM, conf=0.88)
- Supportedcites [230] Kuniishi H, Yamada D, Wada K, Yamada M, Sekiguchi M. Stress induces insertion of calcium-permeable AMPA receptors in the OFC–BLA synapse and modulates emotional behaviours in mice. Transl Psychiatry. 2020;10:1–11. source
The Results section reports that optogenetic activation of the OFC–BLA pathway increased immobility in the tail suspension test (TST) in mice. This supports the pathway-activation example attributed to citation [230]; the other interventions in the sentence have separate citations. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [141] Xu C, Ma XM, Chen HBin, Zhou MH, Qiao H, AN SC. Orbitofrontal cortex 5-HT2A receptor mediates chronic stress-induced depressive-like behaviors and alterations of spine density and Kalirin7. Neuropharmacology . 2016;109:7–17. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the 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].”
§ Prefrontal cortex and depression > PFC AND EXECUTIVE DYSFUNCTION Major depressive disorder
What the sources say
- Supportedcites [16] Pizzagalli DA. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology. 2011;36:183–206. source
The Functional neuroimaging studies section reports potentiated rACC, dACC, and left DLPFC activation in studies where MDD subjects performed at the same level as healthy controls. The Introduction identifies rACC as a region often called pregenual or perigenual ACC. The remission clause has a separate citation in the citing sentence and is not needed to support the portion attributed to this source. (LLM, conf=0.92)
- Partly supportedcites [237] Gärtner M, Elisabetta Ghisu M, Scheidegger M, Bönke L, Fan Y, Stippl A, et al. Aberrant working memory processing in major depression: Evidence from multivoxel pattern classification. Neuropsychopharmacology. 2018;43:1972–9. sourceExperimental — accuracy not yet measured
The Discussion and ROI results report greater dACC and left DLPFC activation in MDD patients than controls despite similar working-memory performance. They do not establish pgACC hyperactivation. The remission statement has a separate citation [239] in the citing sentence, so it is not attributed to this source. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [238] Wang XL, Du MY, Chen TL, Chen ZQ, Huang XQ, Luo Y, et al. Neural correlates during working memory processing in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2015;56:101–8. source
- Partly supportedcites [239] Schöning S, Zwitserlood P, Engelien A, Behnken A, Kugel H, Schiffbauer H, et al. Working-memory fMRI reveals cingulate hyperactivation in euthymic major depression. Hum Brain Mapp. 2009;30:2746–56. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports cingulate hyperactivation during working-memory performance in euthymic MDD patients, despite similar behavioral performance to controls. It says the increase seemed to involve the dorsal and rostral ACC, but does not specifically establish pgACC hyperactivation or track the same patients through remission. Citation [239] is attached to the persistence claim, not the preceding claim about left dlPFC. (LLM, conf=0.78)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In particular, dlPFC regions appear especially important for exerting top-downregulation of treatment and placebo expectancies, whereas mPFC regions play a key role in encoding value of expected outcomes [218,219].”
§ Prefrontal cortex and depression > LEARNED HELPLESSNESS Major depressive disorder
What the sources say
- Partly supportedcites [218] Wager TD, Atlas LY. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci. 2015;16:403–18. sourceExperimental — accuracy not yet measured
In “Placebos engage endogenous pain modulation circuitry” (page unavailable), the review links dlPFC activity and stimulation to placebo analgesia, but does not specifically assign dlPFC a role in top-down regulation of treatment and placebo expectancies. In “Different mechanisms for different outcomes?” (page unavailable), it links vmPFC responses to valuation and beliefs, but does not establish that mPFC encodes the value of expected outcomes as stated. (LLM, conf=0.84)
- Partly supportedcites [219] Zunhammer M, Spisák T, Wager TD, Bingel U. Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data. Nat Commun. 2021;12:1391. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) links DLPFC to the top-down effects of treatment expectation on pain, supporting the first part of the claim. It does not describe mPFC as encoding the value of expected outcomes; the Discussion instead notes that vmPFC coverage was incomplete, so its placebo-related activity could not be assessed. (LLM, conf=0.86)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Altogether, these findings point to an important role of PFC regions in perception of controllability and the impact this has on the valence of the event, which moderates the depressogenic effects of stressors [3].”
§ Prefrontal cortex and depression > LEARNED HELPLESSNESS Major depressive disorder
What the sources say
- Partly supportedcites [3] Pizzagalli DA. Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu Rev Clin Psychol. 2014;10:393–423. sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) reports that detecting control during stress activates the mPFC and that appraisal of coping ability moderates depressogenic effects. It does not establish the intervening claim that PFC activity changes the perceived valence of the event. (LLM, conf=0.84)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Among medication-free patients with MDD, greater deactivation of an anteromedial PFC (amPFC) region encompassing the pgACC and mPFC (BA10) during a WM task predicted greater symptom reduction with escitalopram (and greater WM improvements) [247].”
§ Prefrontal cortex and depression > PFC AND EXECUTIVE DYSFUNCTION Major depressive disorder
What the sources say
- Partly supportedcites [247] Meyer BM, Rabl U, Huemer J, Bartova L, Kalcher K, Provenzano J, et al. Prefrontal networks dynamically related to recovery from major depressive disorder: a longitudinal pharmacological fMRI study. Transl Psychiatry. 2019;9:64. https://doi.org/10.1038/s41398-019-0395-8 sourceExperimental — accuracy not yet measured
The Results (‘Neural mediator of depression recovery and behavioral correlate’; page unavailable) link greater amPFC deactivation during the working-memory task to later depression recovery and working-memory improvement in patients recruited treatment-free. But the deactivation finding arose after clinical response, not as a pretreatment predictor; Table 2 also locates the amPFC mediator in BA32/24, not BA10. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“prolonged ILc pyramidal stimulation for 60 min, mirroring the actions of ketamine to promote active coping on FST [63].”
§ Prefrontal cortex and depression > Preclinical animal studies
What the sources say
- Supportedcites [63] Fuchikami M, Thomas A, Liu R, Wohleb ES, Land BB, DiLeone RJ, et al. Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. Proc Natl Acad Sci USA. 2015;112:8106–8111. source
Methods and Materials reports a 60-minute IL-PFC optical-stimulation session, with light alternating one minute on and one minute off. The Optogenetic Stimulation results report antidepressant effects in the forced swim test after that session; the Discussion describes the responses as similar to ketamine’s. The test measured reduced immobility, consistent with the citing sentence’s description of active coping. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Subsequent studies in rats revealed a similar dissociation, whereby the OFC contributed specifically to lower-order reversal learning of stimulus-reward associations whilst the mPFC (as opposed to the vlPFC in marmosets) contributed selectively to higher-order attentional set-shifting [255,256].”
§ Prefrontal cortex and depression > Preclinical animal studies
What the sources say
- Partly supportedcites [255] Tait DS, Bowman EM, Neuwirth LS, Brown VJ. Assessment of intradimensional/extradimensional attentional set-shifting in rats. Neurosci Biobehav Rev. 2018;89:72–84. sourceExperimental — accuracy not yet measured
The accepted manuscript (p. 21) reports severe reversal-learning impairment after OFC lesions, and its references (p. 37) identify rat medial frontal cortex with attentional set-shifting. But p. 21 also reports slower attentional-set formation and impaired extradimensional-stage performance in OFC-lesioned rats, so the claimed selective dissociation overstates what this source says. (LLM, conf=0.88)
- Partly supportedcites [256] Birrell JM, Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci. 2000;20:4320–4. sourceExperimental — accuracy not yet measured
The Discussion reports that medial frontal cortex lesions selectively impaired extradimensional attentional set-shifting in rats, without impairing reversal learning. That supports the mPFC portion of the sentence, but this paper does not establish the attributed OFC role in reversal learning. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“a reduced ability to deactivate the amPFC along with increased dlPFC-amPFC functional connectivity during the same WM task characterized remitted individuals with past history of MDD.”
§ Prefrontal cortex and depression > PFC AND EXECUTIVE DYSFUNCTION Major depressive disorder
What the sources say
- Partly supportedcites [248] Bartova L, Meyer BM, Diers K, Rabl U, Scharinger C, Popovic A, et al. Reduced default mode network suppression during a working memory task in remitted major depression. J Psychiatr Res. 2015;64:9–18. sourceExperimental — accuracy not yet measured
The Results (Regional activation differences) report reduced amPFC deactivation in remitted MDD patients compared with healthy controls. The Results (Brain systems differences) report significantly increased dlPFC–amPFC connectivity only for the adolescent-onset subgroup; adult-onset patients did not differ significantly from controls. The claim omits that qualification. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“the latter was prevented by LTD in the mediodorsal thalamo-orbitofrontal pathway [258] and locally infused ketamine [259].”
§ Prefrontal cortex and depression > Preclinical animal studies
What the sources say
- Supportedcites [258] Adler SM, Girotti M, Morilak DA. Optogenetically-induced long term depression in the rat orbitofrontal cortex ameliorates stress-induced reversal learning impairment. Neurobiol Stress. 2020;13:100258. source
The Results section, “LTD induction in the OFC rescues a CIC-induced deficit in reversal learning,” reports that optogenetically induced LTD in the mediodorsal thalamus–orbitofrontal cortex pathway rescued stress-induced reversal-learning impairment in rats. The ketamine clause has a separate citation [259] and is not attributed to this source by [258]. Page numbers were not supplied. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [259] Patton MS, Lodge DJ, Morilak DA, Girotti M. Ketamine corrects stress-induced cognitive dysfunction through JAK2/STAT3 signaling in the orbitofrontal cortex. Neuropsychopharmacology. 2017;42:1220–30. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Notably, perception of control increased the reward value of the chosen option by 30% and caudal vmPFC activation was linked to such value inflation [215].”
§ Prefrontal cortex and depression > LEARNED HELPLESSNESS Major depressive disorder
What the sources say
- Partly supportedcites [215] Wang KS, Delgado MR. Corticostriatal circuits encode the subjective value of perceived control. Cereb Cortex. 2019;29:5049–60. sourceExperimental — accuracy not yet measured
The Discussion reports that perceived control inflated the associated outcome’s value by 30%. The ‘Neural Correlates of Subjective Value of SELF-Choices’ section links vmPFC activation to the measured subjective value of control, but our copy does not identify that activation as specifically caudal vmPFC. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“where these regions have been discriminated, regardless of the model, PLc tends to promote active coping [226,227] whilst ILc appears to have the opposite effect, promoting passive coping [228].”
§ Prefrontal cortex and depression > Preclinical animal studies
What the sources say
- Not checked — no full text of the sourcecites [226] Hamani C, Diwan M, Macedo CE, Brandão ML, Shumake J, Gonzalez-Lima F, et al. Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats. Biol Psychiatry. 2010;67:117–24. source
- Supportedcites [227] Kumar S, Black SJ, Hultman R, Szabo ST, Demaio KD, Du J, et al. Cortical control of affective networks. J Neurosci. 2013;33:1116–29. source
This citation is attached to the PLc active-coping clause, not the separately cited ILc clause. In Results (no page supplied), stimulation of prelimbic cortex (PrL) significantly reduced immobility in the forced-swim test, supporting the active-coping characterization. (LLM, conf=0.88)
- Partly supportedcites [228] Slattery DA, Neumann I, Cryan JF. Transient inactivation of the infralimbic cortex induces antidepressant-like effects in the rat. J Psychopharmacol. 2011;25:1295–303. sourceExperimental — accuracy not yet measured
The Results (p. 4) report that infralimbic-cortex inactivation decreased immobility and increased climbing in rats re-exposed to the forced swim test, supporting the inference that ILc activity favors passive over active coping in that setting. The paper does not establish that this relationship holds regardless of the model. (LLM, conf=0.82)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“attentional inflexibility, dependent upon vlPFC [207] could lead to difficulty disengaging from threatrelated stimuli and a resulting negative bias in monkeys [9] including a disruption in approach-avoidance decision making.”
§ Prefrontal cortex and depression > Preclinical animal studies
What the sources say
- Not checked — no full text of the sourcecites [207] Dias R, Robbins TW, Roberts AC. Dissociation in prefrontal cortex of affective and attentional shifts. Nature. 1996;380:69–72. source
- Supportedcites [9] Roberts A. Prefrontal regulation of threat-elicited behaviors: a pathway to translation. Annu Rev Psychol. 2020;71:357–87. source
The “Executive Functions and Emotion Regulation” section proposes that vlPFC-related attentional inflexibility may prevent disengagement from threatening stimuli and increase punishment avoidance in an approach–avoidance task. The “Ventral Prefrontal Cortex” section also reports greater punishment avoidance after vlPFC inactivation in marmosets. Page numbers were not provided in our copy. (LLM, conf=0.91)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“these patterns were linked to greater depression severity and a longer disease [175, 176, 178]”
§ Prefrontal cortex and depression > CONCLUSIONS, FUTURE DIRECTIONS AND CLINICAL IMPLICATIONS
What the sources say
- Partly supportedcites [175] Dannlowski U, Ohrmann P, Konrad C, Domschke K, Bauer J, Kugel H, et al. Reduced amygdalaprefrontal coupling in major depression: Association with MAOA genotype and illness severity. Int J Neuropsychopharmacol. 2009;12:11–22. sourceExperimental — accuracy not yet measured
The Association with illness severity section (page unavailable) reports that reduced amygdala–DLPFC connectivity correlated with an illness-severity index that included duration of illness. The cited passages do not establish that amygdalar hyperactivity was linked to severity or duration; the reported amygdala activation was a task effect across the whole sample. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [176] Matthews SC, Strigo IA, Simmons AN, Yang TT, Paulus MP. Decreased functional coupling of the amygdala and supragenual cingulate is related to increased depression in unmedicated individuals with current major depressive disorder. J Affect Disord. 2008;111:13–20. source
- Not checked — no full text of the sourcecites [178] Dannlowski U, Ohrmann P, Bauer J, Kugel H, Arolt V, Heindel W, et al. Amygdala reactivity to masked negative faces is associated with automatic judgmental bias in major depression: a 3 T fMRI study. J Psychiatry Neurosci. 2007;32:423–9. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Partly supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Specifically, vlPFC, like area 25, contributes to decision making when it is based upon experiencing rewarding and punishing outcomes at the time of one's actions, the only difference being that negative biases are induced by a loss of activity in vlPFC but over-activity in area 25.”
§ Prefrontal cortex and depression > Preclinical studies in animals
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“over-activation of area 32 reduced the bias away from punishment, whilst area 32 inactivation had no effect”
§ Prefrontal cortex and depression > Preclinical studies in animals
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In macaques, a cluster of neurons was identified that displayed activity in the decision period, which was negatively correlated with the overall value; notably, when microstimulated, these neurons enhanced the avoidance response and this effect was ameliorated by the anxiolytic, diazepam.”
§ Prefrontal cortex and depression > Preclinical studies in animals
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“among healthy controls, subjective (but not objective) uncontrollability over an aversive outcome reduced FC between dlPFC and the parahippocampal gyrus (and more generally, between the frontoparietal executive and salience networks) and impaired WM performance [216].”
§ Prefrontal cortex and depression > LEARNED HELPLESSNESS Major depressive disorder
What the sources say
- Not checked — no full text of the sourcecites [216] Wanke N, Schwabe L. Subjective uncontrollability over aversive events reduces working memory performance and related large-scale network interactions. Cereb Cortex. 2020;30:3116–29. source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“This effect of controllability is dependent upon the mPFC [232], in particular the PLc, since PLc inactivation during exposure to controllable stress, disrupts subsequent behavioral immunization effects across a range of contexts, such that the animal acts as if the stress had been inescapable or uncontrollable.”
§ Prefrontal cortex and depression > Preclinical animal studies
What the sources say
- Not checked — no full text of the sourcecites [232] Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 2005;8:365–71. source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“although blunted pgACC activation in MDD has emerged from studies probing reward-related processes (e.g., reward anticipation, consumption and learning), potentiated pgACC (or a general inability to deactivate the pgACC) in MDD has been observed in studies assessing negative processing biases and cognitive control.”
§ Prefrontal cortex and depression > CONCLUSIONS, FUTURE DIRECTIONS AND CLINICAL IMPLICATIONS
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“although the dlPFC has been found to be over-activated in reward-related processes (likely to compensate for hypoactive striatal responses to reward cues), the same region has shown hypo-activation in affective and cognitive tasks requiring emotional or stress regulation, cognitive control, and/ or shifting attention to external task demands.”
§ Prefrontal cortex and depression > CONCLUSIONS, FUTURE DIRECTIONS AND CLINICAL IMPLICATIONS
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“The quicker animals stop swimming or stop struggling, respectively, is proposed to reflect behavioral despair [51,52].”
§ Prefrontal cortex and depression > Box 1. Cross-species prefrontal nomenclature
What the sources say
- Not checked — no full text of the sourcecites [51] Porsolt RD, Anton G, Blavet N, Jalfre M. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol. 1978;47:379–91. source
- Not checked — no full text of the sourcecites [52] Castagné V, Moser P, Roux S, Porsolt RD. Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Curr Protoc Neurosci. 2011;55:8.10A.1–8.10A.14. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Neuroimaging studies have provided important insight into the neural correlates of MDD by identifying alterations in functional activity, resting state and structural integrity.”
§ Prefrontal cortex and depression > Experimental approaches
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, although depressive phenotypes induced by e.g., uncontrollable stressors appear more clinically relevant, the state they produce may, nevertheless, be as variable in their etiology and treatment as human depression, limiting the level of insight gained.”
§ Prefrontal cortex and depression > Experimental approaches
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“Negative processing biases are prevalent in MDD [31] and implicated in its etiology and treatment [31][32][33].”
§ Prefrontal cortex and depression > Symptom complexity
What the sources say
- Not matchedcites [31][32][33]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
- Not matched
In the paper
“Despair is purported measured in rodents using the forced swim (FST) and tail suspension (TST) tests [48][49][50].”
§ Prefrontal cortex and depression > Box 1. Cross-species prefrontal nomenclature
What the sources say
- Not matchedcites [48][49][50]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“findings with the NMDA antagonist ketamine will be emphasized owing to its rapid antidepressant effects as well as robust parallel findings across species.”
§ Prefrontal cortex and depression > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The complexity of depression-associated symptoms makes them difficult to assess with simple questionnaires in the clinic or single behavioral tests in animals.”
§ Prefrontal cortex and depression > Symptom complexity
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Despite its profound impact, the etiology and pathophysiology of MDDand consequently its treatment and preventionremain poorly understood.”
§ Prefrontal cortex and depression > INTRODUCTION
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Aspects of controllability, per se, have been studied in the context of depression in humans although, as shall be seen, such studies are limited.”
§ Prefrontal cortex and depression > Box 1. Cross-species prefrontal nomenclature
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“The literature probing resting state functional connectivity (rsFC) in MDD is vast, and generally points to abnormalities (1) between discrete PFC regions, (2) within networks anchored on different PFC regions (e.g., central executive network, default mode network), and (3) between PFC and other networks (for reviews, see [68][69][70]).”
§ Prefrontal cortex and depression > MDD AND CHRONIC STRESS MODELS IN RODENTS Resting state (task-free) functional connectivity findings in MDD
What the sources say
- Not matchedcites [68][69][70]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“It has been a major focus in preclinical animal studies but has received relatively little attention in humans and when it has, there has been little crossspecies overlap in responses measured.”
§ Prefrontal cortex and depression > Box 1. Cross-species prefrontal nomenclature
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Behavioral despair is often associated with symptoms of helplessness and hopelessness in MDD in which a perceived lack of cognitive control is a core feature [47].”
§ Prefrontal cortex and depression > Box 1. Cross-species prefrontal nomenclature
What the sources say
- Not checked — no full text of the sourcecites [47] Clark DA, Beck AT. Cognitive theory and therapy of anxiety and depression: convergence with neurobiological findings. Trends Cogn Sci. 2010;14:418–24. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This approach allows independent study of specific depression-related alterations in prefrontal activity to determine not only their causal role in symptoms of depression but also their potential differential sensitivity to treatments.”
§ Prefrontal cortex and depression > Experimental approaches
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Critically, imaging findings not only reveal changes associated with MDD but also determine markers that may act as predictors of disease onset as well as predictors of efficacious treatment.”
§ Prefrontal cortex and depression > Experimental approaches
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Specifically, animals display decreased swimming in the FST or struggling in the TST, reductions in sucrose preference or consumption and social interactions, changes in the HPA axis and cardiovascular function, negative judgment biases in ambiguous cue tests [43,44] and impaired cognitive control [93,94].”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
What the sources say
- Not checked — no full text of the sourcecites [43] Harding EJ, Paul ES, Mendl M. Cognitive bias and affective state. Nature. 2004;427:312. source
- Not checked — no full text of the sourcecites [44] Papciak J, Popik P, Fuchs E, Rygula R. Chronic psychosocial stress makes rats more ‘pessimistic’ in the ambiguous-cue interpretation paradigm. Behav Brain Res. 2013;256:305–10. source
- Not checked — no full text of the sourcecites [93] Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, et al. Chronic stress causes frontostriatal reorganization and affects decision-making. Science. 2009;325:621–5. source
- Not checked — no full text of the sourcecites [94] Lapiz-Bluhm MDS, Soto-Piña AE, Hensler JG, Morilak DA. Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats. Psychopharmacology. 2009;202:329–41. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The contrasting patterns between mPFC and OFC in dendritic spine density are particularly intriguing given similar contrasting effects pertaining to hyper-or hypo-activity in MDD, although differences in measures and precise regions involved render comparison challenging.”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Third, some of these PFC abnormalities predicted clinical response and were ameliorated by treatment.”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Second, some of these abnormalities appear early in the course of the disorder and might, in fact, represent risk markers.”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In an instrumental reinforcement learning task, unmedicated MDD subjects showed lower reward value encoding in the pgACC but higher sgACC activation during the decision phase than healthy controls [105].”
§ Prefrontal cortex and depression > Consummatory anhedonia.
What the sources say
- Not checked — no full text of the sourcecites [105] Rupprechter S, Stankevicius A, Huys QJM, Series P, Steele JD. Abnormal reward valuation and event-related connectivity in unmedicated major depressive disorder. Psychol Med. 2020;2020:7. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“For example, chronic cold stress induces cognitive inflexibility specific to reversal learning, while chronic mild unpredictable stress or restraint stress disrupts higher-order attentional set-shifting more consistently than lower-order associative reversal learning [94,97].”
§ Prefrontal cortex and depression > Prolonged Anti-Inactivation of OFC -FST 13
What the sources say
- Not checked — no full text of the sourcecites [94] Lapiz-Bluhm MDS, Soto-Piña AE, Hensler JG, Morilak DA. Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats. Psychopharmacology. 2009;202:329–41. source
- Not checked — no full text of the sourcecites [97] Bondi CO, Rodriguez G, Gould GG, Frazer A, Morilak DA. Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment. Neuropsychopharmacology. 2008;33:320–31. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings are important because they highlight that disruptions within brain reward pathways are not only present in the acute phase of MDD but predates its emergence (for similar conclusions, see [137,138]).”
§ Prefrontal cortex and depression > Interim summary.
plaincorrelationaln = 637- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data suggest that reduced valuation of expected rewards and blunted reward learning represent key vulnerabilities to future MDD.”
§ Prefrontal cortex and depression > Reward learning.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, several markers (e.g., blunted frontostriatal rsFC and reward-related striatal activation) emerged also in unaffected, never-depressed offspring with parental depression and/or predicted the new onset of depressive disorder years later, suggesting that they represent markers of MDD vulnerability (and thus possible targets for prevention).”
§ Prefrontal cortex and depression > Interim summary.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Similarly, fully remitted MZ twins with a past history of mood disorders had blunted expected value signal in the frontal pole extending into middle frontal gyrus (BA10/46) as well as lower RPE signal in the left frontal pole and superior frontal gyrus (BA9/6) [130].”
§ Prefrontal cortex and depression > Reward learning.
What the sources say
- Not checked — no full text of the sourcecites [130] Macoveanu J, Meluken I, Chase HW, Phillips ML, Kessing LV, Siebner HR, et al. Reduced frontostriatal response to expected value and reward prediction error in remitted monozygotic twins with mood disorders and their unaffected high-risk co-twins. Psychol Med. 2020;1–10. https://doi.org/10.1017/S0033291720000367. Online ahead of print. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A case study indeed showed that disruption of such a system (through inhibitory 1 Hz rTMS over the right OFC) reduced both anhedonic symptoms and FC between the right lateral OFC and the ventral striatum [117].”
§ Prefrontal cortex and depression > Anticipatory anhedonia.
What the sources say
- Not checked — no full text of the sourcecites [117] Fettes P, Peters S, Giacobbe P, Blumberger DM, Downar J. Neural correlates of successful orbitofrontal 1 Hz rTMS following unsuccessful dorsolateral and dorsomedial prefrontal rTMS in major depression: a case report. Brain Stimul. 2017;10:165–7. source
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In a reward-related decision making task parsing decision making (anticipation) and outcome, relative to healthy youths, youths with current MDD (9-17 years) showed potentiated responses in the left OFC (during anticipation), but decreased responses in the right OFC and dACC during both phases [131].”
§ Prefrontal cortex and depression > Reward learning.
What the sources say
- Not checked — no full text of the sourcecites [131] Forbes EE, Christopher May J, Siegle GJ, Ladouceur CD, Ryan ND, Carter CS, et al. Reward-related decision-making in pediatric major depressive disorder: an fMRI study. J Child Psychol Psychiatry. 2006;47:1031–40. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, several markers (e.g., blunted frontostriatal rsFC and reward-related striatal activation) emerged also in unaffected, never-depressed offspring with parental depression and/or predicted the new onset of depressive disorder years later, suggesting that they represent markers of MDD vulnerability (and thus possible targets for prevention).”
§ Prefrontal cortex and depression > Interim summary.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, MDD has been associated with hyper-activation in the medial frontal pole (BA10), vmPFC (including sgACC) and dlPFC to reward-related cues, as well as hyper-activation in the lateral OFC to non-rewards.”
§ Prefrontal cortex and depression > Interim summary.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of note, many of these markers correlated with anhedonia, predicted future anhedonia and depressive symptoms, and predated MDD.”
§ Prefrontal cortex and depression > Interim summary.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The distinctions between lateral, central and medial OFC (summarized in Fig. 7) are particularly relevant to our understanding of depression since MDD appears primarily associated with reduced activity in central OFC but increased activity in lateral OFC and also in the caudal aspects of medial OFC, including area 14 (see above).”
§ Prefrontal cortex and depression > Interim summary.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“Studies using backward masking tasks or tasks requiring implicit vs. explicit emotional processing converge in implicating hypo-activation in various PFC regions, most prominently the dlPFC and dACC, as well as hyper-activation in sgACC, pgACC, and vlPFC regions in negative processing biases (for reviews, see [156][157][158]).”
§ Prefrontal cortex and depression > NEGATIVE PROCESSING BIASES Major depressive disorder
What the sources say
- Not matchedcites [156][157][158]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, these findings highlight that MDD and vulnerability to depression in youth samples are characterized by (1) dlPFC hypo-activation to emotional (mostly, negative) stimuli, (2) hyper-activity in limbic regions implicated in responding to emotional cues (pgACC, amygdala), (3) increased coupling between PFC regions implicated in processing negative selfreferential information (vmPFC) and”
§ Prefrontal cortex and depression > Micro-stimulation
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on prior literature, reduced coupling between the central OFC and dACC might index impaired cognitive control of emotion processing, which could result in negative processing biases.”
§ Prefrontal cortex and depression > NEGATIVE PROCESSING BIASES Major depressive disorder
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Whereas amygdalar hyper-activation to negative faces was reported in a similar offspring sample (mean age: 14 years) [186], the PFC findings contrast with reports of blunted dlPFC activation (and normative amygdalar responses) to fearful faces [187] and a sad mood induction [188] among asymptomatic offspring of MDD patients (16-21 years old and 9-14 years old, respectively).”
§ Prefrontal cortex and depression > Micro-stimulation
What the sources say
- Not checked — no full text of the sourcecites [187] Mannie ZN, Taylor MJ, Harmer CJ, Cowen PJ, Norbury R. Frontolimbic responses to emotional faces in young people at familial risk of depression. J Affect Disord. 2011;130:127–32. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, whereas area 14 appears to play a fundamental role in regulating such appetitive arousal, area 25 seems to have its effects only when activated; artificially, in the case of the experimental study in marmosets and perhaps under conditions of stress under naturally-occurring conditions.”
§ Prefrontal cortex and depression > Interim summary.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, these findings highlight that MDD and vulnerability to depression in youth samples are characterized by (1) dlPFC hypo-activation to emotional (mostly, negative) stimuli, (2) hyper-activity in limbic regions implicated in responding to emotional cues (pgACC, amygdala), (3) increased coupling between PFC regions implicated in processing negative selfreferential information (vmPFC) and”
§ Prefrontal cortex and depression > Micro-stimulation
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, the rodent mPFC and OFC have been implicated in the control of consummatory aspects of reward-related behavior, although their precise contribution to such behaviors remain unclear (Figs. 2 and 3).”
§ Prefrontal cortex and depression > Interim summary.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these data suggest that individuals with MDD are more susceptible to stressor uncontrollability, and such experience affects subsequent interaction with the environment even when control over the stressor is re-established.”
§ Prefrontal cortex and depression > LEARNED HELPLESSNESS Major depressive disorder
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“of these abnormalities precede the onset of MDD, since they are present in never-depressed youth with increased MDD vulnerability.”
§ Prefrontal cortex and depression > Interim summary.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, these findings highlight that MDD and vulnerability to depression in youth samples are characterized by (1) dlPFC hypo-activation to emotional (mostly, negative) stimuli, (2) hyper-activity in limbic regions implicated in responding to emotional cues (pgACC, amygdala), (3) increased coupling between PFC regions implicated in processing negative selfreferential information (vmPFC) and”
§ Prefrontal cortex and depression > Micro-stimulation
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In contrast, the attentional inflexibility induced by excitotoxic lesions of vlPFC [207] may lead to persistent attention to intrinsically salient negative outcomes that, through bottom up mechanisms, naturally attract our attention, but through a loss of top down attentional control cause increased negative bias.”
§ Prefrontal cortex and depression > Preclinical studies in animals
What the sources say
- Not checked — no full text of the sourcecites [207] Dias R, Robbins TW, Roberts AC. Dissociation in prefrontal cortex of affective and attentional shifts. Nature. 1996;380:69–72. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“altogether suggesting that area 32 is engaged and only contributes to approach-avoidance conflict under particular contexts.”
§ Prefrontal cortex and depression > Preclinical studies in animals
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“in all studies described so far interventions in PLc, ILc and OFC can all impact on responsivity to acute, uncontrollable stress as measured by the FST and TST.”
§ Prefrontal cortex and depression > Preclinical animal studies
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these findings indicate that the ability to deactivate key nodes within the DMN (pgACC, dmPFC) during an executive task is essential for symptom reduction and that reduced ability to do so might represent a marker of increased MDD vulnerability and a more ruminative style.”
§ Prefrontal cortex and depression > PFC AND EXECUTIVE DYSFUNCTION Major depressive disorder
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Regions of area 32 and area 24 appear directly involved whilst medial OFC/vmPFC may be more related to the valuation process.”
§ Prefrontal cortex and depression > Preclinical animal studies
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Orange and blue arrows denote higher and lower functional connectivity, respectively, in MDD samples than healthy controls.”
§ Prefrontal cortex and depression > CONCLUSIONS, FUTURE DIRECTIONS AND CLINICAL IMPLICATIONS
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“it is likely that different inputs to PFC regions (e.g., weakened input from rewardrelated regions vs. heightened input from threat-related regions) as well as different neuromodulators (e.g., dopamine vs. serotonin) are implicated.”
§ Prefrontal cortex and depression > CONCLUSIONS, FUTURE DIRECTIONS AND CLINICAL IMPLICATIONS
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These phenotypes are not independent, with reductions in sensitivity to reward and loss of subjective control over negative events, for example, likely to induce negative processing biases.”
§ Prefrontal cortex and depression > CONCLUSIONS, FUTURE DIRECTIONS AND CLINICAL IMPLICATIONS
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“These regions do not only have distinct functions but are also modulated by distinct neurochemical transmitter systems, acting through distinct receptor subtypes, associated with distinct cellular and molecular pathways (see Arnsten and Cools, this volume).”
§ Prefrontal cortex and depression > CONCLUSIONS, FUTURE DIRECTIONS AND CLINICAL IMPLICATIONS
What the sources say
- Not matchedcites Arnsten and Cools
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further highlighting insufficient cortical regulation, MDD has been linked to reduced cortico-limbic functional connectivity (e.g., mPFC↔amygdala) when presented with negative cues [175-178].”
§ Prefrontal cortex and depression > CONCLUSIONS, FUTURE DIRECTIONS AND CLINICAL IMPLICATIONS
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The majority of preclinical studies relevant to major depressive disorder are performed in rodents.
“but the majority of preclinical studies relevant to MDD are performed in rodents.”
The paper relies on this without support.
Cross-species translation from animal models to humans is possible and valuable for understanding major depressive disorder.
“This highlights the importance of NHP research, where back translation to rodents and forward translation into the clinic can bridge the gap.”
The paper relies on this without support.
Functional homology exists between PFC regions in rodents/monkeys and humans such that findings in animals can inform MDD.
“altered activity in the PFC of both macaques and marmosets was found to induce negative biases akin to those reported in depression”
“Integrating the MDD and preclinical animal studies, it is apparent that a number of regions within the mPFC may contribute either directly in the learning and maintenance of action-outcome associations that underlie the ability of humans and other animals to control their environment”
The paper relies on this without support.
Negative biases measured in animal tasks are equivalent to negative processing biases in MDD.
“negative biases akin to those reported in depression”
“Negative biases are also multi-determined contributed to by altered activity in primate areas 24, 32, OFC and vlPFC.”
The paper relies on this without support.
The intermediate phenotypes (anhedonia, negative bias, learned helplessness) are valid constructs that map onto MDD.
“these intermediate phenotypes of MDD”
The paper relies on this without support.
Chronic stress models in animals are valid models of MDD.
“results from chronic stress models and interventions in otherwise healthy animals provide causal evidence for the induction of these intermediate phenotypes of MDD”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Prefrontal cortex and depression > Anticipatory anhedonia.
“In tasks probing reward anticipation, MDD has been linked to decreased activation in ventral and dorsal striatum as well as middle frontal gyrus (BA8), but hyperactivation in the dlPFC and mPFC including pgACC and caudal vmPFC [3,102,113].”
§ Prefrontal cortex and depression > CONCLUSIONS, FUTURE DIRECTIONS AND CLINICAL IMPLICATIONS
“| pgACC | ↓ | ↓ | ↓ |”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Prefrontal cortex and depression > Reward learning.
“Interestingly, such dysfunctions did not emerge in their unaffected co-twins (high-risk group), suggesting that they might represent scars (as opposed to pre-existing vulnerabilities) of depression.”
§ Prefrontal cortex and depression > References
“130. Macoveanu J, Meluken I, Chase HW, Phillips ML, Kessing LV, Siebner HR, et al. Reduced frontostriatal response to expected value and reward prediction error in remitted monozygotic twins with mood disorders and their unaffected high-risk co-twins.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Prefrontal cortex and depression > Micro-stimulation
“These findings were complemented by data showing that 8 weeks of sertraline treatment normalized amygdalar hyper-activation to sad faces in MDD [194], replicating prior findings [195,196].”
§ Prefrontal cortex and depression > References
“194. Scheidegger M, Walter M, Lehmann M, Metzger C, Grimm S, Boeker H, et al. Ketamine decreases resting state functional network connectivity in healthy subjects: implications for antidepressant drug action.”
Citations
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Li, S., Jia, J., Xu, B., & Wang, X. (2025) · Psychology of sport and exercise · doi:10.1016/j.psychsport.2025.102824 · Cited by 8
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“The prefrontal cortex (PFC) has emerged as one of the regions most consistently impaired in major depressive disorder (Pizzagalli and Roberts, 2021).”
BackgroundWu, Y.-C., Yu, H., Yen, C., Yeh, Y., Jian, C.-R., Lin, C.-W., & Lin, I. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.01.020 · Cited by 7
Xu, J.-J., Kan, W., Wang, T., Li, L., Zhang, Y., Ge, Z.-Y., Xu, J.-Y., Yin, Z.-J., Feng, Y., Wang, G., et al. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.05.038 · Cited by 7
Yang, B., Miao, R., Wang, T., Zhu, F., Li, W., Liu, Y., & Wu, J. (2024) · BMC Complementary Medicine and Therapies · doi:10.1186/s12906-024-04690-0 · Cited by 8
Guan, M., Xie, Y., Wang, Z., Miao, Y., Li, X., Yu, S.-F., & Wang, H. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03376-6 · Cited by 10
“This region, implicated in emotional and cognitive processing in MDD [13], exhibits hypoactivity that is strongly associated with symptom severity [14].”
Shu, Y., Wei, H., Liu, J., & Zhu, X. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.119461 · Cited by 8
Noninvasive Brain Stimulation Techniques for Treatment-Resistant Depression
Boscutti, A., Figueiredo, J. M. D., Razouq, D., Murphy, N., Cho, R., & Selvaraj, S. (2023) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2023.02.005 · Cited by 10
Schönthaler, E. M. D., Dalkner, N., Schwalsberger, K., Reininghaus, E. Z., & Reininghaus, B. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1061642 · Cited by 8
Gait disorders in unipolar and bipolar depression
Bogdanova, D. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e15864 · Cited by 7
Wunram, H. L., Kasparbauer, A., Oberste, M., & Bender, S. (2023) · Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie · doi:10.1024/1422-4917/a000954 · Cited by 7
Singh, P., Agrawal, P., & Singh, K. P. (2024) · Behavioural Brain Research · doi:10.1016/j.bbr.2024.115128 · Cited by 8
A lifespan transcriptomic atlas of the human prefrontal cortex at single-cell resolutionPreprint
Yang, H., Clarence, T., Scott, M. R., Wang, X., Prashant, N. M., Pjanic, M., Venkatesh, S., Hong, A., Casey, C., Murphy, S. R., et al. (2024) · medRxiv · doi:10.1101/2024.11.06.24316592 · Cited by 7
Depression as a risk factor for Alzheimer’s disease: A human post-mortem study
Morisaki, M., Rezaali, F., Lau, L. C., Boche, D., Khandaker, G. M., Turecki, G., & Sinclair, L. I. (2025) · PLoS ONE · doi:10.1371/journal.pone.0320561 · Cited by 6
“Prefrontal cortex is also one of the brain areas which is most associated with MDD pathology [46] and both structural and functional abnormality are characterised in DLPFC of MDD patients [46–50].”
Liu, J., Hu, Y., Zong, B., Wang, S., Zheng, Y., Guo, D., Shi, C., Cai, R., & Li, L. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.04.166 · Cited by 7
Doolittle, T., & Duque‐Wilckens, N. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-89525-8_11 · Cited by 6
Zheng, Y., Wang, P., Yao, C., Wang, J., Wang, J., & Xue, S. (2025) · Human Brain Mapping · doi:10.1002/hbm.70249 · Cited by 7
“Existing research has revealed disrupted functional connectivity between the orbitofrontal cortex and various brain regions in MDD compared to healthy controls (Gong et al. 2020; Pizzagalli and Roberts 2022).”
NDUFB9 ameliorates CUMS-induced depression-like behavior by promoting mitophagy
Sun, Y., Li, L., Yang, X., Yin, S., & Xiao, Z. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03502-4 · Cited by 8
Li, G., Huang, B., Wang, Y., Zhou, B., Hu, F., & Wang, L. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.120424 · Cited by 6
The neurobiology of major depressive disorder: Updates and perspectives from proteomics
Spero, V., D'Amelio, S., Eligini, S., Molteni, R., Banfi, C., & Cattaneo, M. G. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102855 · Cited by 6
Zhou, Z., Zhang, L., Hu, X., Cao, L., Gao, Y., Li, H., Bao, W., Tang, M., Sun, H., Kuang, W., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03758-w · Cited by 7
Chen, P., Chen, G., Guo, Z., Chen, R., Tang, X., Yang, Z., Ma, W., Chen, C., Sun, S., Zhang, Y., et al. (2026) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2026.106484 · Cited by 7
Algermissen, J., Rascu, M., Weber, L. A. E., den Boer, T., Martin, E. M., Treeby, B. E., Gray, M. D., Cleveland, R. O., Wittmann, M. K., Clarke, W. T., et al. (2026) · Neuron · doi:10.1016/j.neuron.2026.03.009 · Cited by 11
Chen, S., Liu, X., Huang, Z., Su, F., Zhang, W., Li, J., Liu, S., & Ming, D. (2023) · Cerebral Cortex · doi:10.1093/cercor/bhad204 · Cited by 6
The Effect of Transcranial Direct Current Stimulation (tDCS) on Anorexia Nervosa: A Narrative Review
Chmiel, J., Gładka, A., & Leszek, J. (2023) · Nutrients · doi:10.3390/nu15204455 · Cited by 12
“The underlying hypothesis behind using tDCS for depression is that it targets dysfunctions in various cortical and subcortical regions, including the prefrontal cortex [85], amygdala [86], and hippocampus [87].”
BackgroundPrefrontal Dopamine in Flexible Adaptation to Environmental Changes: A Game for Two Players
Latagliata, E. C., Orsini, C., Cabib, S., Biagioni, F., Fornai, F., & Puglisi‐Allegra, S. (2023) · Biomedicines · doi:10.3390/biomedicines11123189 · Cited by 9
Depression, an unmet health need in Africa: Understanding the promise of ketamine
Millen, A. M. E., Daniels, W. M. U., & Baijnath, S. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e28610 · Cited by 7
“Lastly, the pathogenesis of depression has also been linked to other specific functional brain changes including reduced hippocampal neurogenesis and impairments in fronto-cortical executive cognitive functions [26 – 29].”
BackgroundNeuroanatomical substrates of depression in dementia with Lewy bodies and Alzheimer’s disease
Querry, M., Botzung, A., Cretin, B., Demuynck, C., Muller, C., Ravier, A., Schorr, B., Mondino, M., Sanna, L., de Sousa, P. L., et al. (2024) · GeroScience · doi:10.1007/s11357-024-01190-4 · Cited by 7
“This hypothesis is supported by the review of Pizzagalli and Roberts, based on preclinical and clinical data, in which they demonstrated the functional involvement of PFC in the emergence and maintenance of anhe-donic phenotypes, negative processing biases, and learned helplessness [83].”
Isaac, A. R., Chauvet, M. G., Lima‐Filho, R. A. S., Wagner, B. D. A., Caroli, B. G., Leite, R. E. P., Suemoto, C. K., Nunes, P. V., Felice, F. G. D., Ferreira, S. T., et al. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03128-y · Cited by 6
“The PFC is notably morphologically and functionally impaired in MDD and in animal models of depressive-like states [43, 44].”
BackgroundPGAM5 knockout causes depressive‐like behaviors in mice via ATP deficiency in the prefrontal cortex
Cui, W., Chen, C., Gong, L., Wen, J., Yang, S., Zheng, M., Gao, B., You, J., Lin, X., Hao, Y., et al. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14377 · Cited by 8
“5 Voxel-based morphometry analysis (VBM) and functional magnetic resonance imaging (fMRI) are the commonly used methods for noninvasive analysis of gray matter volume and brain functional activity in vivo.”
BackgroundMethodJang, D. C., Choi, S., Chung, G., & Kim, S. K. (2023) · Experimental Neurobiology · doi:10.5607/en23017 · Cited by 6
“Functional and structural abnormalities in this region are known to increase vulnerability to depression [24], and modulating mPFC activity can alter depressive behavior.”
BackgroundKoutsomitros, T., Schwarz, S. A., van der Zee, K. T., Schuhmann, T., & Sack, A. T. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1206805 · Cited by 7
“It is proposed that hypoactivity of the dorsolateral prefrontal cortex (DLPFC) diminishes the top-down ability to regulate emotions (9, 10), while hyperactivity of the limbic system increases negative bottom-up emotionality (11).”
BackgroundActivity of the Mirror Neuron System in People with Depressive Symptomatology
Karimova, E., Smolskaya, D. V., & Naratkina, A. A. (2023) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-023-01516-3 · Cited by 6
“The development of depression in turn leads to social maladjustment, impaired emotional and social perception; at the neurophysiological level, it is most often associated with disorders in the prefrontal cortex (Pizzagalli and Roberts, 2022].”
BackgroundWei, J., Zhang, Z., Yang, X. L., Zhao, L., Wang, M., Dou, Y., Yan, Y., Ni, R., Gong, M., Dong, Z., et al. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.12.072 · Cited by 6
Wang, Q., Hou, C., Jiang, X., & Li, H. (2024) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2023.1305571 · Cited by 7
“The MFG/SFG is generally considered a vital region mainly responsible for high-order cognitive function (Pizzagalli and Roberts, 2022).”
BackgroundVerma, K., Amitabh, Prasad, D., Reddy, M. P., & Kohli, E. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00632 · Cited by 5
Almarzouki, A. F. (2024) · Postgraduate Medicine · doi:10.1080/00325481.2024.2347195 · Cited by 7
“The prefrontal cortex is crucial for WM and is impaired in depression, which further explains the association between depression and WM impairment found in the present study [37].”
Gunn, M. P., Rose, G. M., Whitton, A. E., Pizzagalli, D. A., & Gilbert, D. G. (2024) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntae084 · Cited by 5
“38,39 Taken together, our weaker connectivity between the iPFG and the ACC could be a biomarker for how NIC effectively regulates attention, experience of reward, and cognitive processes.”
Self-citationLees, T., & Gatzke‐Kopp, L. M. (2025) · Psychophysiology · doi:10.1111/psyp.70026 · Cited by 6
“…women who report higher levels of depressive symptoms weigh positive feedback as less salient and negative feedback as more salient; an interpretation supported by both the diminished response to reward and negativity bias frameworks of depression (Pizzagalli and Roberts 2022; Whitton et al. 2015).”
Tsuji, A., Nishida, K., Imazu, S., Kawabata, Y., Toyoda, K., Matsumoto, K., Onishi, N., Kubo, Y., Yamane, T., Kinoshita, S., et al. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.03.168 · Cited by 5
Mou, L., Shen, Y., Wu, B., Zhang, C., Zhu, J., Tan, Q., Zhang, X., Wang, Z., & Shen, Z. (2025) · Scientific Reports · doi:10.1038/s41598-025-05896-z · Cited by 5
“…cortex (DLPFC) included channels 1, 2, 3, 4, 5, 9, 14, and 18; the frontopolar prefrontal cortex (FPC) included channels 6, 8, 10, 11, 12, and 13; the orbitofrontal cortex (OFC) included channels 15, 17, 20, and 21; and the ventrolateral prefrontal cortex (VLPFC) included channels 19 and 22 (Fig.”
Transcription factors Lef1 and Rest stimulate recovery from depressive states
Yamamoto, H., Araki, S., Onodera, R., Go, Y., & Abe, K. (2025) · Neuropsychopharmacology · doi:10.1038/s41386-025-02259-0 · Cited by 6
Ma, M., Zhang, Y., Liu, Z., Lv, S., Tao, K., & Lu, Z. (2026) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2026.111784 · Cited by 7
Prefrontal Cortex Dysfunction as a Precipitating Factor for Schizophrenia and Depression
Uliana, D. L., & Grace, A. A. (2026) · Journal of Neurochemistry · doi:10.1111/jnc.70409 · Cited by 8
Gaszner, T., Farkas, J. I., Kun, D., Ujvari, B., Füredi, N., Kovács, L. Á., Hashimoto, H., Reglődi, D., Kormos, V., & Gaszner, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911739 · Cited by 7
“The question of how this brain area contributes to the pathogenesis of depression has been investigated for a long time [32,33], including through functional imaging [34], studies on individuals who suffered damage of the PFC [35], and reports on cases treated by deep brain stimulation [36,37].”
BackgroundWhat can the psychoneuroimmunology of yoga teach us about depression's psychopathology?
Chiarpenello, C., & Brodmann, K. (2024) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2024.100877 · Cited by 5
“Depressed individuals have dorsolateral PFC hypoactivity, ventromedial PFC and amygdala hyperactivity (Pizzagalli and Roberts, 2021; Koenigs and Grafman, 2009; Fales et al., 2009).”
BackgroundYabuki, Y., Hori, K., Zhang, Z., Matsuo, K., Kudo, K., Usuki, S., Gadotti, V. M., Chen, L., Ueno, S., Chiba, S., et al. (2025) · Acta Physiologica · doi:10.1111/apha.70043 · Cited by 5
Paneva, J., Schuhmann, T., Smet, S. D., Meza, T. D., Duecker, F., & Sack, A. T. (2025) · Brain stimulation · doi:10.1016/j.brs.2025.04.002 · Cited by 5
“RTMS treatments for depression are safe and effective [5 – 9] and most commonly delivered to the left dorsolateral prefrontal cortex (lDLPFC), which has been implicated in the cognitive control and emotional regulation deficits seen in Major Depressive Disorder (MDD) [10,11].”
Bhatti, N. A., Jobilal, A., Asif, K., Villegas, M. J., Pandey, P., Tahir, A. N., Balla, N. V. D. B., Camargo, M. P. A., Ahmad, S., Kataria, J., et al. (2023) · Cureus · doi:10.7759/cureus.44038 · Cited by 6
“MDD is distinguished by the presence of prevalent feelings of sorrow and despair, decreased ability to derive pleasure (anhedonia), lowered motivation, cognitive challenges, and physiological manifestations affecting essential bodily functions [6-8].”
BackgroundRegalado, D., Connolly, M. E., Krutsch, K., Stark, A., Kendall-Tackett, K. A., & Garner, C. D. (2023) · Women s Health · doi:10.1177/17455057231199391 · Cited by 5
Wertz, J., Rüttiger, L., Bender, B., Klose, U., Stark, R. S., Dapper, K., Saemisch, J., Braun, C., Singer, W., Dalhoff, E., et al. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1232446 · Cited by 5
Depression proteomic profiling in adolescents with transcriptome analyses in independent cohorts
Sokolov, A. V., Lafta, M. S., Nordberg, D. O. T., Jonsson, J., & Schiöth, H. B. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1372106 · Cited by 7
“Extensive literature has strongly implicated PFC dysfunction in MDD, revealing functional, structural, and systems-level abnormalities spanning various PFC regions (40).”
BackgroundZhao, T., Guo, H., Yang, J., Cai, A., Liu, J., Zheng, J., Xiao, Y., Zhao, P., Li, Y., Luo, X., et al. (2024) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2024.104092 · Cited by 5
Bergosh, M., Medvidovic, S., Zepeda, N., Crown, L. M., Ipe, J., Debattista, L., Romero, L., Amjadi, E., Lam, T., Hakopian, E., et al. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1389096 · Cited by 6
“The current understanding of steady-state depression etiology is the hyperactivity and excitability of the mPFC, which drives excessive long-range inhibitory signals to regions involved in motivation, cognition, reward, and emotion (Pizzagalli and Roberts, 2022).”
BackgroundSun, Q., Xiong, N., Wang, Y., Xia, Z., Chen, J., Yan, C., & Sun, H. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.07.005 · Cited by 5
Szopa, A., Bogatko, K., Serefko, A., Herbet, M., Ostrowska-Leśko, M., Wróbel, A., Radziwoń-Zaleska, M., Dudka, J., Właź, P., & Poleszak, E. (2024) · Pharmacological Reports · doi:10.1007/s43440-024-00627-z · Cited by 5
“However, similar outcomes were demonstrated in our previous studies [32 ], in which a significant increase in disturbances associated with the A1 receptor may play a role in the pathophysiology of the depression [56].”
BackgroundResultInfluentialCampos, L. O., Macedo, M. D. C., Monerat, V. K. V., Ferreira, K. R. D. R., dos Santos, M. E. C., Esquírio, A. F., Alves, A. L. G., Gama, G. L., Barbosa, M. A., & Barbosa, A. C. (2024) · Applied Sciences · doi:10.3390/app14177901 · Cited by 5
Neurobiological Mechanisms Underlying Psychological Dysfunction After Brain Injuries
Unadkat, P., Rebeiz, T. J., Ajmal, E., Souza, V. D., Xia, A., Jinu, J., Powell, K., & Li, C. (2025) · Cells · doi:10.3390/cells14020074 · Cited by 6
Guo, J., Cao, Q., Jie, H., Li, Y., Bai, W., Liu, T., & Zheng, X. (2025) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2025.111335 · Cited by 5
Int-Veen, I., Eßer, U., Ladegast, S., Liermann, L., Täglich, R., Schopp, B., Nuerk, H., Plewnia, C., Kroczek, A., Smet, S. D., et al. (2025) · Cognitive Affective & Behavioral Neuroscience · doi:10.3758/s13415-025-01305-0 · Cited by 6
“…observe the well-documented prefrontal hypoactivation under stress in the left DLPFC, which has been repeatedly found for patients with depression (Pizzagalli & Roberts, 2022) and has also been observed to be associated with trait rumination (Int-Veen et al., 2023), which is why we expected to…”
How emotional expressions motivate actionPreprint
Mennella, R., & Grèzes, J. (2023) · doi:10.31234/osf.io/vfbcp · Cited by 4
Li, J., Zhao, R., Wang, C., Song, J., Guo, X., Ge, Y., & Chu, X. (2024) · PAIN Reports · doi:10.1097/pr9.0000000000001139 · Cited by 4
“10,14,16,21,22,30 Moreover, studies focused on the molecular mechanisms associated with chronic pain, and depression-induced neural plasticity changes have also identified the shared molecular changes in both pain and depression.”
BackgroundNiu, Z., Haley, A. P., Clark, A. L., & Duarte, A. (2024) · Brain Imaging and Behavior · doi:10.1007/s11682-024-00898-3 · Cited by 5
“It is possible, for example, that these or other factors contributed 2013; Pizzagalli & Roberts, 2022).”
InfluentialQian, R., Duan, N., Wang, M., Fan, S., Ji, Y., Yu, Y., Zheng, H., Wu, X., & Tian, Y. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.119492 · Cited by 5
Li, W., Zhu, W., Zhu, Z., Xie, H., Ali, T., Yu, Z., & Li, S. (2025) · Glia · doi:10.1002/glia.70060 · Cited by 4
“The cortex and hippocampus are well-established as key regulators of mood and cognition, with their dysfunction being strongly implicated in depression pathogenesis (Pizzagalli and Roberts 2022; Tartt et al. 2022).”
Int-Veen, I., Eisenlohr, C., Täglich, R., Schopp, B., Nuerk, H., Plewnia, C., Smet, S. D., Vanderhasselt, M., Kroczek, A., Barth, B., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-15099-1 · Cited by 5
“What is particularly interesting is that, contrary to expectations, we did not observe the well-documented prefrontal hypoactivation under stress 7,42 .”
Liu, W., Heij, J., Liu, S., Liebrand, L. C., Caan, M. W. A., van der Zwaag, W., Veltman, D. J., Lü, L., Aghajani, M., & van Wingen, G. A. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.11.009 · Cited by 5
Zhang, M., Deng, M., Li, X., Zhang, R., Liao, J., Peng, J., Feng, H., Tang, S., Chen, Y., & Mo, L. (2024) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsae086 · Cited by 4
A free association semantic task for fNIRS-based perinatal depression assessment
Chen, D., Yang, X., Liang, Y., Huang, C., Zhang, S., Li, Y., Li, Y., Li, X., Mu, W., Zhang, D., et al. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2024.1491923 · Cited by 4
Costa-López, B., Ruiz‐Robledillo, N., Moreno, O., Tirado, C., Albaladejo-Blázquez, N., & Ferrer‐Cascales, R. (2025) · Current Psychology · doi:10.1007/s12144-025-07459-x · Cited by 4
“Depression increasing the risk of negative prefrontal symptoms is extensive in the literature (Cuerda-Ballester et al., 2023; Liu et al., 2020; Pizzagalli & Roberts, 2022; Stuijfzand et al., 2020).”
Yang, L., Zhang, M., Sun, X., Du, A.-Q., Jia, J., Li, N., Hu, G., Lu, Y., Wang, S., Zhang, J., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-07802-9 · Cited by 4
“Also, the authors should report the raw numbers of cFos measured, the number of CaMKII cells measured, as well as the density of each, in addition to the raw numbers and density for the double-labelled cells.”
Pharmacokinetics and brain distribution of ketamine after nasal administration
Yang, Z., Li, L., Deng, B., Xu, Y., Du, Y., Lv, Y., & Zhai, X. (2025) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2025.116945 · Cited by 4
A Chain Mediation Model for Psychological Maltreatment and Adolescents Social Media Dependence
Fang, J., Liu, Y., Jin, Y., Xiao, T., Pan, M., & Zhou, D. (2025) · Child Abuse Review · doi:10.1002/car.70069 · Cited by 4
Mahmud, A., & Karaman, M. A. (2026) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2026.1843871 · Cited by 7
“…and infralimbic subregions are considered functionally homologous to the human pregenual and subgenual Anterior Cingulate Cortex (Brodmann Areas 24 and 25), both of which are extensively implicated in MDD (Uylings et al., 2003; Kolb et al., 2012; Kolk and Rakic, 2022; Pizzagalli and Roberts, 2022).”
Investigation of Neurofunctional Changes Over the Course of Electroconvulsive Therapy
Gruzman, R., Hartling, C., Domke, A., Stippl, A., Carstens, L., Bajbouj, M., Gärtner, M., & Grimm, S. (2022) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyac063 · Cited by 4
“The present results may also differ from previous studies because of the used task because hyperactivity in the sgACC and pgACC (or inability to deactivate them) is often detected by neuroimaging tasks eliciting negative processing biases (Pizzagalli and Roberts, 2022).”
BackgroundResultKurogi, K., Taniguchi, F., Matsuo, R., Shinozuka, M., Suzaki, R., & Yasuo, S. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.176126 · Cited by 4
Shorter duration of slow wave sleep is related to symptoms of depression in patients with epilepsy
Eyjólfsdóttir, S. G., Trinka, E., & Höller, Y. (2023) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2023.109515 · Cited by 4
Uzungil, V., Luza, S., Opazo, C., Mees, I., Li, S., Ang, C., Williamson, N. A., Bush, A. I., Hannan, A. J., & Renoir, T. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109837 · Cited by 3
Neuronal tuning to threat exposure remains stable in the mouse prefrontal cortex over multiple days
Sylte, O. C., Muysers, H., Chen, H.-L., Bartos, M., & Sauer, J. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002475 · Cited by 8
Xiang, L.-Y., Chen, X.-Y., Lu, L., Kong, M.-H., Ji, Q., Xiong, Y., Xie, M.-M., Jian, X.-L., & Zhu, Z.-R. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.05.030 · Cited by 3
Kuban, W., Haduch, A., Bromek, E., Basińska-Ziobroń, A., Gawlińska, K., Gawliński, D., Filip, M., & Daniel, W. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147904 · Cited by 4
García‐Marín, L. M., Ogonowski, N. S., Han, L. K. M., Maya-Martínez, M., Mitchell, B. L., Schmaal, L., Martin, N. G., & Rentería, M. E. (2024) · Imaging Neuroscience · doi:10.1162/imag_a_00291 · Cited by 5
“In particular, several previous studies have investigated the associations between the human cortex and depression ( Hare & Duman, 2020; Pizzagalli & Roberts, 2022; Wu et al., 2023), while some observational studies and animal models have reported smaller hippocampal volume among individuals with…”
BackgroundStructural alterations as a predictor of depression – a 7-Tesla MRI-based multidimensional approach
Schnellbächer, G. J., Rajkumar, R., Veselinović, T., Ramkiran, S., Hagen, J., Collée, M., Shah, N. J., & Neuner, I. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02854-5 · Cited by 4
“In contrast, the gyri fi cation alterations identi fi ed by the SVM and subsequent permutation procedure were not subject to modi fi cation through disease severity and are most likely more static.”
Khatsko, S. L., Zhdanov, A. V., Kravchenko, D. V., Nikiforova, E. V., Salimova, N. A., Kotova, M. M., Galstyan, D. S., de Abreu, M. S., Yang, L., Stewart, A., et al. (2025) · Behavioural Brain Research · doi:10.1016/j.bbr.2025.115492 · Cited by 5
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“Pizzagalli et al. 52 showed that the mPFC plays an important role in depression.”
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Metadata
- Authors
- Pizzagalli, D. A., & Roberts, A. C.
- Affiliations
- Harvard University (US)
- University of Cambridge (GB)
- Corresponding author
- Pizzagalli, Diego A.
- Roberts, Angela C.
- Venue
- Neuropsychopharmacology
- Published
- 2021-08-02
- Volume
- 47
- Issue
- 1
- Pages
- 225-246
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC8617037
- OpenAlex
- W3189676709
- Cited by
- 667
- References
- 286
- Citations by year
- 2026: 164 · 2025: 198 · 2024: 149 · 2023: 109 · 2022: 42 · 2021: 4
- FWCI
- 9.17
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-08-19)
- Open access
- bronze
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R37 MH068376, R01 MH108602, P50 MH119467, R01 MH095809)
- RCUK | Medical Research Council (M023990/1)
- Wellcome Trust (108089/Z/15/Z)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- prefrontal cortex, major depressive disorder, anhedonia, learned helplessness, despair-like behavior, neural pathways, depression treatment, depression vulnerability
- MeSH terms
- Brain, Depression, Major Depressive Disorder, Humans, Magnetic Resonance Imaging, Prefrontal Cortex, Anhedonia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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