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Cited by 644Functional Brain Connectivity StudiesMental Health Research TopicsTreatment of Major Depression

Prefrontal cortex and depression

Open access
Pizzagalli, Diego A., Roberts, Angela C.·2022·Neuropsychopharmacology
DOI 10.1038/s41386-021-01101-7PMC PMC8617037
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Abstract

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.

AI snapshot

Written from the paper’s full text.

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41386-021-01101-7

Cites

290 of 290 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

194 of 286 cited sources checked · 85 supported · 10 flagged · accuracy not yet measured

  • Premisecitation

    Studies of the neurobiology of reward processing have identified separate subtypes of anhedonia: consummatory, anticipatory, motivational, and decisional.

    “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].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [20] Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011;35:537–55. source

      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)

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    • cites [21] Der-Avakian A, Markou A. The neurobiology of anhedonia and other reward-related deficits. Trends Neurosci. 2012;35:68–77. source

      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)

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  • Premisecitation

    An early meta-analysis of 64 structural MRI studies reported that frontal regions showed the largest volumetric reductions in major depressive disorder, particularly in the anterior cingulate cortex and bilateral orbitofrontal cortex.

    “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]).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [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
    • cites [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. source

      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)

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  • Premisecitation

    Adolescents with major depressive disorder had lower cortical thickness in the medial orbitofrontal/ventromedial prefrontal cortex and superior frontal gyrus than adolescents without major depressive disorder history.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      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)

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  • Premisecitation

    Asymptomatic offspring of MDD patients showed blunted dlPFC activation and normative amygdalar responses to a sad mood induction.

    “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).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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. source

      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)

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  • Premisecitation

    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.

    “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].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [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. source

      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)

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    • cites [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
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    Premisecitation

    In tasks probing consummatory anhedonia, major depressive disorder has been associated with reduced activation in ventral and dorsal striatum, anterior cingulate cortex, and orbitofrontal cortex but hyperactivation in medial prefrontal cortex, ventromedial prefrontal cortex including subgenual anterior cingulate cortex, and dorsolateral prefrontal cortex.

    “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].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [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. source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    • cites [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. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    • cites [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

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    Findingcitation

    Both forms of inflexibility occur after chronic stress; only stress-induced attentional set-shifting deficits are prevented by adrenergic receptor agonist cocktail into mPFC, while reversal learning deficits remain.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      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)

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    Premisecitation

    Alternative accounts suggest that the forced swim test and tail suspension test measure adaptive learned responses to acute stress and reflect a natural shift from active to passive coping strategies, distinct from behavioral despair.

    “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.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [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. source

      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)

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    • cites [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. source

      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)

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    Premisecitation

    In a sample of 421 individuals with major depressive disorder and 488 healthy controls, reduced resting state functional connectivity emerged between the central orbitofrontal cortex and memory-related regions, with increasingly weaker connectivity correlating with higher depression severity.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

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    Premisecitation

    In treatment-resistant depression, higher pre-treatment resting state activity in a region between the perigenual anterior cingulate cortex and subgenual anterior cingulate cortex was found, a course of electroconvulsive therapy normalized activity in this region and its connectivity with the ventromedial prefrontal cortex, and higher pretreatment subgenual anterior cingulate cortex activity predi

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

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    Interpretationcitation

    Structural abnormalities spanning the subgenual anterior cingulate cortex and orbitofrontal cortex emerge early in major depressive disorder and affect regions playing a key role in the regulation of negative emotion, value representation, and self-referential processing.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    Premisecitation

    Although some abnormalities persist after remission, including orbitofrontal cortex hypo-responses to rewards and inability to sustain ventral striatal responses to positive cues, acute striatal responses to rewards appear to normalize in individuals with past major depressive disorder.

    “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].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [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
    • cites [108] Admon R, Pizzagalli DA. Corticostriatal pathways contribute to the natural time course of positive mood. Nat Commun. 2015;6:10065. source
    • cites [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

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    Premisecitation

    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 and increased glucose metabolism in dACC.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

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    Premisecitation

    Changes in the dorsal anterior cingulate cortex emerged only in treatment responders, and early increases in dorsal anterior cingulate cortex cortical thickness 48 hours after the second electroconvulsive therapy administration predicted eventual clinical response.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    Premisecitation

    In reward anticipation tasks, MDD is associated with decreased activation in ventral and dorsal striatum and middle frontal gyrus (BA8), and hyperactivation in dlPFC and mPFC including pgACC and caudal vmPFC.

    “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].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [3] Pizzagalli DA. Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu Rev Clin Psychol. 2014;10:393–423. source

      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)

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    • cites [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. source

      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)

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    • cites [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

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    Premisecitation

    Impaired cognitive control in chronic stress models includes response and attentional inflexibility, spatial working memory deficits, and insensitivity of goal-directed actions to action-outcome contingency and outcome value, although these may vary depending on the nature of the stressor.

    “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.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [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. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    • cites [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

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    • cites [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

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    Premisecitation

    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.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      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)

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    Premisecitation

    In the IMAGEN study, during reward anticipation, individuals with higher depression severity had reduced sensitivity to differing reward values in central OFC (areas 11 and 13) but higher lateral OFC (area 12) activation to non-rewards at both age 14 and 19.

    “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]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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    Premisecitation

    In a subclinical sample, adolescents with elevated depressive symptoms showed blunted perigenual anterior cingulate cortex and rostral ventromedial prefrontal cortex activation during reward consumption, with the former correlating with higher anhedonia.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

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    Premisecitation

    In a 5-year naturalistic prospective study, gray matter volume in the right dorsal anterior cingulate cortex and right inferior frontal gyrus contributed to disease trajectory predictions; larger volume in these areas predicted better clinical outcome and lower depressive symptoms over 5 years.

    “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].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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. source

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    Premisecitation

    At age 19, blunted reward-related central OFC activation correlated with more anhedonic symptoms, whereas potentiated non-reward lateral OFC activation correlated with sadness.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In rodents, the most abundant and consistent changes in chronic stress models are in the medial prefrontal cortex, including anterior cingulate, prelimbic, and infralimbic regions, with somewhat more variable, mixed direction effects in the orbitofrontal cortex.

    “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).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [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. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [99] McEwen BS, Nasca C, Gray JD. Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology. 2016;41:3–23. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Evidence of disrupted frontostriatal activation during reward consumption has been reported also in children with major depressive disorder, suggesting that such dysfunctions emerge early.

    “Evidence of disrupted frontostriatal activation during reward consumption has been reported also in children with MDD, suggesting that such dysfunctions emerge early.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    Left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation treatment increased gray matter volume in the perigenual anterior cingulate cortex, and such volumetric increases correlated with symptom reduction.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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).

    “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]).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    In a large youth sample, 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.

    “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]).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [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
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Fully remitted individuals showed normative ventral striatum RPE but greater RPE in the VTA.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    In a card-guessing task, depressed adolescents had potentiated mPFC (BA10) activation coupled with blunted ventral striatal activation to rewards.

    “In a study using a card-guessing task, depressed adolescents had potentiated mPFC (BA10) activation (coupled with blunted ventral striatal activation) to rewards [111].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a wheel-of-fortune task, adults with MDD showed greater left OFC activation but reduced pgACC activation during the selection phase relative to controls.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Optogenetic stimulation of ILc reduced the BOLD response to optogenetic-induced dopamine stimulation and blocked DA-stimulation-induced place preference.

    “Moreover, optogenetic stimulation of ILc reduced the BOLD response to optogenetic-induced dopamine stimulation and blocked DA-stimulation-induced place preference [62].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Unmedicated adults with MDD showed reduced approach-related activation in the dlPFC and reduced avoidance-related pgACC activation.

    “Moreover, they showed reduced approach-related activation in the dlPFC and, surprisingly, reduced avoidance-related pgACC activation.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    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 relative to controls.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    Both reduced dmPFC-amygdala FC and potentiated vmPFC-amygdala FC to negative faces have been reported in adults with current MDD.

    “Importantly, both patternsreduced dmPFCamygdala FC but potentiated vmPFC-amygdala FC to negative faceshave been reported in adults with current MDD [176,190,191].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [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
    • cites [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 source

      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)

      Experimental — accuracy not yet measured
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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).

    “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).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [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
    • cites [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. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Area 25 over-activation reduced basal heart rate variability and increased sympathetic activity.

    “It also reduced basal heart rate variability and increased sympathetic activity [144], consistent with sympathetically-driven alterations in cardiovascular activity in MDD [148, 149].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    Area 25 overactivation reduced cardiovascular and behavioral Pavlovian conditioned arousal in anticipation of marshmallow reward and decreased the number of responses an animal was willing to perform for reward on a progressive ratio task.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Findingcitation

    In rats, a pathway projecting from PLc to the striatal striosomes is implicated in approach-avoidance decision making, with its inactivation increasing approach.

    “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].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Interpretationcitation

    Altered action-outcome learning and expression could play an important role in modulating actions in response to varying reward and punishment in an approach-avoidance task, and hence underlie the reported negative biases.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [39] Amemori K, Graybiel AM. Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making. Nat Neurosci. 2012;15:776–85. source
    • Rests on an assumption: Functional homology exists between PFC regions in rodents/monkeys and humans such that findings in animals can inform MDD.

  • May combine two claims.

    Findingcitation

    Overactivation of area 25 in marmosets enhanced avoidance of punishment, blunted anticipatory and motivational appetitive arousal, and increased responsivity to uncertain threat and Pavlovian conditioned, certain threat.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Findingcitation

    Higher levels of perceived helplessness and PINV magnitude correlate with rumination.

    “Additionally, higher levels of perceived helplessness and PINV magnitude correlated with rumination.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    In healthy controls, personally chosen vs. passively received rewards elicit stronger activation in the striatum (ventral and dorsal) and PFC (inferior frontal gyrus), which is inversely related to depressive symptoms.

    “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].”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured
    • cites [213] Leotti LA, Delgado MR. The inherent reward of choice. Psychol Sci. 2011;22:1310–8. source

      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)

      Experimental — accuracy not yet measured
    • cites [214] Leotti LA, Delgado MR. The value of exercising control over monetary gains and losses. Psychol Sci. 2014;25:596–604. source

      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)

      Experimental — accuracy not yet measured
    • cites [215] Wang KS, Delgado MR. Corticostriatal circuits encode the subjective value of perceived control. Cereb Cortex. 2019;29:5049–60. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Chronic stress exposure induces response and attentional inflexibility, spatial WM disruption, and insensitivity of goal-directed actions to action-outcome contingency and outcome value.

    “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.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured
    • cites [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
    • cites [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

  • May combine two claims.

    Findingcitation

    Abnormal OFC activity is associated with altered FST/TST performance, including passive coping after histone acetylation inhibition in ventrolateral regions, OFC-amygdala pathway activation, and 5-HT2a agonist infusions into lateral OFC.

    “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].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured
    • cites [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
    • cites [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

  • May combine two claims.

    Findingcitation

    In MDD subjects performing at the same level as controls, MDD is linked to potentiated pgACC, dACC, and left dlPFC; pgACC hyperactivation persists after remission.

    “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].”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [16] Pizzagalli DA. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology. 2011;36:183–206. source
    • cites [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. source

      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)

      Experimental — accuracy not yet measured
    • cites [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
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    dlPFC is especially important for top-down regulation of treatment and placebo expectancies, whereas mPFC plays a key role in encoding value of expected outcomes.

    “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].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [218] Wager TD, Atlas LY. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci. 2015;16:403–18. source

      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)

      Experimental — accuracy not yet measured
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    PFC regions play an important role in perception of controllability and its impact on event valence, which moderates the depressogenic effects of stressors.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] Pizzagalli DA. Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu Rev Clin Psychol. 2014;10:393–423. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    In medication-free MDD patients, greater deactivation of amPFC (pgACC/mPFC BA10) during a WM task predicts greater symptom reduction with escitalopram and greater WM improvements.

    “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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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 source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Prolonged ILc pyramidal stimulation for 60 min promotes active coping on FST, mirroring ketamine.

    “prolonged ILc pyramidal stimulation for 60 min, mirroring the actions of ketamine to promote active coping on FST [63].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Findingcitation

    In rats, OFC contributes specifically to lower-order reversal learning of stimulus-reward associations, while mPFC contributes selectively to higher-order attentional set-shifting.

    “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].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured
    • cites [256] Birrell JM, Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci. 2000;20:4320–4. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Remitted MDD individuals are characterized by reduced ability to deactivate amPFC and increased dlPFC-amPFC functional connectivity during a WM task.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Stress-induced reversal learning deficits are prevented by LTD in mediodorsal thalamo-orbitofrontal pathway and locally infused ketamine.

    “the latter was prevented by LTD in the mediodorsal thalamo-orbitofrontal pathway [258] and locally infused ketamine [259].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [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
    • cites [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

  • May combine two claims.

    Findingcitation

    Perception of control increased the reward value of the chosen option by 30%, and caudal vmPFC activation was linked to this value inflation.

    “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].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [215] Wang KS, Delgado MR. Corticostriatal circuits encode the subjective value of perceived control. Cereb Cortex. 2019;29:5049–60. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    PLc tends to promote active coping, while ILc promotes passive coping.

    “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].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [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
    • cites [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
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Attentional inflexibility dependent on vlPFC can lead to difficulty disengaging from threat-related stimuli and negative bias in monkeys, including disrupted approach-avoidance decision making.

    “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.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [207] Dias R, Robbins TW, Roberts AC. Dissociation in prefrontal cortex of affective and attentional shifts. Nature. 1996;380:69–72. source
    • cites [9] Roberts A. Prefrontal regulation of threat-elicited behaviors: a pathway to translation. Annu Rev Psychol. 2020;71:357–87. source

  • May combine two claims.

    Premisecitation

    These patterns (amygdalar hyperactivity and reduced cortico-limbic functional connectivity) were linked to greater depression severity and a longer disease duration.

    “these patterns were linked to greater depression severity and a longer disease [175, 176, 178]”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured
    • cites [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
    • cites [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

  • May combine two claims.

    Findingreasoning

    vlPFC and area 25 contribute to decision making based on immediate rewarding and punishing outcomes; negative biases are induced by loss of activity in vlPFC but over-activity in area 25.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Over-activation of area 32 reduced the bias away from punishment, while area 32 inactivation had no effect.

    “over-activation of area 32 reduced the bias away from punishment, whilst area 32 inactivation had no effect”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    In macaques, a cluster of neurons in pgACC displayed decision-period activity negatively correlated with overall value; microstimulation of these neurons enhanced avoidance response, and this effect was ameliorated by diazepam.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In healthy controls, subjective (but not objective) uncontrollability over an aversive outcome reduces functional connectivity between dlPFC and parahippocampal gyrus and between frontoparietal executive and salience networks, and impairs working memory performance.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Findingcitation

    The immunization effect of learned control over a stressor is dependent upon mPFC, particularly PLc; PLc inactivation during controllable stress disrupts subsequent behavioral immunization.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Findingreasoning

    In MDD, blunted pgACC activation is found in reward-related processes, while potentiated pgACC (or inability to deactivate) is found in negative processing biases and cognitive control.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    In MDD, dlPFC is over-activated in reward-related processes (likely compensating for hypoactive striatal responses) but hypo-activated in affective/cognitive tasks requiring emotional/stress regulation, cognitive control, or shifting attention.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The quicker animals stop swimming or stop struggling in the forced swim test or tail suspension test is proposed to reflect behavioral despair.

    “The quicker animals stop swimming or stop struggling, respectively, is proposed to reflect behavioral despair [51,52].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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
    • cites [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

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Neuroimaging studies have provided insight into the neural correlates of major depressive disorder by identifying alterations in functional activity, resting state, and structural integrity.

    “Neuroimaging studies have provided important insight into the neural correlates of MDD by identifying alterations in functional activity, resting state and structural integrity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Although depressive phenotypes induced by uncontrollable stressors appear more clinically relevant, the state they produce may be as variable in etiology and treatment as human depression, limiting the level of insight gained.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Negative processing biases are prevalent in major depressive disorder and are implicated in its etiology and treatment.

    “Negative processing biases are prevalent in MDD [31] and implicated in its etiology and treatment [31][32][33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31][32][33]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Despair is purported to be measured in rodents using the forced swim test and tail suspension test.

    “Despair is purported measured in rodents using the forced swim (FST) and tail suspension (TST) tests [48][49][50].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48][49][50]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    The NMDA antagonist ketamine has rapid antidepressant effects and robust parallel findings across species.

    “findings with the NMDA antagonist ketamine will be emphasized owing to its rapid antidepressant effects as well as robust parallel findings across species.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisenone given

    The complexity of depression-associated symptoms makes them difficult to assess with simple questionnaires in the clinic or single behavioral tests in animals.

    “The complexity of depression-associated symptoms makes them difficult to assess with simple questionnaires in the clinic or single behavioral tests in animals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    The etiology and pathophysiology of major depressive disorder, and consequently its treatment and prevention, remain poorly understood.

    “Despite its profound impact, the etiology and pathophysiology of MDDand consequently its treatment and preventionremain poorly understood.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Aspects of controllability have been studied in the context of depression in humans, although such studies are limited.

    “Aspects of controllability, per se, have been studied in the context of depression in humans although, as shall be seen, such studies are limited.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The literature probing resting state functional connectivity in major depressive disorder generally points to abnormalities between discrete prefrontal cortex regions, within networks anchored on different prefrontal cortex regions, and between prefrontal cortex and other networks.

    “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]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68][69][70]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Behavioral despair has been a major focus in preclinical animal studies but has received relatively little attention in humans, with little cross-species overlap in responses measured.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Behavioral despair is often associated with symptoms of helplessness and hopelessness in major depressive disorder, in which a perceived lack of cognitive control is a core feature.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Interpretationreasoning

    Studying the effects of selective interventions within specific prefrontal subregions and circuits allows independent study of specific depression-related alterations in prefrontal activity to determine their causal role in symptoms and their differential sensitivity to treatments.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Imaging findings reveal changes associated with major depressive disorder and determine markers that may act as predictors of disease onset and predictors of efficacious treatment.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In chronic stress models, animals display decreased swimming in the forced swim test or struggling in the tail suspension test, reductions in sucrose preference or consumption and social interactions, changes in the HPA axis and cardiovascular function, negative judgment biases in ambiguous cue tests, and impaired cognitive control.

    “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].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [43] Harding EJ, Paul ES, Mendl M. Cognitive bias and affective state. Nature. 2004;427:312. source
    • cites [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
    • cites [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
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The contrasting patterns between medial prefrontal cortex and orbitofrontal cortex in dendritic spine density are intriguing given similar contrasting effects pertaining to hyper- or hypo-activity in major depressive disorder, although differences in measures and precise regions render comparison challenging.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Some prefrontal cortex abnormalities predicted clinical response and were ameliorated by treatment.

    “Third, some of these PFC abnormalities predicted clinical response and were ameliorated by treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Some prefrontal cortex abnormalities appear early in the course of major depressive disorder and might represent risk markers.

    “Second, some of these abnormalities appear early in the course of the disorder and might, in fact, represent risk markers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In an instrumental reinforcement learning task, unmedicated major depressive disorder subjects showed lower reward value encoding in the perigenual anterior cingulate cortex but higher subgenual anterior cingulate cortex activation during the decision phase than healthy controls.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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
    • cites [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

  • May combine two claims.

    Interpretationreasoning

    Disruptions within brain reward pathways are not only present in the acute phase of MDD but predate its emergence.

    “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]).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Reduced valuation of expected rewards and blunted reward learning represent key vulnerabilities to future MDD.

    “Together, these data suggest that reduced valuation of expected rewards and blunted reward learning represent key vulnerabilities to future MDD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These markers represent markers of MDD vulnerability and possible targets for prevention.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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) and lower RPE signal in the left frontal pole and superior frontal gyrus (BA9/6).

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    A case study showed that disruption of the non-reward 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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    In a reward-related decision making task, 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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Interpretationreasoning

    Several markers (e.g., blunted frontostriatal rsFC and reward-related striatal activation) emerged in unaffected, never-depressed offspring with parental depression and/or predicted the new onset of depressive disorder years later.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Many reward-processing markers correlated with anhedonia, predicted future anhedonia and depressive symptoms, and predated MDD.

    “Of note, many of these markers correlated with anhedonia, predicted future anhedonia and depressive symptoms, and predated MDD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    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.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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]).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156][157][158]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    MDD and vulnerability to depression in youth samples are characterized by hyper-activity in limbic regions implicated in responding to emotional cues (pgACC, amygdala).

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Reduced coupling between the central OFC and dACC might index impaired cognitive control of emotion processing, which could result in negative processing biases.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Asymptomatic offspring of MDD patients showed blunted dlPFC activation and normative amygdalar responses to fearful faces.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Interpretationreasoning

    Area 14 appears to play a fundamental role in regulating appetitive arousal, while area 25 seems to have its effects only when activated.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    MDD and vulnerability to depression in youth samples are characterized by dlPFC hypo-activation to emotional (mostly negative) stimuli.

    “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”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The rodent mPFC and OFC have been implicated in the control of consummatory aspects of reward-related behavior, although their precise contribution remains unclear.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Individuals with MDD are more susceptible to stressor uncontrollability, and this experience affects subsequent interaction with the environment even when control over the stressor is re-established.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Some of these abnormalities precede the onset of MDD, as they are present in never-depressed youth with increased MDD vulnerability.

    “of these abnormalities precede the onset of MDD, since they are present in never-depressed youth with increased MDD vulnerability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    MDD and vulnerability to depression in youth samples are characterized by blunted coupling between PFC regions implicated in cognitive control of emotion (dmPFC) and the amygdala.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Attentional inflexibility induced by excitotoxic lesions of vlPFC may lead to persistent attention to intrinsically salient negative outcomes, causing increased negative bias via loss of top-down attentional control.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [207] Dias R, Robbins TW, Roberts AC. Dissociation in prefrontal cortex of affective and attentional shifts. Nature. 1996;380:69–72. source

  • May combine two claims.

    Interpretationreasoning

    Area 32 is engaged and only contributes to approach-avoidance conflict under particular contexts.

    “altogether suggesting that area 32 is engaged and only contributes to approach-avoidance conflict under particular contexts.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Interventions in PLc, ILc, and OFC can all impact responsivity to acute uncontrollable stress as measured by FST and TST.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Ability to deactivate key DMN nodes (pgACC, dmPFC) during an executive task is essential for symptom reduction; reduced ability may be a marker of increased MDD vulnerability and ruminative style.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Area 32 and area 24 appear directly involved in action-outcome associations, while medial OFC/vmPFC may be more related to valuation.

    “Regions of area 32 and area 24 appear directly involved whilst medial OFC/vmPFC may be more related to the valuation process.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    In MDD samples compared to healthy controls, some functional connections show higher and others lower connectivity.

    “Orange and blue arrows denote higher and lower functional connectivity, respectively, in MDD samples than healthy controls.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Different inputs to PFC regions and different neuromodulators are likely implicated in context-dependent direction of abnormalities.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Anhedonic phenotypes, negative processing biases, and learned helplessness are not independent; reductions in reward sensitivity and loss of subjective control likely induce negative processing biases.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PFC regions have distinct functions and are modulated by distinct neurochemical transmitter systems, receptor subtypes, and cellular/molecular pathways.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Arnsten and Cools

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    MDD involves insufficient cortical regulation, as indicated by reduced cortico-limbic functional connectivity when presented with negative cues.

    “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].”
    Quote in the paperSubstantial claim
108 of 108

  • 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”
6 of 6

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.

  • Opposite directions reported for pgACC activity during reward anticipation

    Major

    The text describes pgACC hyperactivation during reward anticipation in MDD, but Table 1 lists pgACC hypoactivation for the same process. The direction of this central reward-related finding is therefore unclear.

  • Description of unaffected co-twins conflicts with the cited study's title

    Minor

    The review says the reward-signal dysfunctions were absent in unaffected co-twins. The cited study's title explicitly describes reduced responses in those co-twins as well as in remitted twins.

  • Sertraline finding is attributed to a ketamine study

    Minor

    The statement cites reference 194 for an eight-week sertraline result in MDD, whereas that reference is titled as a ketamine study in healthy subjects. The cited treatment and population do not match the stated finding.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Seligman MEP. Depression and learned helplessness. In The psychology of depression: contemporary theory and research. New York: Winston-Wiley; 1974, p. 83–113.

Cited by

Sorted by citations

Related

Authors
Pizzagalli, D. A., & Roberts, A. C.
Affiliations
  • Harvard University (US)
  • University of Cambridge (GB)
Corresponding author
  • Pizzagalli, Diego A.
  • Roberts, Angela C.
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2021-08-02
Volume
47
Issue
1
Pages
225-246
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-021-01101-7
PMC
PMC8617037
OpenAlex
W3189676709
Cited by
644
References
286
Citations by year
2026: 128 · 2025: 191 · 2024: 143 · 2023: 111 · 2022: 42 · 2021: 4
FWCI
34.51
Type
journal article
Language
en
Update notices
correction (2021-08-19)
Open access
Licence
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
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
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Mental Health Research Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
prefrontal cortex, major depressive disorder, anhedonia, learned helplessness, despair-like behavior, neural pathways, depression treatment, depression vulnerability
MeSH terms
Brain, Depression, Depressive Disorder, Major, 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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