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Cited by 217Neural and Behavioral Psychology StudiesTreatment of Major DepressionNeurotransmitter Receptor Influence on Behavior

Localization of Dysfunction in Major Depressive Disorder: Prefrontal Cortex and Amygdala

Open access
Murray, Elisabeth A., Wise, Steven P., Drevets, Wayne C.·2011·Biological Psychiatry
DOI 10.1016/j.biopsych.2010.09.041PMC PMC3058124
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Abstract

Despite considerable effort, the localization of dysfunction in major depressive disorder (MDD) remains poorly understood. We present a hypothesis about its localization that builds on recent findings from primate neuropsychology. The hypothesis has four key components: a deficit in the valuation of "self" underlies the core disorder in MDD; the medial frontal cortex represents "self"; interactions between the amygdala and cortical representations update their valuation; and inefficiency in using positive feedback by orbital prefrontal cortex contributes to MDD.

AI snapshot

Written from the paper’s full text.

TL;DR

The paper proposes that major depressive disorder involves dysfunction in medial and orbital frontal cortex and their interactions with the amygdala, especially in valuing the self, objects, rules, and actions. It argues that inefficient use of positive feedback by orbital prefrontal cortex, together with altered amygdala updating, can produce negative bias and low self-esteem.

Key findings

  • The authors advance a four-part hypothesis: impaired valuation of the self is central to MDD; medial frontal cortex carries a self representation; amygdala–cortical interactions update valuations; and orbital prefrontal cortex contributes through inefficient use of positive feedback.
  • Human evidence cited implicates medial and orbital frontal cortex plus amygdala: altered activation during emotional and reward tasks, frontal lesions in depression after cerebrovascular disease, altered metabolism in depressed Parkinson’s patients, and volume/thickness reductions in PFo area 11, sulcal area 47, and subgenual cortex (areas 24, 32, 25). Subgenual volume reduction is reported before symptom onset in high familial risk, early in illness, persistent across episodes, and most consistent in severe cases.
  • In macaque devaluation tasks, bilateral amygdala lesions, bilateral PFo lesions, or crossed amygdala–PFo disconnection attenuate the devaluation effect, while lesions of ventral/dorsolateral prefrontal cortex, entorhinal cortex, perirhinal cortex, or hippocampus do not. In serial object reversal, PFo lesions slow learning, amygdala lesions do not; trial-by-trial analysis shows PFo lesions impair use of positive feedback, whereas amygdala lesions improve performance one trial after an error followed by a correct response. Buckley et al. reported EC+1 accuracy falling from 77% preoperatively to 50% after PFo lesions.
  • Treatment-related findings include increased activation in medial/orbital frontal and temporal/amygdala regions during depression versus remission; sertraline restored a normal happy-face bias and PFo activation to happy faces in a 26 ms masked-face paradigm. Deep brain stimulation is noted to improve about one-half of cases and produce remission in about one-third.

Methods

  • This is a theoretical review and hypothesis paper, not a primary empirical study; it synthesizes human clinical and neuroimaging findings with nonhuman primate neuropsychology, lesion, and physiology research.
  • The main analysis is a narrative integration of evidence from devaluation tasks, serial object-reversal learning, probabilistic learning, Pavlovian conditioning, and self-representation studies.
  • Cited data include MDD patients, healthy controls, remitted patients, patients with Parkinson’s or cerebrovascular disease, and nonhuman primates including macaques and marmosets, with some rodent findings.

Limitations

  • The paper states that animal conditioning tasks are blunt tools for human conscious emotion; that rodent frontal cortex is not homologous to primate granular prefrontal cortex; that cause versus effect in MDD remains unclear; that some arguments, such as the aversive analogue prediction, are indirect; and that gray matter reductions can produce partial volume effects that complicate activation–severity relationships.
  • Evident from the text: as a review/hypothesis, it does not directly test the proposed mechanism, relies heavily on cross-species inference, and draws on separate studies with varied methods rather than a systematic meta-analysis.

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

Integrity signals

Registry

Crossref · 10.1016/j.biopsych.2010.09.041

Cites

136 of 136 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 185 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    MDD patients have deficits in verbal memory.

    “and deficits in verbal memory (33).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] MacQueen, 2002, Recollection memory deficits in patients with major depressive disorder predicted by past depressions but not current mood state or treatment status, Psychol Med source

      Not checked in the free run.

  • Premisecitation

    MDD patients show altered attentional set-shifting after negative (sad) stimuli.

    “altered attentional set-shifting after the presentation of negative (sad) stimuli (30–32);”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Mogg, 2006, Interpretation of ambiguous information in clinical depression, Behav Res Ther source

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    • cites [31] Erickson, 2005, Mood-congruent bias in affective go/no-go performance of unmedicated patients with major depressive disorder, Am J Psychiatry source

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    • cites [32] Gotlib, 2004, Attentional biases for negative interpersonal stimuli in clinical depression, J Abnorm Psychol source

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  • Premisecitation

    When cognitively challenged, depressed patients show less change in heart-rate variability than controls in response to mildly stressful tasks.

    “When cognitively challenged, depressed patients show less change than controls in heart-rate variability (HRV) in response to mildly stressful tasks (37, 38).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Shinba, 2008, Decrease in heart rate variability response to task is related to anxiety and depressiveness in normal subjects, Psychiatry Clin Neurosci source

      Not checked in the free run.

    • cites [38] Nugent AC, Bain EE, Thayer JF, Sollers J, Drevets WC (in press): Heart rate variability during motor and cognitive tasks in female subjects with and without major depressive disorder. Psychiatry Res Neuroimaging.

      Not checked in the free run.

  • Premisecitation

    MDD is characterized by visceral, neuroendocrine, and autonomic disturbances that often lead to altered weight, appetite, and sleep.

    “Visceral, neuroendocrine, and autonomic disturbances also characterize MDD, and they often lead to altered weight, appetite, and sleep (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Gold, 2002, New insights into the role of cortisol and the glucocorticoid receptor in severe depression, Biol Psychiatry source

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  • Premisecitation

    MDD patients show mood-dependent deficits in integrating sensory and social information.

    “mood-dependent deficits in the integration of sensory and social information (25–28);”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [25] Gotlib, 2004, Coherence and specificity of information-processing biases in depression and social phobia, J Abnorm Psychol source

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    • cites [26] Murphy, 1999, Emotional bias and inhibitory control processes in mania and depression, Psychol Med source

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    • cites [27] Bhagwagar, 2004, Normalization of enhanced fear recognition by acute SSRI treatment in subjects with a previous history of depression, Am J Psychiatry source

      Not checked in the free run.

    • cites [28] Victor TA, Furey ML, Fromm SJ, Ohman A, Drevets WC (in press): Relationship of emotional processing to masked faces in the amgydala to mood state and treatment in major depressive disorder. Arch Gen Psychiatry.

      Not checked in the free run.

  • May combine two claims. 45
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation

    MDD patients show altered incentive and reward processing, which leads to reduced motivation including abulia, apathy, and anhedonia.

    “MDD patients show altered incentive and reward processing, leading to a lack of motivation, including abulia, as well as apathy and anhedonia (18, 19).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Nestler, 2006, The mesolimbic dopamine reward circuit in depression, Biol Psychiatry source

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    • cites [19] Hasler, 2004, Discovering endophenotypes for major depression, Neuropsychopharmacology source

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    Premisecitation

    MDD is associated with abnormally elevated sympathetic function and reduced parasympathetic tone on heart rate under resting conditions.

    “Several studies have reported evidence for abnormally elevated sympathetic function in MDD, coupled with reduced parasympathetic tone on heart rate under resting conditions (35, 36).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Carney, 2005, Depression, the autonomic nervous system, and coronary heart disease, Psychosom Med source

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    • cites [36] Udupa, 2007, Modulation of cardiac autonomic functions in patients with major depression treated with repetitive transcranial magnetic stimulation, J Affect Disord source

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  • May combine two claims.

    Premisecitation

    MDD patients have markedly lowered self-esteem and ruminate on aversive life events, hopelessness, and helplessness.

    “These patients manifest markedly lowered self-esteem and ruminate endlessly on the aversive aspects of events in their lives, their hopelessness about a better future, and their helplessness to do anything about it (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] 1994

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  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based).

    Interpretationnone given

    The amygdala updates the valuation of representations in the medial and orbital frontal cortex, including a representation of self.

    “According to our hypothesis, the amygdala updates the valuation of representations in the medial and orbital frontal cortex, among which is a representation of ‘self’.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The cited findings implicate both granular and agranular parts of frontal cortex, as well as both medial and orbital networks, in MDD.

    “Taken together, the findings cited so far implicate both granular and agranular parts of frontal cortex, as well as both its medial and orbital networks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    MDD patients show a bias toward negative emotions, with excessive amygdala activation for negative stimuli and blunted activation for positive ones.

    “These patients thus seem to show a bias toward negative emotions, with excessive amygdala activation for negative stimuli and blunted activation for positive ones.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In key MFa regions, cortical volume reduction occurs before symptom onset in high familial risk subjects, appears early in illness, persists across depressive episodes, and is consistent in severe cases.

    “In these key parts of the MFa, the reduction in cortical volume arises prior to the onset of symptoms in subjects at high familial risk for depression, appears early in the course of the illness, persists across depressive episodes, and occurs consistently in the most severe cases (48, 49, 51–53).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [48] Coryell, 2005, Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: Diagnostic specificity and prognostic implications, Am J Psychiatry source

      Not checked in the free run.

    • cites [49] Hirayasu, 1999, Subgenual cingulate cortex volume in first-episode psychosis, Am J Psychiatry source

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    • cites [51] Botteron, 2002, Volumetric reduction in left subgenual prefrontal cortex in early onset depression, Biol Psychiatry source

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    • cites [52] Boes, 2008, Rostral anterior cingulate cortex volume correlates with depressed mood in normal healthy children, Biol Psychiatry source

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    • cites [53] McDonald, 2004, Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes, Arch Gen Psychiatry source

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  • May combine two claims.

    Interpretationreasoning

    Several findings implicate orbital frontal cortex, medial frontal cortex, and amygdala in MDD, and several correlates exist with its affective and autonomic symptoms.

    “Thus, several findings implicate the orbital frontal cortex, the medial frontal cortex, and the amygdala in MDD. And several correlates have been found with its affective and autonomic symptoms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In both MDD patients and healthy controls, HRV regulation correlates with activation in ventromedial area 10p (part of PFm), but the sign of the correlation differs between groups.

    “In both MDD patients and healthy controls, HRV regulation correlated with activation levels in the ventromedial part of area 10p (a part of PFm), but the sign of the correlation differed between the groups.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Nugent AC, Bain EE, Thayer JF, Sollers J, Drevets WC (in press): Heart rate variability during motor and cognitive tasks in female subjects with and without major depressive disorder. Psychiatry Res Neuroimaging.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Depressed patients show reductions in cortical volume and thickness in several frontal cortex regions, most reliably in PFo area 11, sulcal area 47, and subgenual frontal cortex.

    “Furthermore, reductions of cortical volume and thickness occur in several parts of the frontal cortex in depressed patients, with the most reliable and best characterized of these abnormalities occurring in PFo area 11 (44), the sulcal part of area 47 (45, 46), and the subgenual frontal cortex (47–50).”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [44] Rajkowska, 1997, Morphometric methods for studying the prefrontal cortex in suicide victims and psychiatric patients, Ann N Y Acad Sci source

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    • cites [45] Nugent, 2006, Cortical abnormalities in bipolar disorder investigated with MRI and voxel-based morphometry, Neuroimage source

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    • cites [46] Lyoo, 2004, Frontal lobe gray matter density decreases in bipolar I disorder, Biol Psychiatry source

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    • cites [47] Drevets, 1997, Subgenual prefrontal cortex abnormalities in mood disorders, Nature source

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    • cites [48] Coryell, 2005, Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: Diagnostic specificity and prognostic implications, Am J Psychiatry source

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    • cites [49] Hirayasu, 1999, Subgenual cingulate cortex volume in first-episode psychosis, Am J Psychiatry source

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    • cites [50] Koo, 2008, A cross-sectional and longitudinal magnetic resonance imaging study of cingulate gyrus gray matter volume abnormalities in first-episode schizophrenia and first-episode affective psychosis, Arch Gen Psychiatry source

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

    Interpretationreasoning

    The representation of self is an emergent property arising from interaction of MFa and OFa with PFm and PFo, and was further modified during human evolution.

    “A corollary of that hypothesis is that the representation of self is an emergent property arising from the interaction of the phylogenetically older areas of frontal cortex, MFa and OFa, with those that evolved in advanced primates, PFm and PFo, and underwent further modification during human evolution.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Electrical stimulation of the amygdala can produce fear, anxiety, dysphoria, sympathetic autonomic arousal, social withdrawal, and cortisol release.

    “Electrical stimulation of the amygdala can produce fear, anxiety, dysphoria, sympathetic autonomic arousal, social withdrawal, and cortisol release (61, 62).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Gloor, 1969, Electrophysiological studies of amygdalo-hypothalamic connections, Ann N Y Acad Sci source

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    • cites [62] Rubin, 1966, Corticosteroid responses to limbic stimulation in man: Localization of stimulus sites, Science source

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  • May combine two claims.

    Interpretationreasoning

    The devaluation effect does not depend on learning about the objects and the now-devalued food; updating of valuations occurs automatically and monkeys predict the food's value before choosing.

    “As a result, the devaluation effect does not depend on learning about the objects and the now-devalued food. Instead, the updating of valuations occurs automatically; the monkeys predict the value of the food before they make a choice between the two objects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cerebrovascular disease patients who develop depression have lesions in orbital and medial frontal cortex, whereas cerebrovascular patients without depression do not.

    “Patients with cerebrovascular disease who develop depression have lesions in the orbital and medial frontal cortex, but other cerebrovascular patients—those without depression—do not (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] MacFall, 2001, Medial orbital frontal lesions in late-onset depression, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The amygdala updates the value of food as monkeys consume it, and this change in value is registered elsewhere in the brain, presumably including but not restricted to PFo.

    “Thus, the amygdala updates the value of the food as monkeys consume it, and this change in value is registered elsewhere in the brain, presumably including but not restricted to PFo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Trial-by-trial analysis indicates both PFo and amygdala lesions influence the use of positive feedback, in opposite directions.

    “A more detailed, trial-by-trial analysis indicates that both PFo and amygdala lesions influence the use of positive feedback. As Figure 4B shows, however, they do so in opposite directions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Rudebeck, 2008, Amygdala and orbitofrontal cortex lesions differentially influence choices during object reversal learning, J Neurosci source

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    Premisecitation

    Preoperatively monkeys scored 77% correct on the EC+1 trial type; postoperatively monkeys with PFo lesions scored only 50% correct.

    “Whereas preoperatively their monkeys scored 77% correct on the EC+1 trial type, postoperatively the monkeys with PFo lesions scored only 50% correct.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Buckley, 2009, Dissociable components of rule-guided behavior depend on distinct medial and prefrontal regions, Science source

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  • May combine two claims.

    Interpretationcitation

    The PFo lesion group was inefficient in using positive feedback after rule changes, suggesting PFo plays an important role in valuation of rule representations as well as object representations.

    “Like the monkeys studied by Rudebeck and Murray (91), the PFo lesion group studied by Buckley et al. was inefficient in using positive feedback after rule changes, suggesting that PFo plays an important role in the valuation of rule representations as well as object representations.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] Rudebeck, 2008, Amygdala and orbitofrontal cortex lesions differentially influence choices during object reversal learning, J Neurosci source

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    • cites [95] Buckley, 2009, Dissociable components of rule-guided behavior depend on distinct medial and prefrontal regions, Science source

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  • May combine two claims.

    Premisecitation

    Monkeys with bilateral PFo ablations or crossed disconnection of the amygdala and PFo show markedly attenuated devaluation effect.

    “Some monkeys received bilateral PFo ablations (blue) and others received a crossed surgical disconnection (green) of the amygdala and PFo (a unilateral amygdala lesion in one hemisphere along with unilateral PFo lesion in the other hemisphere, combined with section of the forebrain commissures). In all lesion groups, the devaluation effect was markedly attenuated.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Malkova, 1997, Excitotoxic lesions of the amygdala fail to produce impairment in visual learning for auditory secondary reinforcement but interfere with reinforcer devaluation effects in rhesus monkeys, J Neurosci source

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    • cites [75] Izquierdo, 2007, Selective bilateral amygdala lesions in rhesus monkeys fail to disrupt object reversal learning, J Neurosci source

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  • May combine two claims.

    Interpretationreasoning

    Monkeys with these lesions could not update valuations based on current biological needs and use those updated valuations to make adaptive choices.

    “Instead, results from this test show that the monkeys could not update valuations based on current biological needs and use those updated valuations to make adaptive choices.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    With more consecutive correct choices, the amygdala lesion effect disappears, perhaps because scores approach the maximum.

    “(With more consecutive correct choices, this effect disappears, perhaps because the scores approach the maximum.)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premiseown data

    The same operated monkeys showed little or no change in food preferences and worked for food like control monkeys.

    “The same groups of operated monkeys showed little or no change in food preferences and worked for food like control monkeys.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Malkova, 1997, Excitotoxic lesions of the amygdala fail to produce impairment in visual learning for auditory secondary reinforcement but interfere with reinforcer devaluation effects in rhesus monkeys, J Neurosci source

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    • cites [75] Izquierdo, 2007, Selective bilateral amygdala lesions in rhesus monkeys fail to disrupt object reversal learning, J Neurosci source

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  • May combine two claims.

    Interpretationreasoning

    Monkeys do not need to experience receiving the food in its devalued state; updating occurs automatically and monkeys predict the food's value before choice.

    “Importantly, monkeys do not need to experience receiving the food in its devalued state. This updating occurs automatically, and the monkeys predict the food’s value before they make a choice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    PFo contributes to updating valuations in two ways: registering changes in outcome value via interaction with the amygdala, and registering changes in object-reward mappings.

    “Taken together with the results from the devaluation task, these results show that PFo contributes to updating valuations in two ways: (1) by registering the changes in outcome value as they occur, a function mediated via interaction with the amygdala, and (2) by registering changes in object-reward mappings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    PFo lesions cause a deficit in using positive feedback, but not in the use of negative feedback.

    “These findings indicate that PFo lesions cause a deficit in using positive feedback, but not in the use of negative feedback (91, but cf. 94).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] Rudebeck, 2008, Amygdala and orbitofrontal cortex lesions differentially influence choices during object reversal learning, J Neurosci source

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    • cites [94] Clarke, 2008, Lesions of the medial striatum in monkeys produce perseverative impairments during reversal learning similar to those produced by lesions of the orbitofrontal cortex, J Neurosci source

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    Interpretationcitation

    Amygdala activity is critical during selective satiation while food value changes, but not after the updating process has run its course.

    “This finding indicates that amygdala activity is critical during the selective satiation procedure, while the food value changes, but not after the updating process has run its course.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    Medial frontal areas play a key role in linking actions with outcomes, in parallel with object or rule representation linking with outcomes.

    “Several lines of evidence point to medial frontal areas as playing a key role in linking actions with outcomes, in parallel with the results just mentioned on linking object or rule representation with outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Perseveration occurs to a small extent but is a minor aspect of the PFo syndrome.

    “Perseveration occurs to a small extent, but it appears to be a minor aspect of the “PFo syndrome”.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    After viewing a videotape of their interview, patients with PFo or OFa damage downgraded their behavior based on social embarrassment but did not change ratings of nonsocial factors.

    “After watching a videotape of their own interview, they changed their assessment. The patients then downgraded their behavior, based on how socially embarrassing their behavior had been, but they did not change their ratings of other (nonsocial) factors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Beer, 2006, Orbitofrontal cortex and social behavior: Integrating self-monitoring and emotion-cognition interactions, J Cogn Neurosci source

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  • May combine two claims.

    Interpretationcitation

    Updating of object-outcome and rule-outcome mappings needs to occur to make good choices in serial object-reversal and to optimize reward probability.

    “This updating needs to occur in order to make good choices in the serial object-reversal task (91) and when making object choices that optimize the probability of reward (90).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] Rudebeck, 2008, Amygdala and orbitofrontal cortex lesions differentially influence choices during object reversal learning, J Neurosci source

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    • cites [90] Rudebeck, 2008, Frontal cortex subregions play distinct roles in choices between actions and stimuli, J Neurosci source

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  • May combine two claims.

    Premisecitation

    PFo lesions produce a deficit in stimulus-based, but not action-based learning, whereas anterior cingulate cortex lesions have the opposite effect.

    “They found that PFo lesions produced a deficit in stimulus-based, but not action-based learning, whereas anterior cingulate cortex lesions had the opposite effect.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Rudebeck, 2008, Frontal cortex subregions play distinct roles in choices between actions and stimuli, J Neurosci source

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  • May combine two claims.

    Interpretationreasoning

    PFo and OFa contribute to valuations of self, or at least of one's own actions.

    “These findings support the idea that PFo and OFa contribute to valuations of ‘self’, or at least of one’s own actions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In humans, anterior cingulate cortex activation is related to learning action-outcome associations but not stimulus-outcome associations.

    “Neuroimaging studies in humans confirm that activations in anterior cingulate cortex are related to the learning of action-outcome associations, but not to learning stimulus-outcome associations (100).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Glascher, 2009, Determining a role for ventromedial prefrontal cortex in encoding action-based value signals during reward-related decision making, Cereb Cortex source

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  • May combine two claims.

    Premisecitation

    MFa shows activation when people consider personality characteristics about themselves or receive social feedback about themselves from others.

    “MFa shows activation when people consider personality characteristics about themselves or receive social feedback about themselves from others (104, 105).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [104] Somerville, 2010, Self-esteem modulates medial prefrontal cortical responses to evaluative social feedback, Cereb Cortex source

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    • cites [105] Moran, 2006, Neuroanatomical evidence for distinct cognitive and affective components of self, J Cogn Neurosci source

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  • Classified as probably not a substantial claim.

    Premisecitation

    When an aversive event becomes linked to a context, that context serves as a constant reminder of the US, putting the subject in a sustained state of fearful apprehension.

    “When an aversive event becomes linked to a context, that context serves as a constant reminder of the US, putting the subject in “a sustained state of fearful apprehension” (118).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Davis, 2010, Phasic vs sustained fear in rats and humans: Role of the extended amygdala in fear vs anxiety, Neuropsychopharmacology source

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    Premisecitation

    In the absence of immediate reward, MDD patients were impaired at integrating reinforcement history over time and expressing a response bias toward a more frequently rewarded cue.

    “In the absence of immediate reward, i.e., when they needed to predict an outcome, MDD patients were impaired at integrating reinforcement history over time and in expressing a response bias toward a more frequently rewarded cue.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pizzagalli et al. (22) Pizzagalli, 2008, Reduced hedonic capacity in major depressive disorder: Evidence from a probabilistic reward task, J Psychiatr Res source

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  • May combine two claims.

    Premisecitation

    Activation decreases in these regions during both antidepressant treatment and deep brain stimulation of the subgenual MFa or anterior capsule.

    “Activation decreases in these regions during both antidepressant treatment and deep brain stimulation of the subgenual MFa or the anterior capsule (4, 126–128).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [4] Mayberg, 2005, Deep brain stimulation for treatment-resistant depression, Neuron source

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    • cites [126] Mayberg, 1999, Reciprocal limbic-cortical function and negative mood: Converging PET findings in depression and normal sadness, Am J Psychiatry source

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    • cites [127] Drevets, 2002, Glucose metabolism in the amygdala in depression: Relationship to diagnostic subtype and plasma cortisol levels, Pharmacol Biochem Behav source

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    • cites [128] Van Laere, 2006, Metabolic imaging of anterior capsular stimulation in refractory obsessive-compulsive disorder: A key role for the subgenual anterior cingulate and ventral striatum, J Nucl Med

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  • May combine two claims.

    Premisecitation

    Healthy controls showed greater amygdala activation and faster behavioral responses to happy faces compared to sad or neutral faces in a backward masking paradigm.

    “Healthy controls showed greater amygdala activation and faster behavioral responses to happy faces, compared to sad or neutral faces.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Victor et al. (28) Victor TA, Furey ML, Fromm SJ, Ohman A, Drevets WC (in press): Relationship of emotional processing to masked faces in the amgydala to mood state and treatment in major depressive disorder. Arch Gen Psychiatry.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This exaggerated affective response in depressed subjects is associated with attenuation of normal activation of ventral PF cortex areas 12/47 and 45 and failure of normal deactivation of the amygdala during the task.

    “This effect is associated with an attenuation of the normal activation of ventral PF cortex (areas 12/47 and 45) and a failure of the normal deactivation of the amygdala as they perform this task (117).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Taylor Tavares, 2008, Neural basis of abnormal response to negative feedback in unmedicated mood disorders, Neuroimage source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both depressed and remitted MDD patients, when off medication, showed greater amygdala activation and faster behavioral responses to sad faces compared to happy faces.

    “both depressed and remitted MDD patients—when off medication—showed greater amygdala activation and faster behavioral responses to sad faces, compared to happy faces.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Victor et al. (28) Victor TA, Furey ML, Fromm SJ, Ohman A, Drevets WC (in press): Relationship of emotional processing to masked faces in the amgydala to mood state and treatment in major depressive disorder. Arch Gen Psychiatry.

      Not checked in the free run.

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

    Interpretationnone given

    In monkeys, valuations involve objects, rules, or actions, whereas humans additionally have a representation of self.

    “In monkeys, these valuations involve either objects, rules, or actions, but humans have in addition a representation of self.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings from nonhuman primates about frontal-amygdala function can be extended to humans and to MDD.

  • May combine two claims.

    Interpretationreasoning

    PFo lesions lead to an abnormally persistent autonomic and emotional response when an emotional event fails to materialize, and CSs become more associable.

    “PFo lesions lead to an abnormally persistent autonomic and emotional response and CSs become more associable.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Negative affective responses would be affected by PFo and amygdala lesions in the same way as positive affective responses.

  • May combine two claims.

    Premisecitation

    GAD and other anxiety disorders are frequent antecedents of MDD and increase the risk of developing secondary major depressive episodes.

    “GAD and other anxiety disorders are frequent antecedents of MDD and increase the risk of developing “secondary” major depressive episodes (119).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Wittchen, 2000, Why do people with anxiety disorders become depressed?, Acta Psychiatr Scand Suppl source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During successful treatment, MDD patients exhibited normal bias toward happy faces, and this behavioral improvement correlated with PFo neuroimaging; before treatment PFo showed no activation to happy faces, whereas during successful treatment robust activation occurred.

    “During successful treatment, MDD patients exhibited the normal bias toward happy faces, and this behavioral improvement correlated with neuroimaging results from PFo; before treatment, PFo showed no activation in response to happy faces, whereas during successful treatment a robust activation occurred in response to such stimuli.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Victor et al. (28) Victor TA, Furey ML, Fromm SJ, Ohman A, Drevets WC (in press): Relationship of emotional processing to masked faces in the amgydala to mood state and treatment in major depressive disorder. Arch Gen Psychiatry.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Corticostriatal projections from agranular areas target the nucleus accumbens, and those from granular prefrontal areas terminate in the caudate nucleus.

    “Corticostriatal projections from the agranular areas target the nucleus accumbens, and those from the granular prefrontal areas terminate in the caudate nucleus.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Haber, 2003, The primate basal ganglia: Parallel and integrative networks, J Chem Neuroanat source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metabolic activation appears elevated in depressed samples of mild-to-moderate severity but reduced in more severe, treatment-refractory cases.

    “metabolic activation appears elevated in depressed samples of mild-to-moderate severity, but reduced in more severe, treatment-refractory cases (1, 121)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Drevets, 1992, A functional anatomical study of unipolar depression, J Neurosci source

      Not checked in the free run.

    • cites [121] Ketter, 2001, Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder, Biol Psychiatry source

      Not checked in the free run.

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

    Premisenone given

    Neuroimaging and clinical studies have repeatedly implicated PFo, PFm, OFa, MFa, and the amygdala in MDD.

    “neuroimaging and clinical studies have repeatedly implicated PFo, PFm, OFa, MFa, and the amygdala in MDD.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Studies of nonhuman primates have pointed to homologues of these brain structures as fundamental to affective responses and processing reward feedback.

    “studies of nonhuman primates have pointed to the homologues of these brain structures as fundamental to affective responses and processing reward feedback.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Depressed individuals fail to sustain nucleus accumbens activation over time compared with controls, correlating with individual differences in self-reported positive affect.

    “depressed individuals fail to sustain nucleus accumbens activation over time compared with controls, which correlates with individual differences in self-reported positive affect (133).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Heller, 2009, Reduced capacity to sustain positive emotion in major depression reflects diminished maintenance of fronto-striatal brain activation, Proc Natl Acad Sci U S A source

      Not checked in the free run.

49 of 49

  • The paper relies on this without support.

    The neural mechanisms revealed by macaque devaluation and reversal tasks are relevant to the pathophysiology of major depressive disorder in humans.

    “Despite this limitation, recent advances in primate neuropsychology can contribute to understanding MDD, and the largest part of this article considers some of these findings.”
    “In the next two sections, we explore recent neuropsychological results from nonhuman primates in order to gain insight into this problem.”

  • The paper relies on this without support.

    PFo receives relatively direct inputs from olfactory, gustatory, and visceral receptors via OFa.

    “PFo also receives relatively direct inputs from olfactory, gustatory and visceral receptors via the OFa (which includes the agranular insular cortex).”

  • The authors state this as an assumption.

    Negative affective responses would be affected by PFo and amygdala lesions in the same way as positive affective responses.

    “We will assume, however, that negative affective responses would be similarly affected by PFo and amygdala lesions.”

  • The paper relies on this without support.

    Findings from nonhuman primates about frontal-amygdala function can be extended to humans and to MDD.

    “using insights gained mainly from the study of nonhuman primates, we suggest how dysfunction in amygdala–frontal interactions could produce certain key symptoms of MDD.”

  • The paper relies on this without support.

    The same valuation mechanisms that operate on object, rule, and action representations in nonhuman primates also operate on the representation of self in humans.

    “Understanding how the frontal lobe functions in the valuation of object-, rule-, and action representations in nonhuman primates will illuminate how homologous areas function in the valuation of self in humans.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

3 of the 139 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Drevets, 1997, Subgenual prefrontal cortex abnormalities in mood disorders, Nature, 386, 824, 10.1038/386824a0 · DOI · Paper page
  2. Martin-Soelch, 2006, Dysfunctional learning and neurophysiological activation during appetitive and aversive conditioning in major depression: An fMRI study, Neuroimage

Cited by

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Related

Authors
Murray, E. A., Wise, S. P., & Drevets, W. C.
Affiliations
  • National Institutes of Health (US)
  • Laureate Institute for Brain Research (US)
Corresponding author
Murray, Elisabeth A.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2011-06
Volume
69
Issue
12
Pages
e43-e54
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2010.09.041
PMC
PMC3058124
OpenAlex
W2078617766
Cited by
208
References
139
Citations by year
2026: 7 · 2025: 6 · 2024: 11 · 2023: 10 · 2022: 13 · 2021: 13 · 2020: 15 · 2019: 16 · 2018: 12 · 2017: 12 · 2016: 21 · 2015: 16 · 2014: 13 · 2013: 22 · 2012: 15
FWCI
0.98
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Mental Health (ZIAMH002886, ZIAMH002887)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
major depressive disorder, prefrontal cortex, amygdala, self-representation, self-valuation, medial frontal cortex, orbitofrontal cortex, positive feedback
MeSH terms
Amygdala, Animals, Choice Behavior, Major Depressive Disorder, Ego, Emotions, Frontal Lobe, Humans, Psychomotor Performance, Reversal Learning, Self Concept, Prefrontal Cortex

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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.

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