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Cited by 103Treatment of Major DepressionNeural and Behavioral Psychology StudiesNeurotransmitter Receptor Influence on Behavior

Neural Correlates of Three Promising Endophenotypes of Depression: Evidence from the EMBARC Study

Open access
Webb, Christian A, Dillon, Daniel G, Pechtel, Pia, Goer, Franziska K, Murray, Laura, Huys, Quentin JM, Fava, Maurizio, McGrath, Patrick J +13 more·2016·Neuropsychopharmacology
DOI 10.1038/npp.2015.165PMC PMC5130121
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Abstract

Major depressive disorder (MDD) is clinically, and likely pathophysiologically, heterogeneous. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes. Guided by the NIMH Research Domain Criteria initiative, we used source localization of scalp-recorded EEG resting data to examine the neural correlates of three emerging endophenotypes of depression: neuroticism, blunted reward learning, and cognitive control deficits. Data were drawn from the ongoing multi-site EMBARC study. We estimated intracranial current density for standard EEG frequency bands in 82 unmedicated adults with MDD, using Low-Resolution Brain Electromagnetic Tomography. Region-of-interest and whole-brain analyses tested associations between resting state EEG current density and endophenotypes of interest. Neuroticism was associated with increased resting gamma (36.5-44 Hz) current density in the ventral (subgenual) anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC). In contrast, reduced cognitive control correlated with decreased gamma activity in the left dorsolateral prefrontal cortex (dlPFC), decreased theta (6.5-8 Hz) and alpha2 (10.5-12 Hz) activity in the dorsal ACC, and increased alpha2 activity in the right dlPFC. Finally, blunted reward learning correlated with lower OFC and left dlPFC gamma activity. Computational modeling of trial-by-trial reinforcement learning further indicated that lower OFC gamma activity was linked to reduced reward sensitivity. Three putative endophenotypes of depression were found to have partially dissociable resting intracranial EEG correlates, reflecting different underlying neural dysfunctions. Overall, these findings highlight the need to parse the heterogeneity of MDD by focusing on promising endophenotypes linked to specific pathophysiological abnormalities.

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Written from the paper’s full text.

TL;DR

In 82 unmedicated adults with MDD from the EMBARC study, three candidate depression endophenotypes—neuroticism, blunted reward learning, and cognitive control deficits—showed partially dissociable resting EEG/LORETA correlates, mostly in the gamma band. Neuroticism related to ventral ACC/OFC gamma, reward learning to OFC/left dlPFC gamma, and cognitive control to left dlPFC and dACC activity across gamma/theta/alpha2 bands.

Key findings

  • Neuroticism was associated with increased resting gamma (36.5–44 Hz) current density in subgenual ACC (β=0.31, p=0.018) and OFC; dACC gamma was not significant (β=−0.01, p=0.965), and rACC showed a trend (β=0.24, p=0.054).
  • Blunted reward learning correlated with lower OFC gamma (β=0.33, p=0.004) and left dlPFC gamma (β=0.34, p=0.002), but not right dlPFC or dACC. Computational modeling showed OFC gamma positively predicted reward sensitivity (β=0.27, p=0.043), not learning rate.
  • Cognitive control: Flanker interference accuracy effect was negatively predicted by left dlPFC gamma (β=−0.31, p=0.009); interference RT effects were negatively predicted by left dlPFC gamma (β=−0.23, p=0.045), theta dACC (β=−0.33, p=0.019), and alpha2 dACC (β=−0.31, p=0.020), and positively by alpha2 right dlPFC (β=0.51, p=0.012).
  • Whole-brain analyses found 36 voxels in bilateral OFC/sgACC for neuroticism (mean r=0.27), 51 voxels in left dlPFC/OFC for reward learning (mean r=0.38), and 4 voxels in left dlPFC for Flanker accuracy (mean r=−0.38). A three-cluster solution differentiated endophenotype profiles without significant HRSD differences (F(2,78)=1.32, p=0.27).

Methods

  • Baseline data from the multi-site EMBARC study; 82 unmedicated adults with current MDD (aged 18–65, DSM-IV MDD, QIDS ≥14, medication-free >3 weeks) who passed quality control for Flanker and PRT and had NEO scores.
  • Measures included NEO-FFI-3 neuroticism, Probabilistic Reward Task reward learning, Eriksen Flanker cognitive control, HRSD depression severity, and 8 min resting EEG. LORETA estimated intracranial current density for theta (6.5–8 Hz), alpha1 (8.5–10 Hz), alpha2 (10.5–12 Hz), and gamma (36.5–44 Hz).
  • ROI multiple regressions with site covariate tested associations with ACC, OFC, and dlPFC regions; specificity analyses controlled for HRSD and other endophenotypes. Whole-brain FSL Randomise used 5000 permutations, p<0.05 FWE-corrected. Reinforcement-learning models extracted reward sensitivity and learning rate; two-step cluster analysis derived subgroups.

Limitations

  • Stated: EEG source localization cannot adequately probe subcortical structures such as amygdala or caudate; findings were primarily in the gamma band, and higher-band current density may be contaminated by muscle/EMG artifacts, though the authors argue this is unlikely given specificity. Nicotine dependence was not exclusionary and may confound cognitive/reward function.
  • Evident: the study is cross-sectional baseline data from an ongoing treatment trial with the blind unbroken, so causal or treatment-response inferences are not supported. The cluster analysis is exploratory, and several ROI findings—especially theta/alpha2 effects—were not confirmed in whole-brain analyses and require replication.

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Registry

Crossref · 10.1038/npp.2015.165

Cites

93 of 93 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 57 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Results

    Greater gamma activity in the OFC predicts reward learning.

    “Greater gamma activity in the OFC (β=0.33, p=0.004) and left dlPFC (β=0.34, p=0.002)—but not right dlPFC (β=−0.11, p=0.358) or dACC (β=−0.05, p=0.682)—predicted reward learning (Figure 1b and c).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    Gamma activity in dACC does not predict neuroticism.

    “In contrast, gamma activity in dACC did not predict neuroticism (β=−0.01, p=0.965).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Results

    The correlations between reward learning and gamma activity in the left and right dlPFC were significantly different.

    “Importantly, the correlations between reward learning and gamma activity in the left (r=0.31, p=0.005) and right dlPFC (r=−0.04, p=0.711) were significantly different (z=2.36, p=0.018; Meng et al, 1992).”
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    • cites Meng et al, 1992 source

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  • Findingown data
    § Results

    dACC gamma activity does not predict reward learning.

    “Greater gamma activity in the OFC (β=0.33, p=0.004) and left dlPFC (β=0.34, p=0.002)—but not right dlPFC (β=−0.11, p=0.358) or dACC (β=−0.05, p=0.682)—predicted reward learning (Figure 1b and c).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Results

    Neuroticism is associated with increased resting gamma current density in the subgenual ACC.

    “As expected, when controlling for dACC, gamma activity in sgACC was associated with neuroticism (β=0.31, p=0.018; Figure 1a).”
    Quote in the paperSubstantial claim
  • May combine two claims. 13
  • Classified as probably not a substantial claim. 33

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    Findingown data
    § Results

    The relationships for interference RT were confirmed when accounting for current depressive symptoms, with the exception of gamma activity in the left dlPFC.

    “The above relationships were confirmed when accounting for (1) current depressive symptoms (theta dACC: β=−0.34, p=0.018; alpha2 dACC: β=−0.34, p=0.012; alpha2 right dlPFC: β=0.58, p=0.005), with the exception of gamma activity in the left dlPFC (β=−0.22, p=0.054), and (2) neuroticism and reward learning (theta dACC: β=−0.32; gamma left dlPFC: β=−0.32; alpha2 right dlPFC: β=0.58; alpha2 dACC: β=−0”
    Quote in the paperNot a substantial claim

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    Findingown data
    § Discussion

    Reduced left dlPFC gamma correlated with lower accuracy for incongruent trials (r=0.35, p=0.001), but not congruent trials (r=0.08, p=0.440).

    “reduced left dlPFC gamma correlated with lower accuracy for incongruent (r=0.35, p=0.001), but not congruent (r=0.08, p=0.440), trials.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Findingown data
    § Results

    The relationships for interference RT were confirmed when accounting for neuroticism and reward learning.

    “The above relationships were confirmed when accounting for (1) current depressive symptoms (theta dACC: β=−0.34, p=0.018; alpha2 dACC: β=−0.34, p=0.012; alpha2 right dlPFC: β=0.58, p=0.005), with the exception of gamma activity in the left dlPFC (β=−0.22, p=0.054), and (2) neuroticism and reward learning (theta dACC: β=−0.32; gamma left dlPFC: β=−0.32; alpha2 right dlPFC: β=0.58; alpha2 dACC: β=−0”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    ANOVAs revealed significant differences across clusters in neuroticism, reward learning, and the interference effect.

    “ANOVAs revealed significant differences across clusters in neuroticism (F(2,78)=52.39, p<0.001), reward learning (F(2,78)=75.41, p<0.001), and the interference effect (F(2,78)=11.46, p<0.001).”
    Quote in the paperSubstantial claim

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    Findingown data
    § Results

    The cluster sizes were 41% (N=34), 29% (N=24), and 28% (N=23).

    “The first cluster included 41% (N=34) of the sample, the second cluster 29% (N=24), and the third cluster 28% (N=23).”
    Quote in the paperNot a substantial claim

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    Findingown data
    § Discussion

    An exploratory cluster analysis indicated that three subgroups of depressed patients could be differentiated on the basis of endophenotype profiles: one with relatively elevated neuroticism, one with greater impairments in cognitive control, and one with relatively blunted reward learning.

    “an exploratory cluster analysis indicated that three subgroups of depressed patients could be differentiated on the basis of endophenotype profiles, including a subgroup with relatively elevated neuroticism, another with greater impairments in cognitive control, and a final group with relatively blunted reward learning (Figure 4).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The three endophenotypes (neuroticism, reward learning, cognitive control) are promising for parsing MDD heterogeneity.

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

    Premisecitation
    § Introduction

    Neuroticism has been associated with increased amygdala and ACC activity.

    “With regards to neural substrates, neuroticism has been associated with increased amygdala and anterior cingulate cortex (ACC) activity (Haas et al, 2007; Servaas et al, 2013), both in the ‘affective' (ie, rostral (rACC) and subgenual (sgACC)) and ‘cognitive' subdivisions (ie, dorsal (dACC)).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Haas et al, 2007

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    • cites Servaas et al, 2013

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    Premisecitation
    § Introduction

    Measures of neuroticism (eg, NEO Personality Inventory) have relatively strong psychometric properties.

    “Finally, measures of neuroticism (eg, NEO Personality Inventory) have relatively strong psychometric properties (Costa et al, 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Costa et al, 2005

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

    Premisecitation
    § Introduction

    Strong test-retest reliability and internal consistency have been reported for commonly used cognitive control paradigms.

    “Moderate-to-high heritability (Friedman et al, 2008; Stins et al, 2004), as well as strong test–retest reliability and internal consistency (Wöstmann et al, 2013) have been reported for commonly used cognitive control paradigms (eg, Stroop, Eriksen Flanker).”
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    • cites Wöstmann et al, 2013 source

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    Premisecitation
    § Introduction

    Moderate-to-high heritability has been reported for commonly used cognitive control paradigms.

    “Moderate-to-high heritability (Friedman et al, 2008; Stins et al, 2004), as well as strong test–retest reliability and internal consistency (Wöstmann et al, 2013) have been reported for commonly used cognitive control paradigms (eg, Stroop, Eriksen Flanker).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Friedman et al, 2008 source

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    • cites Stins et al, 2004

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    Premisecitation
    § Introduction

    There is a moderate (r=0.29) genetic correlation between depression and reward learning.

    “In addition, the same study reported a moderate (r=0.29) genetic correlation between depression and reward learning.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bogdan and Pizzagalli, 2009

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    Premisecitation
    § Introduction

    Reward learning has significant test-retest reliability (r=0.57) over 38 days.

    “Data related to the reliability of reward learning is limited, with one study finding significant test–retest reliability (r=0.57) over 38 days (Pizzagalli et al, 2005a).”
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    • cites Pizzagalli et al, 2005a

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    Premisecitation
    § Introduction

    Neuroticism is moderately heritable.

    “Twin studies indicate that neuroticism shares significant genetic variance with depression, and is moderately heritable (eg, Birley et al, 2006; Kendler et al, 2006).”
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    Premisecitation
    § Introduction

    Tasks tapping reward learning recruit the striatum, OFC, dACC, and left dlPFC.

    “In contrast, tasks tapping reward learning have been shown to recruit the striatum, orbitofrontal cortex (OFC; Hornak et al, 2004; O'Doherty, 2004), dACC (Rushworth et al, 2007; Santesso et al, 2008), and left dorsolateral prefrontal cortex (dlPFC; BA 9/46; Ahn et al, 2013; Pizzagalli et al, 2005b), especially in tasks requiring integration of reinforcements over time (eg, PRT).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hornak et al, 2004 source

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    • cites O'Doherty, 2004

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    • cites Rushworth et al, 2007

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    Premisecitation
    § Introduction

    MDD is characterized by broad impairments in cognitive control, which often persist following remission.

    “Finally, MDD is characterized by broad impairments in cognitive control, which often persist following remission (Snyder, 2013) and exhibit trait-like stability (Sarapas et al, 2012).”
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    • cites Snyder, 2013 source

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    Premisecitation
    § Introduction

    Cognitive control has been reliably linked to the dlPFC and dACC.

    “Finally, cognitive control has been reliably linked to the dlPFC and dACC (Pizzagalli, 2011; Ridderinkhof et al, 2004).”
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    • cites Pizzagalli, 2011 source

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    Study design and conductnone given
    § Materials and Methods

    McLean Hospital was responsible for site training and certification, quality assurance, and analysis of Flanker and PRT data as well as LORETA analyses.

    “McLean Hospital was responsible for site training and certification, quality assurance, and analysis of Flanker and PRT data as well as Low-Resolution Brain Electromagnetic Tomography (LORETA) analyses.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Discussion

    Greater neuroticism correlated with elevated subgenual ACC activation in a nonclinical sample engaged in an emotional conflict task.

    “One study (Haas et al, 2007) observed that greater neuroticism correlated with elevated subgenual ACC activation in a nonclinical sample engaged in an emotional conflict task.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Haas et al, 2007

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    Premisecitation
    § Discussion

    Neuroticism has previously been linked to reduced cortical thickness and gray matter volume in the OFC.

    “neuroticism has previously been linked to both reduced cortical thickness (Rauch et al, 2005; Wright et al, 2006) and gray matter volume (Kringelbach and Rolls, 2004) in the OFC.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Rauch et al, 2005

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    • cites Wright et al, 2006

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    • cites Kringelbach and Rolls, 2004 source

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    Premisecitation
    § Discussion

    More recent research has implicated gamma activity in reward processing.

    “More recent research has implicated gamma activity in reward processing (Marco-Pallarés et al, 2015).”
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    • cites Marco-Pallarés et al, 2015

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    Study design and conductown data
    § Materials and Methods

    Outliers (absolute value z>3.0) were omitted from relevant analyses.

    “[Several univariate outliers (absolute value z>3.0) were identified. Specifically, gamma, theta, alpha1, and alpha2 current density values in BA24/32 (rACC) for 1 subject; theta, alpha1 and alpha2 in BA24'/32' (dACC) for 1 subject; gamma and alpha1 left dlPFC values for 1 subject. These data were omitted from the relevant analyses.]”
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    Premisecitation
    § Discussion

    The OFC has been implicated in emotional processing and regulation/expression, in addition to its role in value encoding.

    “the OFC has been implicated in emotional processing and regulation/expression (Goodkind et al, 2012; Rolls and Grabenhorst, 2008).”
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    • cites Goodkind et al, 2012

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    • cites Rolls and Grabenhorst, 2008

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    Study design and conductcitation
    § Materials and Methods

    Whole-brain analyses used permutation-based inference to control for multiple comparisons.

    “To control for multiple comparisons, analyses were carried out using the ‘Randomise' permutation-based inference tool in FSL for nonparametric statistical thresholding (5000 permutations, p<0.05, FWE corrected; Winkler et al, 2014).”
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    • cites Winkler et al, 2014 source

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    Interpretationown data
    § Abstract

    These findings highlight the need to parse the heterogeneity of MDD by focusing on promising endophenotypes linked to specific pathophysiological abnormalities.

    “Overall, these findings highlight the need to parse the heterogeneity of MDD by focusing on promising endophenotypes linked to specific pathophysiological abnormalities.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: MDD is clinically and pathophysiologically heterogeneous.

  • May combine two claims.

    Study design and conductown data
    § Discussion

    Variance in accuracy was reduced for congruent trials (SD=0.02) relative to incongruent trials (SD=0.13), which may have limited the ability to detect a significant association between LORETA current density and accuracy on congruent trials.

    “variance in accuracy was reduced for the congruent (SD=0.02), relative to the incongruent (SD=0.13), trials, which may have limited the ability to detect a significant association between LORETA current density and accuracy on congruent trials.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Discussion

    Ventral ACC regions correspond to the affective subdivision of the ACC, are densely interconnected with limbic and paralimbic structures, have been implicated in emotion expression/regulation, and are a critical hub in the default mode network linked to self-referential processing.

    “These ventral ACC regions correspond to the ‘affective' subdivision of the ACC, which is densely interconnected with limbic and paralimbic structures (eg, amygdala, nucleus accumbens), has been implicated in emotion expression/regulation, and is a critical hub in the default mode network linked to self-referential processing (Buckner et al, 2008; Etkin et al, 2011).”
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    Premisecitation
    § Discussion

    Previous fMRI studies have associated elevated neuroticism with ACC activity.

    “Previous fMRI studies have associated elevated neuroticism with ACC activity (Haas et al, 2007; Servaas et al, 2013).”
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    • cites Haas et al, 2007

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    Premisecitation
    § Discussion

    Previous studies have linked the left, but not right, dlPFC with cognitive control, including studies using the Flanker task.

    “previous studies have linked the left, but not right, dlPFC with cognitive control (MacDonald et al, 2000), including studies using the Flanker task (Fassbender et al, 2006).”
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    Premisecitation
    § Discussion

    In a prior study using a different task, blunted reward responsiveness was associated with reduced resting OFC and left dlPFC activity among healthy controls.

    “In a prior study using a different task, blunted reward responsiveness was associated with reduced resting OFC and left dlPFC activity among healthy controls (Pizzagalli et al, 2005b).”
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    • cites Pizzagalli et al, 2005b

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    Study design and conductown data
    § Materials and Methods

    All models included site as a covariate.

    “all models included site (CU/MGH/UT/UM) as a covariate.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § Discussion

    Prior research has implicated both the OFC and left dlPFC in reward learning.

    “Prior research has implicated both the OFC (Hornak et al, 2004; O'Doherty, 2004) and left dlPFC (Ahn et al, 2013; Pizzagalli et al, 2005b) in reward learning.”
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    Study design and conductnone given
    § Materials and Methods

    Site certification, intersite standardization, quality assurance, and preprocessing of resting EEG for all sites were performed at the Columbia site.

    “Site certification, intersite standardization, quality assurance, and preprocessing of resting EEG for all sites were performed at the Columbia site (see Supplementary Materials for details).”
    Quote in the paperNot a substantial claim

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    Study design and conductown data
    § Materials and Methods

    Specificity analyses were performed to test whether associations remained when accounting for depression severity and the other endophenotypes.

    “For significant findings, specificity analyses were performed to test whether associations remained when accounting for (1) depression severity (by entering HRSD scores as an additional predictor) and (2) the other endophenotypes.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Discussion

    The dlPFC has been strongly implicated in cognitive control.

    “The dlPFC has been strongly implicated in cognitive control (Pizzagalli, 2011; Ridderinkhof et al, 2004)”
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    • cites Pizzagalli, 2011 source

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    Premisecitation
    § Discussion

    Current depressive symptoms have been associated with hyperactivity in ventral ACC regions.

    “which, in turn, have been associated with hyperactivity in ventral ACC regions (Gotlib et al, 2005; Siegle et al, 2007).”
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    • cites Gotlib et al, 2005 source

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    • cites Siegle et al, 2007

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    Study design and conductreasoning
    § Discussion

    Nicotine dependence was not exclusionary, which may represent a possible confound.

    “nicotine dependence was not exclusionary, which may represent a possible confound (eg, due to nicotine's possible effects on cognitive and reward function).”
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    Premisecitation
    § Discussion

    There is evidence that gamma oscillations may facilitate cortical circuit performance and enhance information transmission by increasing signal-to-noise ratio within neocortical circuits.

    “there is evidence that gamma oscillations may facilitate cortical circuit performance and enhance information transmission by increasing signal-to-noise ratio within neocortical circuits (Sohal et al, 2009).”
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    • cites Sohal et al, 2009 source

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    Premisecitation
    § Discussion

    There is some evidence suggesting that current density in higher bands (eg, gamma and beta) may be contaminated by muscle or EMG artifacts.

    “There is some evidence suggesting that current density in higher bands (eg, gamma and beta) may be contaminated by muscle or EMG artifacts (Whitham et al, 2007).”
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    • cites Whitham et al, 2007 source

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    Study design and conductown data
    § Discussion

    The theta and alpha2 effects were not confirmed in whole-brain analyses, so replications are warranted.

    “Because the theta and alpha2 effects were not confirmed in whole-brain analyses, replications are warranted.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given
    § Discussion

    EEG source localization techniques cannot adequately probe subcortical structures (eg, amygdala, caudate).

    “EEG source localization techniques cannot adequately probe subcortical structures (eg, amygdala, caudate).”
    Quote in the paperNot a substantial claim
40 of 40

  • The paper relies on this without support.

    MDD is clinically and pathophysiologically heterogeneous.

    “Major depressive disorder (MDD) is clinically, and likely pathophysiologically, heterogeneous.”

  • The authors state this as an assumption.

    Endophenotypes lie on the pathway between genotype and disease.

    “Endophenotypes are assumed to lie on the pathway between genotype and disease, and be less complex than the downstream symptom clusters that currently define psychiatric diagnoses.”

  • The authors state this as an assumption.

    Endophenotypes are less complex than downstream symptom clusters.

    “Endophenotypes are assumed to lie on the pathway between genotype and disease, and be less complex than the downstream symptom clusters that currently define psychiatric diagnoses.”

  • The paper relies on this without support.

    No study has evaluated whether reward learning fulfills the cosegregation or familial association endophenotype criteria.

    “To our knowledge, no study has evaluated whether reward learning fulfills the cosegregation or familial association endophenotype criteria.”

  • The paper relies on this without support.

    Evidence for cosegregation and familial association of cognitive control is lacking.

    “Evidence for cosegregation and familial association is lacking.”

  • The paper relies on this without support.

    EEG source localization techniques cannot probe subcortical structures.

    “within the constraints of EEG source localization techniques, which cannot probe subcortical structures (eg, amygdala, caudate).”

  • The paper relies on this without support.

    MDD is highly heterogeneous in symptom presentation and etiology/pathophysiology.

    “MDD is increasingly recognized as a highly heterogeneous disorder both in terms of symptom presentation and etiology/pathophysiology.”

  • The paper relies on this without support.

    The three endophenotypes (neuroticism, reward learning, cognitive control) are promising for parsing MDD heterogeneity.

    “three promising endophenotypes of depression”

  • The paper relies on this without support.

    The measures of neuroticism (NEO), reward learning (PRT), and cognitive control (Eriksen Flanker Task) are well-validated.

    “well-validated measures of neuroticism (NEO), reward learning (PRT), and cognitive control (Eriksen Flanker Task)”
9 of 9

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?

  • Anhedonia is often conceptualized as the behavioral manifestation of altered reward processing in depressed patients.

    “Anhedonia is often conceptualized as the behavioral manifestation of altered reward processing in depressed patients (Beck, 2004; Nutt et al., 2007; Webb et al., 2016; Winer and Salem, 2015), and may underlie many of the profound social impairments that are central to depression (Kupferberg et al., 2016).”

    From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Webb et al., 2016

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Consistentz = 2.36reported p = .018 · recomputed p = .018

    “(z=2.36, p = .018”

  • Consistentz = -1.72reported p = .085 · recomputed p = .085

    “(z=−1.72, p = .085”

  • ConsistentF(2, 78) = 52.39reported p < .001 · recomputed p < .001

    “F(2,78)=52.39, p < .001”

  • ConsistentF(2, 78) = 75.41reported p < .001 · recomputed p < .001

    “F(2,78)=75.41, p < .001”

  • ConsistentF(2, 78) = 11.46reported p < .001 · recomputed p < .001

    “F(2,78)=11.46, p < .001”

  • ConsistentF(2, 78) = 1.32reported p = .27 · recomputed p = .273

    “F(2,78)=1.32, p = .27”

6 of 6

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Cites

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Related

Authors
Webb, C. A., Dillon, D. G., Pechtel, P., Goer, F. K., Murray, L., Huys, Q. J., Fava, M., McGrath, P. J., Weissman, M., Parsey, R., Kurian, B. T., Adams, P., Weyandt, S., Trombello, J. M., Grannemann, B., Cooper, C. M., Deldin, P., Tenke, C., Trivedi, M., Bruder, G., & Pizzagalli, D. A.
Affiliations
  • Harvard University (US)
  • University of Zurich (CH)
  • New York State Psychiatric Institute (US)
  • Stony Brook University (US)
  • The University of Texas Southwestern Medical Center (US)
  • Michigan Medicine (US)
Corresponding author
Pizzagalli, Diego A
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2015-06-12
Volume
41
Issue
2
Pages
454-463
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2015.165
PMC
PMC5130121
OpenAlex
W1595717333
Semantic Scholar
ebee9760a0c2f10fb2ec34266220e407c7f975dd
Cited by
103
References
93
Citations by year
2026: 5 · 2025: 6 · 2024: 5 · 2023: 12 · 2022: 2 · 2021: 10 · 2020: 13 · 2019: 13 · 2018: 16 · 2017: 10 · 2016: 10 · 2015: 1
FWCI
8.90
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Columbia Academic Commons (Columbia University)
Funders
  • John Templeton Foundation
  • Pfizer
  • GlaxoSmithKline
  • Sunovion
  • National Alliance for Research on Schizophrenia and Depression
  • University of Oxford
  • Mitsubishi Tanabe Pharma Corporation
  • H. Lundbeck A/S
  • Agency for Healthcare Research and Quality
  • National Institute of Mental Health (R00MH094438, U01MH092250, R01MH068376, F32MH099801, U01MH092221)
  • National Institute on Drug Abuse
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
major depressive disorder, endophenotypes, neuroticism, cognitive control deficits, resting-state EEG, gamma oscillations, subgenual anterior cingulate cortex, orbitofrontal cortex, dorsolateral prefrontal cortex, reinforcement learning, reward sensitivity
MeSH terms
Neuroticism, Adolescent, Adult, Aged, Anxiety Disorders, Brain, Depressive Disorder, Major, Major Depressive Disorder, Electroencephalography, Humans, Middle Aged, Motor Activity, Neuropsychological Tests, Psychiatric Status Rating Scales, Reaction Time, Rest, Reward, Tomography, Young Adult, Endophenotypes

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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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