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Cited by 241Tryptophan and brain disordersStress Responses and CortisolNeuroinflammation and Neurodegeneration Mechanisms

Dose-dependent effects of endotoxin on neurobehavioral functions in humans

Open access
Grigoleit, Jan-Sebastian, Kullmann, Jennifer S., Wolf, Oliver T., Hammes, Florian, Wegner, Alexander, Jablonowski, Stephanie, Engler, Harald, Gizewski, Elke +2 more·2011·PLoS ONE
DOI 10.1371/journal.pone.0028330PMC PMC3229570
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Abstract

Clinical and experimental evidence document that inflammation and increased peripheral cytokine levels are associated with depression-like symptoms and neuropsychological disturbances in humans. However, it remains unclear whether and to what extent cognitive functions like memory and attention are affected by and related to the dose of the inflammatory stimulus. Thus, in a cross-over, double-blind, experimental approach, healthy male volunteers were administered with either placebo or bacterial lipopolysaccharide (LPS) at doses of 0.4 (n = 18) or 0.8 ng/kg of body weight (n = 16). Pro- and anti-inflammatory cytokines, norephinephrine and cortisol concentrations were analyzed before and 1, 1.75, 3, 4, 6, and 24 h after injection. In addition, changes in mood and anxiety levels were determined together with working memory (n-back task) and long term memory performance (recall of emotional and neutral pictures of the International Affective Picture System). Endotoxin administration caused a profound transient physiological response with dose-related elevations in body temperature and heart rate, increases in plasma interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α and IL-1 receptor antagonist (IL-1ra), salivary and plasma cortisol, and plasma norepinephrine. These changes were accompanied by dose-related decreased mood and increased anxiety levels. LPS administration did not affect accuracy in working memory performance but improved reaction time in the high-dose LPS condition compared to the control conditon. In contrast, long-term memory performance was impaired selectively for emotional stimuli after administration of the lower but not of the higher dose of LPS. These data suggest the existence of at least two counter-acting mechanisms, one promoting and one inhibiting cognitive performance during acute systemic inflammation.

AI snapshot

Written from the paper’s full text.

TL;DR

In a double-blind, crossover human endotoxemia study, LPS at 0.4 or 0.8 ng/kg induced transient inflammatory, neuroendocrine, and mood/anxiety changes in healthy men. Working memory accuracy was unaffected while high-dose LPS improved reaction time, and low-dose LPS selectively impaired long-term memory for emotional pictures.

Key findings

  • Endotoxin increased body temperature and heart rate in both dose groups without significant differences between doses, and increased plasma IL-6, TNF-α, IL-10, IL-1ra, plasma/salivary cortisol, and norepinephrine; TNF-α, IL-10, and IL-1ra showed dose-related differences, while IL-6 did not.
  • Positive mood, calmness, and alertness decreased 3 h after endotoxin in both groups, and state anxiety increased; the positive-mood decrease was larger in the high-dose group (−6.00 vs. −2.06 at 3 h).
  • Working memory accuracy was unaffected (F = 0.20, p > 0.05; low-dose: 15.9 ± 5.4 vs. 15.2 ± 5.0), but reaction time improved by 27.6 ms in the high-dose group (504.9 ± 71.5 ms vs. 532.5 ± 59.3 ms; t = 3.21, p < 0.01).
  • Long-term memory for emotional stimuli was impaired after low-dose LPS (6.4 ± 2.4 vs. 7.8 ± 2.4; t = 2.88, p < 0.05) but not after high-dose LPS (8.5 ± 1.8 vs. 8.5 ± 1.3); neutral memory was not significantly affected in either group, with a trend toward impairment after high-dose LPS (5.9 ± 2.0 vs. 6.8 ± 1.7; t = 2.09, p = 0.10).

Methods

  • Placebo-controlled, double-blind, crossover study in 34 healthy male volunteers randomized to low-dose LPS (0.4 ng/kg, n = 18) or high-dose LPS (0.8 ng/kg, n = 16); each participant received LPS and saline on separate days 10–14 days apart.
  • Blood and saliva were sampled before and 1, 1.75, 3, 4, 6, and 24 h after injection; cytokines were measured by multiplex bead-based assays, and cortisol/norepinephrine by ELISA. Mood/anxiety were assessed with MDBF and STAI at baseline, 3 h, and 6 h; working memory used a 2-back task, and long-term memory used IAPS picture acquisition before 3 h and recall 24 h later.
  • Analyses used repeated-measures ANOVA with Bonferroni post hoc tests, paired/unpaired t-tests, and Pearson correlations with Bonferroni correction; p < 0.05 was considered significant.

Limitations

  • Stated: the exact nature of possible compensatory mechanisms and whether the compensatory effect on memory performance is paralleled by or due to increased attention need future studies; effects on consolidation and retrieval remain unknown.
  • Evident: the sample was restricted to healthy young male volunteers (n = 34; age ranges 19–33 years), so findings may not generalize to women, older adults, or clinical populations.
  • Evident: mechanistic interpretations rely on peripheral cytokine, hormone, and behavioral measures without direct neural measures in this study.

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

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0028330

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 77 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Subjects recognized emotional stimuli better than neutral stimuli (emotionality effect).

    “In general, subjects recognized emotional stimuli better compared to stimuli with neutral content indicated by a pronounced emotionality effect (F = 26.26, p<0.001, emotionality×treatment×group ANOVA) (Fig. 7).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Low-dose LPS significantly impaired long-term memory for emotional stimuli.

    “In contrast, long term-memory for emotional but not for neutral stimuli was significantly impaired by the administration of low-dose LPS, whereas in the high-dose LPS condition memory remained unaffected.”
    • Also stated in: § Discussion · plain
      “Administration of low-dose LPS 3 h before acquisition impaired memory performance for emotional but not for neutral stimuli.”
    Quote in the paperSubstantial claim
  • Findingown data

    Higher LPS concentration (0.8 ng/kg) further increased TNF-α, IL-10 and IL-1ra plasma concentrations.

    “In addition, higher LPS concentration (0.8 ng/kg) further increased TNF-α, IL-10 and IL-1ra plasma concentrations, but not plasma levels of IL-6, cortisol, or norepinephrine.”
    Quote in the paperNot a substantial claim
  • Findingown data

    LPS administration did not affect accuracy in working memory.

    “LPS administration did not affect accuracy in working memory, however induced a significant improvement in reaction time in the high-dose LPS condition.”
    • Also stated in: § Discussion · plain
      “We did not find any effect on accuracy in the n-back test, reflected by the number of correct responses minus the number of false reactions, neither in the low- nor high-dose LPS condition.”
    Quote in the paperSubstantial claim
  • Findingown data

    LPS at 0.4 ng/kg significantly decreased alertness at 3 h compared to placebo.

    “Self-reported positive mood (low-dose: F = 6.21, p = 0.01; high-dose: F = 25.97, p<0.001), calmness (low-dose: F = 6.42, p<0.01; high-dose: F = 5.52, p<0.01), and alertness (low-dose: F = 5.07, p<0.01; high-dose: F = 7.09, p<0.01), were significantly decreased 3 h after endotoxin injection in both groups.”
    Quote in the paperSubstantial claim
  • May combine two claims. 17
  • The quote only partly states this claim. 10
  • Classified as probably not a substantial claim. 30

  • May combine two claims.

    Findingown data

    ANOVA did not reveal significant treatment×group, emotionality×group, or treatment×emotionality effects in long-term memory.

    “Moreover, ANOVA did not reveal significant treatment×group, emotionality×group, or treatment×emotionality effects, however showed a significant treatment×emotionality×group interaction effect (F = 6.14, p<0.05) indicating a specific effect depending on the quality of memory content and the employed dose of LPS.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    LPS at 0.4 ng/kg significantly increased plasma IL-6 compared to placebo.

    “Endotoxin administration induced significant increases in plasma concentrations of the pro-inflammatory cytokines IL-6 (low-dose: F = 31.11, p<0.001, high-dose: F = 17.74, p<0.001) and TNF-α (low-dose: F = 12.05, p<0.001, high-dose: F = 21.26, p<0.001) with most pronounced increases 1.75 h after LPS injection (Fig. 3).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    LPS at 0.4 ng/kg significantly increased plasma TNF-α compared to placebo.

    “Endotoxin administration induced significant increases in plasma concentrations of the pro-inflammatory cytokines IL-6 (low-dose: F = 31.11, p<0.001, high-dose: F = 17.74, p<0.001) and TNF-α (low-dose: F = 12.05, p<0.001, high-dose: F = 21.26, p<0.001) with most pronounced increases 1.75 h after LPS injection (Fig. 3).”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    LPS at 0.8 ng/kg did not significantly affect long-term memory performance for neutral stimuli.

    “In contrast, a higher dose of LPS did not significantly affect memory performance neither for emotional (8.5±1.8 vs. 8.5±1.3) nor for neutral stimuli (5.9±2.0 vs. 6.8±1.7; F = 1.29, p>0.05), although there was a trend towards decreased memory performance for neutral stimuli after high-dose LPS treatment (t = 2.09, p = 0.10).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    LPS at 0.4 ng/kg significantly increased plasma IL-10 compared to placebo.

    “The anti-inflammatory cytokine IL-10 was significantly increased in both endotoxin groups (low-dose: F = 25.47, p<0.001; high-dose: F = 12.80, p<0.001) with significantly more pronounced elevations in the high-dose group 3 h post injection (F = 5.02, p<0.001; Fig. 3C).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). The quote only partly states this claim.

    Findingown data

    LPS at 0.8 ng/kg significantly increased plasma TNF-α compared to placebo.

    “Endotoxin administration induced significant increases in plasma concentrations of the pro-inflammatory cytokines IL-6 (low-dose: F = 31.11, p<0.001, high-dose: F = 17.74, p<0.001) and TNF-α (low-dose: F = 12.05, p<0.001, high-dose: F = 21.26, p<0.001) with most pronounced increases 1.75 h after LPS injection (Fig. 3).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    LPS at 0.8 ng/kg significantly increased plasma IL-1ra compared to placebo.

    “The most pronounced differences in cytokine levels between the two groups were observed for IL-1 receptor antagonist (IL-1ra) (F = 15.59, p<0.001, low-dose vs. high-dose; F = 33.45, p<0.001, high-dose vs. control; F = 21.01, p<.001, low-dose vs. control; Fig. 3D).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    LPS at 0.8 ng/kg did not significantly affect long-term memory performance for emotional stimuli.

    “In contrast, a higher dose of LPS did not significantly affect memory performance neither for emotional (8.5±1.8 vs. 8.5±1.3) nor for neutral stimuli (5.9±2.0 vs. 6.8±1.7; F = 1.29, p>0.05), although there was a trend towards decreased memory performance for neutral stimuli after high-dose LPS treatment (t = 2.09, p = 0.10).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LPS administration produced significant, mainly dose-dependent increases in body temperature, heart rate, pro- and anti-inflammatory cytokines, cortisol, and norepinephrine.

    “We observed significant, mainly dose-dependent, increases in body temperature, heart rate, levels of pro- (IL-6, TNF-α) and anti-inflammatory (IL-10, IL-1ra) cytokines, cortisol, and norepinephrine.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Findingown data

    LPS at 0.8 ng/kg significantly increased plasma IL-6 compared to placebo.

    “Endotoxin administration induced significant increases in plasma concentrations of the pro-inflammatory cytokines IL-6 (low-dose: F = 31.11, p<0.001, high-dose: F = 17.74, p<0.001) and TNF-α (low-dose: F = 12.05, p<0.001, high-dose: F = 21.26, p<0.001) with most pronounced increases 1.75 h after LPS injection (Fig. 3).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    LPS at 0.8 ng/kg significantly increased plasma IL-10 compared to placebo.

    “The anti-inflammatory cytokine IL-10 was significantly increased in both endotoxin groups (low-dose: F = 25.47, p<0.001; high-dose: F = 12.80, p<0.001) with significantly more pronounced elevations in the high-dose group 3 h post injection (F = 5.02, p<0.001; Fig. 3C).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    LPS at 0.4 ng/kg significantly increased plasma IL-1ra compared to placebo.

    “The most pronounced differences in cytokine levels between the two groups were observed for IL-1 receptor antagonist (IL-1ra) (F = 15.59, p<0.001, low-dose vs. high-dose; F = 33.45, p<0.001, high-dose vs. control; F = 21.01, p<.001, low-dose vs. control; Fig. 3D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LPS had a pronounced and dose-dependent impact on self-reported mood with increased anxiety levels and impaired calmness and alertness.

    “We also observed a pronounced and dose-dependent impact of LPS on self-reported mood with increased anxiety levels and impaired calmness and alertness.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    LPS at 0.8 ng/kg significantly increased state anxiety compared to placebo.

    “State anxiety significantly increased after endotoxin administration in both groups (low-dose: F = 4.13, p<0.05; high-dose: F = 6.47, p<0.01).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The data in the current study show an association between cortisol and mood parameters at a lower grade of inflammation in contrast to a more pronounced inflammatory effect where mood parameters are predominantly associated to IL-6 levels.

    “The data in the current study show an association between cortisol and mood parameters at a lower grade of inflammation in contrast to a more pronounced inflammatory effect where mood parameters are predominantly associated to IL-6 levels.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    The n-back task is a common and well-established continuous performance test for measurements of working memory performance.

    “The n-back task is a common and well-established continuous performance test for measurements of working memory performance [33], [34].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] WK Kirchner, 1958, Age differences in short-term retention of rapidly changing information., J Exp Psychol source

      Not checked in the free run.

    • cites [34] AM Owen, 2005, N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies., Human Brain Mapping source

      Not checked in the free run.

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

    Study design and conductcitation

    The MDBF is a well-established and validated scale in German.

    “The multidimensional mood questionnaire (Multidimensionaler Befindlichkeitsfragebogen, MDBF), which is a well-established and -validated scale in German language.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] V Pollock, 1979, Profile of Mood States: the factors and their physiological correlates., J Nerv Ment Dis source

      Not checked in the free run.

    • cites [30] R Steyer, 1997, Der Mehrdimensionale Befindlichkeitsfragebogen (MDBF)

      Not checked in the free run.

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

    Study design and conductnone given

    The alpha level was adjusted according to the number of comparisons (Bonferroni correction).

    “The alpha level was adjusted according to the respective number of comparisons (Bonferroni correction).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Behavioral changes induced by immune activation include psychomotor slowing, social withdrawal, anhedonia, depressed mood, and disturbed sleep architecture, collectively termed sickness behavior.

    “Behavioral changes induced by immune activation include symptoms such as psychomotor slowing, social withdrawal, anhedonia, depressed mood, and disturbed sleep architecture, collectively termed “sickness behavior” [4], [5], [6].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] R Dantzer, 2001, Cytokine-induced sickness behavior: where do we stand?, Brain, Behavior, and Immunity source

      Not checked in the free run.

    • cites [5] J Mullington, 2000, Dose-dependent effects of endotoxin on human sleep., American Journal of Physiology - Regulatory, Integrative and Comperative Physiology source

      Not checked in the free run.

    • cites [6] AV Turnbull, 1995, Regulation of the HPA axis by cytokines., Brain, Behavior, and Immunity source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The study used a placebo-controlled, double-blind, crossover design.

    “In this placebo-controlled, double-blind, crossover study, participants were randomly allocated to two different groups:”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. The quote only partly states this claim.

    Study design and conductown data

    Participants were randomly allocated to the high-dose or low-dose group.

    “In this placebo-controlled, double-blind, crossover study, participants were randomly allocated to two different groups:”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The groups did not differ in age, years of education, body weight, or physical/psychological screening parameters, and these parameters had no detectable influence on any outcome measures.

    “The groups did not differ in age, years of education or body weight, nor in any of the physical or psychological screening parameters, and there was no detectable influence of these parameters on any of the outcome measures.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    The STAI is a widely used scale to quantify anxiety in health research.

    “The State Trait Anxiety Inventory (STAI, state version), a widely used scale to quantify anxiety in health research [31], [32].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] P Keedwell, 1996, What do anxiety scales measure?, Acta Psychiatr Scand source

      Not checked in the free run.

    • cites [32] CD Spielberger, 1983, Manual for the State-Trait Anxiety Inventory (Form Y)

      Not checked in the free run.

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

    Study design and conductnone given

    Subjects and investigators were blinded with respect to the study condition.

    “Subjects and investigators where blinded with respect to the study condition.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The IAPS neutral pictures were reported to elicit medium levels of valence and low levels of arousal, and emotional pictures were known to elicit high arousal and low valence values.

    “Whereas 50% of pictures had neutral contents and were reported to elicit medium levels of valence and low levels of arousal, 50% of pictures consisted of highly emotional pictures known to elicit high arousal and low valence values [35].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] PJ Lang, 1999, International affective picture system (IAPS): Technical manual and affective ratings

      Not checked in the free run.

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

    Interpretationreasoning

    The conflicting results might be due to different experimentally induced grades of inflammation or the neuropsychological tools employed to assess working memory performance.

    “These conflicting results might be either due to the different experimentally induced grades of inflammation or the neuropsychological tools (Digit Span Forward, Backward Test by Wechsler) employed in these studies to assess working memory performance.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    The alterations in cytokines and cortisol levels observed in this study resemble those reported in other studies employing comparable amounts (0.4 ng/kg) of intravenously administered LPS.

    “The alterations in cytokines and cortisol levels observed in this study resemble those reported in other studies employing comparable amounts (0.4 ng/kg) of intravenously administered LPS [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] M Bahador, 2007, From therapy to experimental model: a hundred years of endotoxin administration to human subjects., Journal of Endotoxin Research source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    These data suggest the existence of at least two counter-acting mechanisms, one promoting and one inhibiting cognitive performance during acute systemic inflammation.

    “These data suggest the existence of at least two counter-acting mechanisms, one promoting and one inhibiting cognitive performance during acute systemic inflammation.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Studies in experimental animals together with clinical observations in humans suggest a cytokine-mediated modulation of memory functions as a consequence of acute peripheral inflammatory processes.

    “Studies in experimental animals together with clinical observations in humans suggest a cytokine-mediated modulation of memory functions as a consequence of acute peripheral inflammatory processes [3], [37].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] R Yirmiya, 2011, Immune modulation of learning, memory, neural plasticity and neurogenesis., Brain Behav Immun source

      Not checked in the free run.

    • cites [37] JS Kullmann, 2011, Effects of an Acute Inflammation on Memory Performance, Mood and Brain Activity., Zeitschrift für Medizinische Psychologie source

      Not checked in the free run.

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

    Premisecitation

    Associations between circulating IL-6 levels and negative mood have been reported previously.

    “Associations between circulating IL-6 levels and negative mood have been reported previously [28], [62] and IL-6 frequently has been discussed as a potential modulator of mood during sickness behavior and even depression and other neuropsychological diseases [2], [3], [9].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] A Reichenberg, 2001, Cytokine-associated emotional and cognitive disturbances in humans., Archives of General Psychiatry source

      Not checked in the free run.

    • cites [62] CE Wright, 2005, Acute inflammation and negative mood: mediation by cytokine activation., Brain, Behavior, and Immunity source

      Not checked in the free run.

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

    Interpretationreasoning

    Greater effects on mood and anxiety than after low-dose stimulation, together with reduced reaction time in the working memory test, might indicate an elevated stress reaction and an "alarmed state" of the organism probably going along with increased attention.

    “In addition, greater effects on mood and anxiety than after low-dose stimulation, together with reduced reaction time in the working memory test also might indicate an elevated stress reaction and an “alarmed state” of the organism probably going along with increased attention.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    IL-6 frequently has been discussed as a potential modulator of mood during sickness behavior and even depression and other neuropsychological diseases.

    “Associations between circulating IL-6 levels and negative mood have been reported previously [28], [62] and IL-6 frequently has been discussed as a potential modulator of mood during sickness behavior and even depression and other neuropsychological diseases [2], [3], [9].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] N DellaGioia, 2010, A critical review of human endotoxin administration as an experimental paradigm of depression., Neurosci Biobehav Rev source

      Not checked in the free run.

    • cites [3] R Yirmiya, 2011, Immune modulation of learning, memory, neural plasticity and neurogenesis., Brain Behav Immun source

      Not checked in the free run.

    • cites [9] RC Drexhage, 2010, The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder., Expert Review of Neurotherapeutics source

      Not checked in the free run.

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

    Interpretationreasoning

    The abrogation of this impairment in the high-dose LPS group might either reflect a balanced state between cytokine induced increased neural excitability and the counter-acting regulatory mechanisms, or might be due to increased stress exposure.

    “The abrogation of this impairment in the high-dose LPS group might either reflect a balanced state between cytokine induced increased neural excitability and the counter-acting regulatory mechanisms, or might be due to increased stress exposure:”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Slow genomic effects of cortisol enhance PFC functioning.

    “These authors suggest that slow genomic effects of cortisol enhance PFC functioning [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] MJ Henckens, 2011, Time-dependent corticosteroid modulation of prefrontal working memory processing., Proceedings of the National Academy of Sciences of the United States of America source

      Not checked in the free run.

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

    Premisecitation

    A recent fMRI study reported that several hours after cortisol intake DLPFC activity during an n-back task was enhanced with a similar trend at the behavioral level.

    “Of interest for the current experiments is a recent functional magnetic resonance (fMRI) study reporting that several hours after cortisol intake DLPFC activity during an n-back task was enhanced with a similar trend being observed at the behavioral level.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] MJ Henckens, 2011, Time-dependent corticosteroid modulation of prefrontal working memory processing., Proceedings of the National Academy of Sciences of the United States of America source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Recent work in rodents demonstrated enhanced neural activity in the amygdala after peripheral LPS-administration.

    “This hypothesis is supported by recent work in rodents, which demonstrated enhanced neural activity in the amygdala after peripheral LPS-administration [59], [60].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] R Doenlen, 2011, Electrical activity in rat cortico-limbic structures after single or repeated administration of lipopolysaccharide or staphylococcal enterotoxin B., Proceedings: Biological sciences, The Royal Society

      Not checked in the free run.

    • cites [60] H Engler, 2011, Acute amygdaloid response to systemic inflammation., Brain, Behavior and Immunity source

      Not checked in the free run.

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

    Premisecitation

    In humans experimental or pharmacological stress studies have reported inconsistent effects with impairments as well as enhancements.

    “In humans experimental or pharmacological stress studies have reported inconsistent effects with impairments as well as enhancements being reported [42], [46], [47].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] D Schoofs, 2008, Psychosocial stress induces working memory impairments in an n-back paradigm., Psychoneuroendocrinology source

      Not checked in the free run.

    • cites [46] S Cornelisse, 2011, Implications of psychosocial stress on memory formation in a typical male versus female student sample., Psychoneuroendocrinology source

      Not checked in the free run.

    • cites [47] D Schoofs, 2009, Cold pressor stress impairs performance on working memory tasks requiring executive functions in healthy young men., Behavioral Neuroscience source

      Not checked in the free run.

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

    Premisecitation

    Animal data suggest detrimental effects of acute systemic inflammation on long term memory.

    “Animal data suggest detrimental effects of acute systemic inflammation on long term memory [3], [19], [21], 22,23.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [3] R Yirmiya, 2011, Immune modulation of learning, memory, neural plasticity and neurogenesis., Brain Behav Immun source

      Not checked in the free run.

    • cites [19] M Gibertini, 1995, Legionella pneumophila-induced visual learning impairment reversed by anti-interleukin-1 beta., Proc Soc Exp Biol Med source

      Not checked in the free run.

    • cites [21] CR Pugh, 1998, Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning., Brain, Behavior, and Immunity source

      Not checked in the free run.

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

    Premisecitation

    Studies in rodents and monkeys have established that acute stress rapidly impairs dorsolateral prefrontal cortex (DLPFC) functioning via noradrenergic and dopaminergic mechanisms.

    “Studies in rodents and monkeys have established that acute stress rapidly impairs dorsolateral prefrontal cortex (DLPFC) functioning via noradrenergic and dopaminergic mechanisms [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] AF Arnsten, 2009, Stress signalling pathways that impair prefrontal cortex structure and function., Nature Reviews Neuroscience source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Behavioral and pharmacological studies in humans showed enhanced long-term memory consolidation for emotional stimuli after stress or glucocorticoid (GC) treatment directly before or after encoding, while impairing the consolidation of neutral material.

    “Behavioral and pharmacological studies in humans showed enhanced long-term memory consolidation for emotional stimuli after stress or glucocorticoid (GC) treatment directly before or after encoding, while impairing the consolidation of neutral material [56], [57], [58].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [56] L Cahill, 2003, Enhanced human memory consolidation with post-learning stress: interaction with the degree of arousal at encoding., Learning and Memory source

      Not checked in the free run.

    • cites [57] S Kuhlmann, 2006, Arousal and cortisol interact in modulating memory consolidation in healthy young men., Behav Neurosci source

      Not checked in the free run.

    • cites [58] JD Payne, 2007, Stress administered prior to encoding impairs neutral but enhances emotional long-term episodic memories., Learning and Memory source

      Not checked in the free run.

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

    Premisecitation

    Recent findings in rodents show that acute stress enhanced working memory via an enhancement of glutamatergic neurotransmission.

    “In line with this conclusion are recent findings in rodents showing that acute stress enhanced working memory via an enhancement of glutamatergic neurotransmission [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] EY Yuen, 2009, Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory., Proceedings of the National Academy of Sciences of the United States of America source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The improvement in reaction time after high-dose LPS possibly indicates a positive effect of peripheral inflammation on alertness and response speed rather than on memory performance.

    “However, administration of 0.8 ng/kg LPS significantly improved the reaction time, possibly indicating a positive effect of the peripheral inflammation on alertness and response speed rather than on memory performance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    This study demonstrates that sub-septic systemic inflammation in humans along with the release of pro- and anti-inflammatory cytokines does dose-dependently affect neurobehavioral functions in humans reflecting an adaptive response as a consequence of a refined immune-to-brain communication.

    “This study demonstrates that sub-septic systemic inflammation in humans along with the release of pro- and anti-inflammatory cytokines does dose-dependently affect neurobehavioral functions in humans reflecting an adaptive response as a consequence of a refined immune-to-brain communication.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human endotoxemia model with LPS in healthy subjects is a valid model for studying neurobehavioral effects of systemic inflammation.

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

    Premisecitation

    This effect appears to be rather short lived.

    “However this effect appears to be rather short lived [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] DM Diamond, 2007, The temporal dynamics model of emotional memory processing: a synthesis on the neurobiological basis of stress-induced amnesia, flashbulb and traumatic memories, and the Yerkes-Dodson law., Neural Plasticity source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The discrepancy underlines the basic independency of these two processes and might fortify the view on sickness behavior as an adaptive response rather than a simple impairment by the inflammatory challenge.

    “Although the reasons for this discrepancy remain unclear, it underlines the basic independency of these two processes and might fortify the view on sickness behavior as an adaptive response rather than a simple impairment by the inflammatory challenge [4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] R Dantzer, 2001, Cytokine-induced sickness behavior: where do we stand?, Brain, Behavior, and Immunity source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Yirmiya and Goshen proposed a model of adaptive down-regulation of neural excitability to prevent potentially dangerous hyper-excitability and proneness to errors by the "price" of impairments of learning and memory.

    “A possible explanation for this phenomenon was given by Yirmiya and Goshen, who proposed a model of adaptive down-regulation of neural excitability to prevent potentially dangerous hyper-excitability and proneness to errors by the “price” of impairments of learning and memory [3].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] R Yirmiya, 2011, Immune modulation of learning, memory, neural plasticity and neurogenesis., Brain Behav Immun source

      Not checked in the free run.

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

    Premisecitation

    HPA system activation with increased levels of cortisol and corticotropin releasing hormone have also been suggested to play a role in depressive symptoms and in mediating inflammatory effects on mood and anxiety.

    “HPA system activation with increased levels of cortisol and corticotropin releasing hormone have also been suggested to play a role in depressive symptoms and in mediating inflammatory effects on mood and anxiety [6], [28], [37], [63].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] AV Turnbull, 1995, Regulation of the HPA axis by cytokines., Brain, Behavior, and Immunity source

      Not checked in the free run.

    • cites [28] A Reichenberg, 2001, Cytokine-associated emotional and cognitive disturbances in humans., Archives of General Psychiatry source

      Not checked in the free run.

    • cites [37] JS Kullmann, 2011, Effects of an Acute Inflammation on Memory Performance, Mood and Brain Activity., Zeitschrift für Medizinische Psychologie source

      Not checked in the free run.

47 of 47

  • The paper relies on this without support.

    Data on dose-dependent effects of LPS-induced inflammation on neural responses are completely lacking.

    “Since data on dose dependent effects of LPS-induced inflammation on neural responses are completely lacking, one can only hypothesize about the underlying neurobiological mechanisms responsible for these differential effects.”

  • The paper relies on this without support.

    Two classes of soluble factors (cytokines and stress hormones) are most often discussed to modulate cognitive functions during an inflammatory reaction.

    “Two classes of soluble factors are most often discussed to modulate cognitive functions during an inflammatory reaction: cytokines and stress hormones.”

  • The paper relies on this without support.

    The human endotoxemia model with LPS in healthy subjects is a valid model for studying neurobehavioral effects of systemic inflammation.

    “We employed a human endotoxemia model in healthy subjects and analyzed the effects on circulating cytokines, neuroendocrine parameters as well as mood and memory performance by either administering lower (0.4 ng/kg) or higher (0.8 ng/kg) doses of LPS.”

  • The paper relies on this without support.

    Correlations between cytokine or cortisol levels and mood reflect causal mediation.

    “Our results confirm earlier observations which suggested both circulating cytokines as well as cortisol to be involved in mediating the effects on emotions [28].”
4 of 4

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?

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.

  • Treatment is classified as a between-subjects factor in a crossover study

    Minor

    The statistical methods classify LPS versus placebo as a between-subjects factor, but the study design says every participant received both treatments. Treatment is therefore a within-subject factor in the described design.

  • Stimulus emotionality is classified as a between-subjects factor

    Minor

    The long-term memory analysis calls stimulus quality a between-subjects factor, although each subject was tested with both emotional and neutral pictures.

2 of 2

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Authors
Grigoleit, J.-S., Kullmann, J. S., Wolf, O. T., Hammes, F., Wegner, A., Jablonowski, S., Engler, H., Gizewski, E., Oberbeck, R., & Schedlowski, M.
Affiliations
  • University of Duisburg-Essen (DE)
  • Essen University Hospital (DE)
  • Ruhr University Bochum (DE)
Corresponding author
Schedlowski, Manfred
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-12-02
Volume
6
Issue
12
Pages
e28330
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0028330
PMC
PMC3229570
OpenAlex
W1964505086
Semantic Scholar
5d51a0d850bd026e5fc5937456b7b1ad6e711819
Cited by
241
References
65
Citations by year
2026: 8 · 2025: 17 · 2024: 18 · 2023: 15 · 2022: 13 · 2021: 17 · 2020: 21 · 2019: 23 · 2018: 21 · 2017: 19 · 2016: 13 · 2015: 23 · 2014: 11 · 2013: 15 · 2012: 7
FWCI
3.06
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • United States Pharmacopeia
  • Deutsche Forschungsgemeinschaft (/14-1)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
endotoxin, lipopolysaccharide, acute systemic inflammation, dose-response relationship, working memory, long-term memory, emotional memory, anxiety, mood, cytokines, interleukin-6, cortisol, norepinephrine, neurobehavioral effects
MeSH terms
Adult, Attention, Behavior, Body Temperature, Body Weight, Dose-Response Relationship, Drug, Double-Blind Method, Endotoxins, Heart Rate, Humans, Inflammation, Lipopolysaccharides, Male, Memory, Models, Neurological, Placebos, Tumor Necrosis Factor-alpha, Interleukin-6, Body Mass Index, Interleukin-10, Cross-Over Studies, Interleukin 1 Receptor Antagonist Protein

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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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

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