Dose-Dependent Effects of Endotoxin on Neurobehavioral Functions in Humans

In the paper

“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.”

In the paper

“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).”

In the paper

“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).”

In the paper

“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).”

In the paper

“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).”

In the paper

“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).”

In the paper

“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).”

In the paper

“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).”

In the paper

“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.”

In the paper

“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).”

In the paper

“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).”

In the paper

“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).”

In the paper

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

In the paper

“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).”

In the paper

“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.”

In the paper

“The n-back task is a common and well-established continuous performance test for measurements of working memory performance [33], [34].”

What the sources say

• Not checked yetcites [33] WK Kirchner, 1958, Age differences in short-term retention of rapidly changing information., J Exp Psychol source
• Not checked yetcites [34] AM Owen, 2005, N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies., Human Brain Mapping source

In the paper

“The multidimensional mood questionnaire (Multidimensionaler Befindlichkeitsfragebogen, MDBF), which is a well-established and -validated scale in German language.”

What the sources say

• Not checked yetcites [29] V Pollock, 1979, Profile of Mood States: the factors and their physiological correlates., J Nerv Ment Dis source
• Not checked yetcites [30] R Steyer, 1997, Der Mehrdimensionale Befindlichkeitsfragebogen (MDBF)

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [4] R Dantzer, 2001, Cytokine-induced sickness behavior: where do we stand?, Brain, Behavior, and Immunity source
• Not checked yetcites [5] J Mullington, 2000, Dose-dependent effects of endotoxin on human sleep., American Journal of Physiology - Regulatory, Integrative and Comperative Physiology source
• Not checked yetcites [6] AV Turnbull, 1995, Regulation of the HPA axis by cytokines., Brain, Behavior, and Immunity source

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“The State Trait Anxiety Inventory (STAI, state version), a widely used scale to quantify anxiety in health research [31], [32].”

What the sources say

• Not checked yetcites [31] P Keedwell, 1996, What do anxiety scales measure?, Acta Psychiatr Scand source
• Not checked yetcites [32] CD Spielberger, 1983, Manual for the State-Trait Anxiety Inventory (Form Y)

In the paper

“Subjects and investigators where blinded with respect to the study condition.”

In the paper

“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].”

What the sources say

• Not checked yetcites [35] PJ Lang, 1999, International affective picture system (IAPS): Technical manual and affective ratings

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [36] M Bahador, 2007, From therapy to experimental model: a hundred years of endotoxin administration to human subjects., Journal of Endotoxin Research source

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [3] R Yirmiya, 2011, Immune modulation of learning, memory, neural plasticity and neurogenesis., Brain Behav Immun source
• Not checked yetcites [37] JS Kullmann, 2011, Effects of an Acute Inflammation on Memory Performance, Mood and Brain Activity., Zeitschrift für Medizinische Psychologie source

In the paper

“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].”

What the sources say

• Not checked yetcites [28] A Reichenberg, 2001, Cytokine-associated emotional and cognitive disturbances in humans., Archives of General Psychiatry source
• Not checked yetcites [62] CE Wright, 2005, Acute inflammation and negative mood: mediation by cytokine activation., Brain, Behavior, and Immunity source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [2] N DellaGioia, 2010, A critical review of human endotoxin administration as an experimental paradigm of depression., Neurosci Biobehav Rev source
• Not checked yetcites [3] R Yirmiya, 2011, Immune modulation of learning, memory, neural plasticity and neurogenesis., Brain Behav Immun source
• Not checked yetcites [9] RC Drexhage, 2010, The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder., Expert Review of Neurotherapeutics source

In the paper

“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:”

In the paper

“These authors suggest that slow genomic effects of cortisol enhance PFC functioning [48].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“This hypothesis is supported by recent work in rodents, which demonstrated enhanced neural activity in the amygdala after peripheral LPS-administration [59], [60].”

What the sources say

• Not checked yetcites [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 yetcites [60] H Engler, 2011, Acute amygdaloid response to systemic inflammation., Brain, Behavior and Immunity source

In the paper

“In humans experimental or pharmacological stress studies have reported inconsistent effects with impairments as well as enhancements being reported [42], [46], [47].”

What the sources say

• Not checked yetcites [42] D Schoofs, 2008, Psychosocial stress induces working memory impairments in an n-back paradigm., Psychoneuroendocrinology source
• Not checked yetcites [46] S Cornelisse, 2011, Implications of psychosocial stress on memory formation in a typical male versus female student sample., Psychoneuroendocrinology source
• Not checked yetcites [47] D Schoofs, 2009, Cold pressor stress impairs performance on working memory tasks requiring executive functions in healthy young men., Behavioral Neuroscience source

In the paper

“Animal data suggest detrimental effects of acute systemic inflammation on long term memory [3], [19], [21], 22,23.”

What the sources say

• Not checked yetcites [3] R Yirmiya, 2011, Immune modulation of learning, memory, neural plasticity and neurogenesis., Brain Behav Immun source
• Not checked yetcites [19] M Gibertini, 1995, Legionella pneumophila-induced visual learning impairment reversed by anti-interleukin-1 beta., Proc Soc Exp Biol Med source
• Not checked yetcites [21] CR Pugh, 1998, Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning., Brain, Behavior, and Immunity source

In the paper

“Studies in rodents and monkeys have established that acute stress rapidly impairs dorsolateral prefrontal cortex (DLPFC) functioning via noradrenergic and dopaminergic mechanisms [44].”

What the sources say

• Not checked yetcites [44] AF Arnsten, 2009, Stress signalling pathways that impair prefrontal cortex structure and function., Nature Reviews Neuroscience source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [57] S Kuhlmann, 2006, Arousal and cortisol interact in modulating memory consolidation in healthy young men., Behav Neurosci source
• Not checked yetcites [58] JD Payne, 2007, Stress administered prior to encoding impairs neutral but enhances emotional long-term episodic memories., Learning and Memory source

In the paper

“In line with this conclusion are recent findings in rodents showing that acute stress enhanced working memory via an enhancement of glutamatergic neurotransmission [49].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“However this effect appears to be rather short lived [45].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [4] R Dantzer, 2001, Cytokine-induced sickness behavior: where do we stand?, Brain, Behavior, and Immunity source

In the paper

“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].”

What the sources say

• Not checked yetcites [3] R Yirmiya, 2011, Immune modulation of learning, memory, neural plasticity and neurogenesis., Brain Behav Immun source

In the paper

“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].”

What the sources say

• Not checked yetcites [6] AV Turnbull, 1995, Regulation of the HPA axis by cytokines., Brain, Behavior, and Immunity source
• Not checked yetcites [28] A Reichenberg, 2001, Cytokine-associated emotional and cognitive disturbances in humans., Archives of General Psychiatry source
• Not checked yetcites [37] JS Kullmann, 2011, Effects of an Acute Inflammation on Memory Performance, Mood and Brain Activity., Zeitschrift für Medizinische Psychologie source