Dose-Dependent Effects of Endotoxin on Neurobehavioral Functions in Humans
PLoS One. 2011;6(12):e28330. Epub 2011 Dec 2.
Grigoleit JS, Kullmann JS, Wolf OT, Hammes F, Wegner A, Jablonowski S, Engler H, Gizewski E, Oberbeck R, Schedlowski M.
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.
PMID: 22164271
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QUOTES FROM THE ARTICLE:
Two classes of soluble factors are most often discussed to modulate cognitive functions during an inflammatory reaction: cytokines and stress hormones.
Under physiological conditions cytokines have a beneficial role on learning and memory, e.g. by promoting long term potentiation (LTP), neural plasticity and neural excitability [3], [52], [53]. Administered in higher doses or during acute inflammation cytokines demonstrated detrimental effects on learning and memory [3], [54], [55].
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]. Thus, the impaired memory performance following low-doseLPS administration might reflect this down-regulation of neural excitability.
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: 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].
Thus, the absence of a memory impairment of emotional stimuli in the high-dose LPS group together with a trend towards impaired memory performance for neutral stimuli might be due to actions of the higher and more sustained cortisol response observed after high-dose LPS administration.
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.