Cytokine-associated emotional and cognitive disturbances in humans.
Level 2 - randomized trial
Randomized double-blind crossover trial
PubMed 11343523 · doi:10.1001/archpsyc.58.5.445
What was done
In a double-blind crossover study, 20 healthy male volunteers completed psychological questionnaires and neuropsychological tests at 1, 3, and 9 hours after an intravenous injection of Salmonella abortus equi endotoxin (0.8 ng/kg) or saline across 2 experimental sessions. Blood samples were collected hourly to measure tumor necrosis factor alpha (TNF-alpha), soluble TNF receptors, interleukin (IL)-6, IL-1 receptor antagonist, and cortisol. Rectal temperature and heart rate were continuously monitored.
What was found
Endotoxin did not affect physical sickness symptoms, blood pressure, or heart rate, but caused a mild rectal temperature increase of 0.5 degrees C and elevated circulating levels of TNF-alpha, soluble TNF receptors, IL-6, IL-1 receptor antagonist, and cortisol. Following endotoxin injection, subjects exhibited a transient significant increase in anxiety (effect size [ES] = 0.55) and depressed mood (ES = 0.66), and a significant decrease in verbal and nonverbal memory functions (ES = 0.55 to 0.64). Cytokine secretion positively correlated with endotoxin-induced anxiety (r = 0.49 to r = 0.60), depressed mood (r = 0.40 to r = 0.75), and memory performance declines (r = 0.46 to r = 0.68).
Why it matters
This study provides experimental evidence in humans that systemic cytokine release induced by low-dose innate immune activation directly impairs emotional state and memory performance without causing overt physical illness.
Limits
The study was conducted in a small sample of only 20 individuals, all of whom were healthy males, limiting generalizability to females and clinical populations with chronic inflammation. The acute endotoxin challenge models transient immune activation rather than prolonged or chronic inflammatory states.
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