Cytokine-associated emotional and cognitive disturbances in humans

Background: Infectious, autoimmune, and neurodegenerative diseases are asso ciated with profound psychological disturbances. Studies in animals clearly demonstrate that cytokines mediate illness-associated behavioral changes. However, the mechanisms underlying the respective psychological alterations in humans have not been established yet. Therefore, we investigated the ef fects of low-dose endotoxemia, a well-established and safe model of host-de fense activation, on emotional, cognitive, immunological, and Endocrine par ameters. Methods: In a double-blind, crossover study, 20 healthy male volunteers com pleted psychological questionnaires and neuropsychological tests 1, 3, and 9 hours after intravenous injection of Salmonella abortus equi endotoxin (0 .8 ng/kg) or saline in 2 experimental sessions. Blood samples were collecte d hourly, and rectal temperature and heart rate were monitored continuously . Results; Endotoxin had no effects on physical sickness symptoms, blood. pre ssure, or heart rate. Endotoxin caused a mild increase in rectal temperatur e (0.5 degreesC), and increased the circulating levels of tumor necrosis fa ctor or (TNF-alpha), soluble TNF receptors, interleukin (IL)-6, IL-1 recept or antagonist, and cortisol. After endotoxin administration, the subjects s howed a transient significant increase in the levels of anxiety (effect siz e [ES] = 0.55) and depressed mood (ES = 0.66). Verbal and nonverbal memory functions were significantly decreased (ES = 0.55 to 0.64). Significant pos itive correlations were found between cytokine secretion and endotoxin-indu ced anxiety (r = 0.49 to r = 0.60), depressed mood (r = 0.40 to r = 0.75), and decreases in memory performance (r = 0.46 to r = 0.68). Conclusions: In humans, a mild stimulation of the primary host defense has negative effects on emotional and memory functions, which are probably caus ed by cytokine release. Hence, cytokines represent a novel target for neuro psychopharmacological research.