CENTER ON BEHAVIORAL MEDICINE

BODY-MIND CONNECTION

DISEASE

Disease:  Research Article

Disease Menu

Cytokine-Associated Emotional and Cognitive Disturbances

CITATION:  Reichenberg, A., Yirmlya, R., et al. (2001). Cytokine-Associated Emotional and Cognitive Disturbances.  Arch Gen Psychiatry. 58:445-452

ABSTRACT:  

Background: Infectious, autoimmune, and neurodegenerative diseases are associated 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 effects of low-dose endotoxemia, a well-established and safe model of host-defense activation, on emotional, cognitive, immunological, and endocrine parameters.

Methods: In a double-blind, crossover study, 20 healthy male volunteers completed 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 collected hourly, and rectal temperature and heart rate were monitored continuously.

Results: Endotoxin had no effects on physical sickness symptoms, blood pressure, or heart rate. Endotoxin caused a mild increase in rectal temperature (0.5C), and in-creased the circulating levels of tumor necrosis factor a (TNF-a), soluble TNF receptors, interleukin (IL)-6, IL-1 receptor antagonist, and cortisol. After endotoxin ad-ministration, the subjects showed a transient significant increase in the levels of anxiety (effect size [ES] =0.55) and depressed mood (ES=0.66). Verbal and nonverbal memory functions were significantly decreased (ES = 0.55 to 0.64). Significant positive correlations were found between cytokine secretion and endotoxin-induced 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 caused by cyto-kine release. Hence, cytokines represent a novel target for neuropsychopharmacological research.

References

1. Capuron L, Lamarque D, Dantzer R, Goodall G. Attentional and mnemonic deficit associated with infectious disease in humans. Psycho/ Med. 1999;29:291-297.

2. Maier SF, Watkins LR. Cytokines for psychologists: implications of bi-directional immune-to-brain communication for understanding behavior, mood, and cognition. Psycho/ Rev. 1998;1501:83-107.Yirmiya R, Weidenfeld J, Pollak Y, Morag M, Morag A, Avitsur R, Barak 0, Reichenberg A, Cohen A, Shavit Y, Ovdia H. Cytokines: "depression due to a general medical condition," and antidepressant drugs. In: Dantzer R, Wollman EE, Yirmiya R, eds. Cytokines, Stress and Depression. New York, NY: Plenum Publishers; 1999:238-316.

3. Dantzer R, Aubert A, Bluthe RM, Gheusi G, Cremona S, Laye S, Konsman JP, Parnet P, Kelley KW. Mechanisms of the behavioral effects of cytokines. In: Dantzer R, Wollman EE, Yirmiya R, eds. Cytokines, Stress and Depression. New York, NY: Plenum Publishers; 1999:83-106.

4. Kent S, Bluthe RM, Kelley KW, Dantzer R. Sickness behavior as a new target for drug development. Trends Pharmacol Sci. 1992;13:24-28.

5. Fent K, Zbinden G. Toxicity of interferon and interleukin. Trends Pharmacol Sci. 1987;8:100-105.

6. McDonald EM, Mann AH, Thomas HC. Interferons as mediators of psychiatric morbidity: an investigation in a trial of recombinant alpha-interferon in hepatitis B carriers. Lancet. 1987;2:1175-1178.

7. Smith A, Tyrrell D, Coyle K, Higgins P. Effects of interferon alpha on perfor-
mance in man: a preliminary report. Psychopharmacology. 1988;96:414-416.

8. Meyers CA, Valentine AD. Neurologic and psychiatric adverse effects of immu-
nological therapy. CNS Drugs. 1995;3:56-68.

9. Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P. Mood and cognitive side effects of interferon-alpha therapy. Semin Oncol. 1998;25:39-47.

10. Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, Ulmer AJ, Zahringer U, Seydel U, Di Padova F. Bacterial endotoxin: molecular relation-ships of structure to activity and function. FASEB J. 1994;8:217-225.

11. Burrell R. Human responses to bacterial endotoxin. Circ Shock. 1994;43:137-153.

12. Michie HR, Manogue KR, Spriggs DR, Revhaug A, O'Dwyer ST, Dinarello CA, Cerami A, Wolff SM, Wilmore DW. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988;318:1481-1486.

13. Spinas GA, Bloesch D, Keller U, Zimmerli W, Cammisuli S. Pretreatment with ibuprofen augments circulating tumor necrosis factor-alpha, interleukin-6 and elastase during acute endotoxinemia. J Infect Dis. 1991;163:89-95.

14. Hermann DM, Mullington J, Hinze-Selch D, Schreiber W, Galanos C, Pollmacher T. Endotoxin-induced changes in sleep and sleepiness during the day. Psychoneuroendocrinology. 1998;23:427-437.

15. Korth C, Mullington J, Schreiber W, Pollmacher T. Influence of endotoxin on day-time sleep in humans. Infect Immun. 1996;64:1110-1115.

16. Pollmacher T, Mullington J, Korth C, Schreiber W, Hermann D, Orth A, Galanos C, Holsboer F. Diurnal variations in the human host response to endotoxin. J Infect Dis. 1996;174:1040-1045.

17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994.

18. McCaffrey RJ, Ortega A, Orsillo SM, Nelles WB, Haase RF. Practice effects in repeated neuropsychological assessments. Clin Neuropsychol. 1992;6:32-42.

19. Galanos C, Luderitz 0, Westphal O. Isolation and purification of a standardized lipopolysaccharide from Salmonella abortus equi. In: Homma JY, Kanegasaki S, Luderitz 0, Shitsa T, Westphal 0, eds. Bacterial Endotoxins. Weinheim, Germany: Verlag Chemie; 1984:409-420.

20. Green P, Allen LM. Manual for the CogniSyst Story Recall Test. Durham, NC: CogniSyst Inc; 1995.

21. Meador KJ, Taylor HS, Loring DW. Medical College of Georgia (MCG) Complex Figures. Augusta: Medical College of Georgia; 1991.

22. Spreen 0, Strauss E. A Compendium of Neuropsychological Tests. 2nd ed. New York, NY: Oxford University Press; 1998.

23. Lezak MD. Neuropsychological Assessment. 3rd ed. New York, NY: Oxford University Press; 1995.

24. Ruff RM, Allen CC. Ruff 2 & 7 Selective Attention Test: Professional Manual. Lutz, Fla: Psychological Assessment Resources Inc; 1996.

25. Wechsler D. WAIS-R Manual. New York, NY: Psychological Corp; 1981.

26. Miller EN. California Computerized Assessment Package. Los Angeles: University of California at Los Angeles; 1993.

27. D'Elia LF, Satz P. Manual for the Color Trail Making Test. Lutz, Fla, Psychological Assessment Resources Inc; 1996.

28. Borkowski JG, Benton AL, Spreen 0. Word fluency and brain damage. Neuropsychologia. 1967;5:135-140.

29. Lubin B. Depression Adjectives Check List: Manual. San Diego, Calif: Educational and Industrial Testing Service; 1981.

30. Spielberger CA, Gorsuch RL, Lushene RE. Manual for the State-Trait Anxiety Inventory. Palo Alto, Calif: Psychologists Press; 1970.

31. Mullington J, Korth C, Hermann DM, Orth A, Galanos C, Holsboer F, Pollmacher T. Dose-dependent effects of endotoxin on human sleep. Am J Physiol Regul lntegr Comp Physiol. 2000;278:R947-R955.

32. Winer BJ. Statistical Principles in Experimental Design. 2nd ed. New York, NY: McGraw-Hill Co; 1971.

34. Cohen J. Statistical Power Analysis for the Behavioral Sciences, Revised Edi-tion. New York, NY: Academic Press; 1977.

35. Norusis MJ. SPSS Advanced Statistics 6.1. Chicago, Ill: SPSS Inc; 1998

36. Tabachnick BG, Fidell LS. Using Multivariate Statistics. 2nd ed. New York, NY: Harper-Collins Publishers; 1989.

37. Hall SR, Smith AP. Behavioral effects of infectious mononucleosis. Neuropsychobiology. 1996;33:202-209.

38. Smith AP, Tyrrell DA, Barrow GI. Mood and experimentally induced respiratory virus infections and illness. Psycho! Health. 1992;6:205-212.

39. Meijer A, Zakay-Rones Z, Morag A. Post-influenza psychiatric disorder in adolescents. Acta Psychiatr Scand. 1988;78:176-181.

40. Morag M, Yirmiya R, Lerer B, Morag A. Influence of socioeconomic status on
behavioral, emotional and cognitive effects of rubella vaccination: a prospec-
tive, double blind study. Psychoneuroendocrinology. 1998;23:337-351.

41. Yirmiya R. Behavioral and psychological effects of immune activation: implica-
tions for "depression due to a general medical condition." CurrOpin Psychiatry.
1997;10:470-476.

42. Holsboer F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J Psychiatr Res. 1999;33:181-214.

43. Ferrari R. The role of TNF in cardiovascular disease. Pharmacal Res. 1999;40: 97-105.

44. Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry. 1998;55:580-592.

45. Bauer J, Hohagen F, Gimmel E, Bruns F, Lis S, Krieger S, Ambach W, Guthmann A, Grunze H, Fritsch-Montero R, Weissbach A, Ganter V, Frommberger V, Riemann D, Berger M. Induction of cytokines synthesis and fever suppresses REM sleep and improves mood in patients with major depression. Biol Psychiatry. 1995;38:611-621.

46. Meyers C. Mood and cognitive disorders in cancer patients receiving cytokine therapy. In: Dantzer R, Wollman EE, Yirmiya R, eds. Cytokines, Stress and De-pression. New York, NY: Plenum Publishing Corp; 1999:75-82.

47. Aubert A, Vega C, Dantzer R, Goodall G. Pyrogens specifically disrupt the acquisition of a task involving cognitive processing in the rat. Brain Behav Immun. 1995;9:129-148.

48. Gibertini M. IL1 beta impairs relational but not procedural rodent learning in a water maze task. Adv Exp Med Biol. 1996;402:207-217.

49. Oitzl MS, van Oers H, Schobitz B, de Kloet ER. Interleukin-1 beta, but not interleukin-6, impairs spatial navigation learning. Brain Res. 1993;613:160-163.

50. Pugh RC, Kumagawa K, Fleshner M, Watkins LR, Maier SF. Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning. Brain Behavlmmun. 1998;12:212-229.

51. Bender BG, Lerner JA, Poland JE. Association between corticosteroids and psychological change in hospitalized asthmatic children. Ann Allergy Asthma lmmunol. 1991;66:414-419.

52. Hatzinger M, Z'Brun A, Hemmeter U, Seifritz E, Baumann F, Holsboer-Trachsler E, Heuser IJ. Hypothalmic-pituitary-adrenal system function in patients with Alzheimer's disease. Neurobiol Aging. 1995;16:205-209.

53. Kirschbaum C, Wolf OT, May M, Wippich W, Hellhammer DH. Stress and drug-induced elevation of cortisol levels impair explicit memory in healthy adults. Life Sci. 1996;58:1475-1483.

54. Newcomer JW, Craft S, Hershey T, Askins K, Bardgett ME. Glucocorticoid-induced impairment in declarative memory performance in adult humans. JNeurosci. 1994;14:2047-2053.

55. Plihal W., Born J. Memory consolidation in human sleep depends on inhibition of glucocorticoid release. Neuro report. 1999;10:2741-2747.

56. de Quervain DJ, Roozendaal B, McGaugh JL. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature. 1998;394:787-790.

57. Roozendaal B, Nguyen BT, Power AE, McGaugh JL. Basolateral amygdala nor-adrenergic influence enables enhancement of memory consolidation induced by hippocampal glucocorticoid receptor activation. Proc Nat/Acad Sci U S A. 1999; 96:11642-11647.

58. Wolkowitz OM, Reus VI, Weingartner H, Thompson K, Breier A, Doran A, Rubinow D, Pickar D. Cognitive effects of corticosteroids in man. Am J Psychiatry. 1990;147:1297-1303.

59. Newcomer JW, Selke G, Melson AK, Hershey T, Craft S, Richards K, Alderson AL. Decreased memory performance in healthy humans induced by stress-level cortisol treatment. Arch Gen Psychiatry. 1999;56:527-533.

60. Wechsler D. Wechsler Memory Scale, Revised Manual. San Antonio, Tex: Psychological Corp; 1987.

61. Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Annu Rev Med. 2000;51:207-229.

62. McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Rev. 1995;21:195-218.

63. Thornton AE, Raz N. Memory impairments in multiple sclerosis: a quantitative review. Neuropsychology. 1997;11:357-366.