 |
|
Cytokine-Associated Emotional and Cognitive Disturbances in Humans
Abraham Reichenberg, PhD;
Raz Yirmiya, PhD;
Andreas Schuld, MD;
Thomas Kraus, MD;
Monika Haack, MA;
Abraham Morag, MD;
Thomas Pollmächer, MD
Arch Gen Psychiatry. 2001;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 (0.5°C),
and increased the circulating levels of tumor necrosis factor  (TNF-),
soluble TNF receptors, interleukin (IL)-6, IL-1 receptor antagonist, and cortisol.
After endotoxin administration, 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 cytokine
release. Hence, cytokines represent a novel target for neuropsychopharmacological
research.
INTRODUCTION
INFECTIOUS DISEASES are associated with profound behavioral disturbances.
These are collectively termed sickness behavior (SB)
and include malaise, fatigue, depression, anorexia, hyposomnia or hypersomnia,
decreased physical and social activities, and cognitive disturbances.1, 2, 3 Several lines of evidence
suggest that inflammatory cytokines, such as tumor necrosis factor
(TNF-), interleukin (IL)-1, and IL-6, meditate these disturbances.
In animals, SB can be induced by administration of cytokines, and antagonists
or synthesis blockers of cytokines abolish SB in response to various immune
challenges.2, 3, 4, 5
Studies in humans indicate that administration of cytokines (particularly
interferons and IL-2) produces behavioral alterations similar to SB in animals,
as well as depressive symptoms and impairments of memory, attention, and executive
functions.6, 7, 8, 9, 10
However, these studies are limited because of 2 major reasons: (1) In general,
effects of cytokines have been studied in severely ill patients, and thus
may add to or interfere with different preexisting medical and psychological
conditions. (2) The high doses that have been administered induce prominent
physical sickness symptoms that by themselves are likely to compromise cognitive
performance and the patients' emotional condition. Therefore, it is desirable
to investigate the emotional and cognitive effects of experimental immunostimulation
in healthy subjects.
The only established experimental model for assessing the acute host
response to infection in humans is the administration of endotoxin (lipopolysaccharide).
Purified endotoxin is not infectious, but provides a potent acute stimulus
of primary host responses.11 In experimental
animals, endotoxin rapidly induces the production and secretion of cytokines,
and elicits SB symptoms, which can be blocked by antagonists, synthesis blockers,
or antibodies to proinflammatory cytokines.3, 4
In humans, endotoxin administration was found to induce a "flu-like" syndrome
characterized by fever, malaise, and increased production and secretion of
cytokines (particularly TNF-, IL-6, and IL-1 receptor antagonist) and
cortisol. Studies using purified endotoxin preparations for use in humans
from Escherichia coli or from Salmonella abortus equi have shown that low doses are safe and well
tolerated.12, 13, 14, 15, 16, 17
Extent and duration of endotoxin-induced host responses are dose-dependent.
For example, low amounts of S abortus equi endotoxin
(0.8 ng/kg body weight) administered to healthy volunteers in the morning
have been shown to induce clear-cut increases in the circulating levels of
cytokines and cortisol, but no physical sickness symptoms.15, 16, 17
Hence, we used this dose and preparation of endotoxin to test the hypotheses
that endotoxin negatively affects mood, the level of anxiety, memory, attention,
and executive functions in healthy volunteers. Moreover, we explored whether
these effects are quantitatively related to the secretion of cytokines or
cortisol.
SUBJECTS AND METHODS
SUBJECTS
The study was approved by an independent ethics committee. Twenty male
subjects (mean age, 23.7 ± 3.3 years; range, 19-30 years; mean years
of education, 15.4 ± 2.9; range, 13-23; and mean body weight, 73.1
± 9.6 kg; range, 52-90 kg) participated in the study. Subjects were
recruited by advertisements presented on the advertising boards of the universities
in Munich. Before detailed screening, the subjects were informed about the
study design, including information about the immunological and endocrine
effects of endotoxin, and the extent and time course of symptoms to be expected.
Afterward, each subject went through a complete physical and psychiatric assessment.
The physical examination included electroencephalogram, electrocardiogram,
blood sedimentation rate, complete blood cell count, liver enzymes, electrolytes,
urinalysis, quantitative urine screening for cannabinoids, amphetamines, opioids,
benzodiazepines, barbiturates, cocaine metabolites, and phenylcyclidine, as
well as hepatitis B virus test. Moreover, an interview was conducted by an
experienced psychiatrist to evaluate the presence and the history of any Axis
I psychiatric disorder according to DSM-IV.18 Exclusion criteria were as follows: (1) presence
of any medical illness; (2) presence of any clinically significant abnormality
in blood and urine tests (including evidence for recent drug use), in the
electroencephalogram, electrocardiogram, and neuropsychological tests assessing
memory, attention, and executive functions (Figure Recall, Digit Span Forward,
and Trail Making Test [TMT A and B], respectively); (3) history of allergies,
autoimmune, liver, and other severe or chronic diseases; (4) presence or history
of any Axis I psychiatric disorder; (5) history of seizures; (6) actual or
recent (during the last 2 weeks) intake of any kind of prescription or nonprescription
drug; and (7) shift work or time zone shifts (>3 hours) during the last 6
weeks. Subjects who successfully passed the screening procedure were considered
eligible to participate in the experiment and enrolled after written informed
consent had been obtained.
PROCEDURE
The study was conducted in a clinical research unit using a balanced,
randomized, double-blind, crossover design. All technical equipment, including
the blood sampling device, was housed in a room adjacent to the sound-shielded
experimental room. Every subject passed 2 testing sessions, separated by 10
days. Subjects spent the night before each experimental session in the research
unit. Upon their first arrival in the evening, a battery of neuropsychological
and emotional tests, assessing memory, learning, attention, executive functions,
and mood was given for adaptation and to control for practice effects.19 Different versions of these tests were used in the
experimental testing sessions. In the next morning, an intravenous cannula
was inserted into an antecubital forearm vein for intermittent blood sampling
and drug injection. At 9 AM each subject was injected intravenously with endotoxin
(0.8 ng of S abortus equi endotoxin per kilogram
of body weight) in one session and with the same volume of 0.9% saline solution
in the other session. Salmonella abortus equi endotoxin
had been prepared for use in humans and was available as a sterile solution
free of proteins and nucleic acids (for more details, see Galanos et al20). This preparation has proven to be safe in various
studies of other groups (for review, see Burrell12)
and in studies at the Max Planck Institute of Psychiatry, including more than
80 subjects since 1991.15, 16, 17
The order of injections was balanced, so that half of the subjects received
the saline injection and half received the endotoxin injection first. No significant
differences were found between the groups defined by the treatment order in
age, years of education, or body weight. The experimenter and the subject
were blind with respect to the group assignment. For safety reasons, a physician
was aware of the subject's group assignment, but he did not take part in the
testing procedures. Yet, this physician was also permanently on call during
every experimental session. During each session, subjects were tested 3 times,
at 1 to 2, 3 to 4, and 9 to 10 hours postinjection (see shaded areas over Figure 1), using different versions of the
neuropsychological tests every time. Blood was collected at baseline, and
at hourly intervals up to 10 hours postinjection. Rectal temperature was measured
continuously using a thermistor probe. Heart rate was monitored continuously
and blood pressure hourly. At the end of each experimental day, subjects underwent
a thorough physical examination before discharge from the clinical research
unit.
NEUROPSYCHOLOGICAL ASSESSMENT
The neuropsychological test battery assessed verbal and nonverbal memory,
learning, attention, and executive functions. Six parallel test versions were
used, so each subject was administered a different version on each of the
3 testing periods in each of the 2 testing sessions (see the "Procedure" subsection
of the "Subjects and Methods" section). The order in which the different test
versions were administered was counterbalanced across subjects to avoid any
nonrandom version-dependent bias.19 The individual
tests were presented in a fixed order in all 6 versions.
Memory and learning were assessed using 3 tests. Story Recall21: subjects are requested to repeat a 25-item story
from memory immediately, and 30 minutes after presentation. Figure Recall22, 23: subjects are instructed to copy
an 18-item figure, and to reproduce it from memory 3 and 30 minutes later,
and Word List Learning24: subjects are requested
to immediately repeat a 15-word list. This procedure is repeated 5 consecutive
times. For all memory tests the total number of correct verbatim recall is
counted. The Ruff 2 and 7 cancellation test,25
the Digit Span Forward,26 and the Digit Symbol26 tests were used to assess attention. The numbers
of correct responses were counted. Attention was also assessed using a computerized
Simple Reaction Time test,27 in which subjects
are instructed to press the space bar on a keyboard as soon as they see a
digit, as well as the Continuous Performance Test,27
in which subjects are instructed to press the space bar as soon as they see
2 identical digits one after the other. The mean response time in both tasks
was measured. The colored TMT A and B28 and
the Word Fluency test23, 29 were
used to assess executive functions. The time needed to complete the TMT A
and B, and the sum of correct words produced for the 3 letters in the Word
Fluency test were counted.
Emotional state was assessed during the middle of each testing period.
Depressed mood was assessed using the Depression Adjectives Check List,30 and anxiety was assessed using the State Anxiety
Inventory.31
BEHAVIORAL ASSESSMENT
Physical sickness symptoms (headaches, muscle pain, shivering, nausea,
breathing difficulties, and fatigue) were assessed at the end of each testing
period, by a questionnaire using a 5-point Likert scale (0, no symptoms, to
4, very severe symptoms). Food and water consumption were measured at 0 to
4 (consumption of crackers), 4 to 5 (standardized lunch), and 5 to 10 hours
(consumption of crackers).
PLASMA LEVELS OF CYTOKINES AND CORTISOL
Plasma blood was collected in tubes containing sodium ethylenediaminetetraacetic
acid and aprotinin, and was immediately centrifuged, aliquoted, and frozen
to -20°C. The plasma level of cortisol was determined by a radioimmunoassay,
and the plasma levels of cytokines and soluble cytokine receptors were assessed
by commercial enzyme-linked immunosorbent assays (for more details see Mullington
et al32).
STATISTICAL ANALYSES
The main hypothesis concerning treatment effects on emotional status
and neuropsychological performance was tested using repeated-measures analyses
of variance. Analyses of variance were also used to examine the treatment
effect on physical sickness symptoms, plasma levels of cytokines and cortisol,
and body temperature. The level of significance was set at the critical value
of P = .05 (2-tailed). Whenever significant treatment
x time interactions were found, the simple effects were analyzed as
suggested by Winer,33 and Scheffe's adjustments
were applied. Effect sizes (ES) were calculated using Cohen's formula.34 To assess the associations between changes from the
placebo to the endotoxin condition in physiological (cytokines and cortisol
secretion) and psychological (emotional states and neuropsychological performance)
parameters, Pearson correlation coefficients were calculated. In these correlations,
the variable that represented the difference between endotoxin- and placebo-induced
secretion of cytokines and cortisol was computed as the cumulative area under
the response curve (the area between the endotoxin and placebo curves) for
each cytokine and for cortisol. This variable was calculated for each time
interval in which psychological assessment was conducted (ie, 0-2, 0-4, and
0-10 hours postinjection). In addition, partial correlations were calculated
to estimate the independent associations between the physiological and psychological
parameters. For example, the partial correlation between TNF- secretion
and the change in anxiety level is the correlation between the change in TNF-
levels and the change in anxiety level, after controlling for their mutual
association with cortisol secretion.35 Since
the intercorrelations between the cytokines were very high (r>0.8), they were not entered simultaneously into the analyses.36
The assumption of normal distributions of the dependent variables was
assessed.36 No deviation from normality was
evident for any of the dependent variables. Univariate outliers were assessed
using z scores,36
and multivariate outliers were assessed using the Mahalanobis distance.36 No outliers were found with either method. To adjust
for any nonhomogeneity of covariance for the within-subject effects, we used P values that were adjusted using the Huynh-Feldt (H-F)
method.35 Analyses were carried out using SPSS
9.
RESULTS
PHYSIOLOGICAL EFFECTS OF ENDOTOXIN
Endotoxin induced a significant increase in heart rate during all testing
periods (F1,18 = 4.5, P = .04) (data not
shown). Endotoxin did not produce any significant effects on systolic or diastolic
blood pressure levels, or on the subjective rating of physical sickness symptoms
(data not shown). Food, but not water consumption was significantly reduced
in the first 4 hours postinjection (46.6 ± 6.6 vs 64.9 ± 8.0
g, in the endotoxin and saline conditions, respectively; t19 = 3.1; P = .006). Endotoxin
induced a significant increase in plasma levels of TNF-, soluble TNF
receptor p55, soluble TNF receptor p75, and IL-6, which peaked during the
first testing period and monotonically declined thereafter (Figure 1A-C). These effects were reflected by significant treatment
x time interactions (F7,126 = 43.8, 26.7, 14.6, and 18.5,
respectively, all P<.001, by the H-F method).
Plasma levels of IL-1 receptor antagonist started to rise during the first
testing period, peaked during the second, and were still elevated at the last
period (F7,126 = 90.6, P<.001, by H-F
method, for a treatment x time interaction) (Figure 1D). Endotoxin induced a significant increase in rectal temperature
(reaching about 0.5°C), which started during the first testing period,
and peaked during the second period (Figure
1E). This finding was reflected by a significant treatment x
time interaction (F7,126 = 8.4, P<.001,
by H-F method). The endotoxin-induced elevation in cortisol levels began at
the first session, peaked at the second, and returned to placebo levels at
the last (F7,126 = 5.8, P<.001, by
H-F method, for a treatment x time interaction) (Figure 1F).
EMOTIONAL AND COGNITIVE EFFECTS OF ENDOTOXIN
A significant endotoxin-induced increase in anxiety level was observed
at 1 to 2 hours postinjection, but not later on. This finding was reflected
by a significant treatment x time interaction (F2,36 = 5.4, P = .009, ES = 0.55). Endotoxin produced a significant
increase in depressed mood, which was evident at 3 to 4 hours, and was followed
by relatively lower levels of depressed mood at 9 to 10 hours postinjection.
This effect was reflected by a significant treatment by time interaction (F2,36 = 7.7, P = .003, by H-F method; ES = 0.66)
(Figure 2).
|
|
|
|
Figure 2. Endotoxin-induced changes over
time (mean ± SEM) in emotional and memory parameters (N = 20). The
effects of endotoxin on anxiety levels (A), depressed mood (B), immediate
Story Recall (C), delayed Story Recall (D), Word List Learning (E), and delayed
Figure Recall (F) were measured at 1, 3, and 9 hours after either endotoxin
or placebo injection.
|
|
|
Endotoxin did not cause any significant changes in measures of attention
or executive functions (ie, the simple reaction time, Continuous Performance
Test, Digit Cancellation, Digit Symbol, Digit Span, TMT A and B, or Word Fluency
tests) during any testing session. In contrast, endotoxin administration produced
a global decrease in memory functions, during all testing periods, reflected
by decreased immediate recall of story items (F1,18 = 7.1; P = .01; ES = 0.62), reduced delayed Story Recall (F1,18 = 5.4; P = .03; ES = 0.55), a deficit
in immediate and delayed recall of figure items (F1,18 = 8.8, P = .008, ES = 0.70; F1,18 = 7.5, P = .01, ES = 0.64, respectively), and decreased performance in Word
List Learning (F1,18 = 6.9, P = .01, ES
= 0.61) (Figure 2). No order effects
were evident in any of the emotional or cognitive measures.
All analyses of variance are based on a priori hypotheses regarding
elevated negative mood and decreased cognitive performance, and therefore
no correction for multiple comparisons was necessary.36
However, it should be noted that even after Bonferroni corrections, all mood
and memory tests (except the delayed recall of the logical memory) remained
significant (P = .01).
Endotoxin-induced changes in anxiety level were significantly (P<.05) and positively correlated with the secretion
of each cytokine in the first testing period (r =
0.49 to r = 0.60) (Figure 3). Endotoxin-induced changes in depressed mood were significantly
(P<.01) and positively correlated with the secretion
of each cytokine in the first and second testing periods (r = 0.40 to r = 0.75), but not in the last
period (Figure 3). Endotoxin-induced
impairments in immediate and delayed Story Recall were significantly (P<.01) and positively correlated with the secretion
of every cytokine in the first testing period (r
= 0.55 to r = 0.68), and endotoxin-induced impairments
in immediate and delayed Figure Recall were significantly (P<.05) correlated with the secretion of every cytokine, in the first
and second testing periods (r = 0.46 to r = 0.63), but not in the last period (Figure 3). The association between endotoxin-induced changes in
Word List Learning and cytokine secretion was positive, but it did not reach
significance. Endotoxin-induced changes in depressed mood (at 1 to 2 and 3
to 4 hours postinjection), and Figure Recall (at all testing periods) were
also significantly (P<.05) and positively correlated
with serum cortisol secretion (r = 0.44 to r = 0.74). In contrast, endotoxin-induced decrease in depressed
mood at 9 to 10 hours postinjection was significantly (P<.05) and negatively correlated with serum cortisol secretion (r = -0.48).
Partial correlation analysis with each cytokine completely eliminated
the correlation between cortisol secretion and both anxiety and memory impairments
(Table 1). However, the partial
correlations between depressed mood and cortisol secretion as well as between
depressed mood and cytokine secretion were still significant, suggesting that
cytokines and cortisol are independently associated with endotoxin-induced
increase in depressed mood.
|
|
|
|
Partial Correlations Between Endotoxin-Induced Cytokines and Cortisol
Secretion and Changes in Psychological Variables*
|
|
|
Partial correlation analysis was also employed to examine the relationships
between the emotional and memory changes. After controlling for the association
between cytokines and memory, no significant correlations were found between
anxiety or depression levels and any of the memory functions.
COMMENT
The results of this study demonstrate that experimental immune activation
by endotoxin produces alterations in emotional states and decreased performance
in memory tests. In this study, we used a dose of endotoxin that consistently
stimulates cytokine production without inducing subjective feelings of illness.
Thus, the endotoxin-induced increase in anxiety and depressed mood and the
decrement in performance in both verbal and nonverbal memory cannot be attributed
to a perceived illness-associated distress.
Endotoxin-induced changes in emotional parameters were found to have
a complex time course, characterized by an early elevation in anxiety levels,
followed by an increase in depressed mood, which later reversed into relatively
lower levels of depressed mood. An elevation in anxiety and depression levels
after immune challenges has been documented in both clinical and experimental
settings.9, 37, 38, 39, 40, 41
Our findings extend these reports by demonstrating that endotoxin-induced
increases in anxiety and depressed mood are strongly associated with the extent
of cytokine secretion. Both anxiety and depression were also significantly
associated with cortisol secretion. However, the time course of cortisol secretion,
which began to increase when anxiety was already present, and the results
of the partial correlation analysis, which demonstrated that the association
between cortisol and anxiety is entirely mediated by the association between
cytokines and anxiety, suggest that increased anxiety is produced through
the actions of cytokines, rather than hypothalamic-pituitary-adrenal system
activation. In contrast, the simultaneous elevation in cortisol secretion
and depressed mood, and the independent associations between cytokines, cortisol,
and depressed mood, suggest that both cytokine secretion and hypothalamic-pituitary-adrenal
activation contribute to endotoxin-induced increase in depressed mood. This
is consistent with previously suggested roles for both cytokines41
and hypothalamic-pituitary-adrenal system activation (particularly corticotropin-releasing
hormone secretion)42 in depressive symptoms.
Inflammatory cytokines have also been implicated in cardiovascular disease.43 Increasing knowledge about the effects of cytokines
on mood might be very stimulating for the discussions about the association
between depression and cardiovascular disease. This association is at present
mainly discussed from the perspective of a presumed negative influence of
depression on the cardiovascular system.44
However, it is tempting to speculate that cytokines may mediate a negative
influence of cardiovascular disease on mood.
Somewhat unexpectedly, depressed mood ratings were lower in the endotoxin
condition compared with placebo, at 9 to 10 hours after injection. Similarly,
depressed patients given a high dose of endotoxin in the evening "rapidly
exhibited pronounced apathy," but reported improved mood 15 hours after endotoxin
administration, when cytokine levels and fever subsided.45
In that study, a high amount of endotoxin was administered, inducing chills
and an increase in rectal temperature to about 39°C. Therefore, improved
mood in the following morning might indicate psychological relief caused by
the disappearance of physical sickness symptoms. However, in the present study
subjects did not perceive major physical sickness symptoms. Therefore, the
biphasic mood response to endotoxin might indicate that very low amounts of
cytokines, which the subjects were exposed to at the end of the present experiment,
might have a positive effect on mood, in contrast to the negative effect of
higher concentrations reached rapidly after the injection of endotoxin. Interestingly,
very low amounts of endotoxin (0.2 ng/kg) administered at night promote slow-wave
sleep, whereas the same dose as administered in the present study induces
a transient sleep disturbance.32 Hence, it
seems worthwhile to pursue the idea that inflammatory cytokines might influence
some complex brain functions in opposite directions, depending on the amounts
present in the brain. For this purpose, a study similar to the present one,
but including various doses of endotoxin, would be useful.
The results of the present study indicate that experimental immune activation
produces a global decrement in performance of declarative memory: both verbal
and nonverbal, immediate and delayed memory functions were decreased. These
findings are consistent with previous research in clinical populations, reporting
that memory impairments are a common adverse effect of cytokine (especially
interferon) therapy,46 and viral (eg, influenza)
infection.1 The findings are also consistent
with research in animals, which demonstrated that peripheral or central administration
of either endotoxin or IL-1ß produces decreased performance in various
learning and memory paradigms.47, 48, 49, 50
Endotoxin-induced memory decrements in performance are relatively long-lasting,
as they were evident even 10 hours after the injection, when all of the other
responses to endotoxin (fever, anorexia, anxiety, and depressed mood) had
already subsided. The decrease in memory functions was probably not secondary
to the changes in either anxiety or depression, because memory was affected
even after the mood effects had resolved, and because there were no correlations
between the mood and cognitive changes, at each testing period.
The endotoxin-induced decrease in memory performance were selectively
associated with cytokine secretion in the first 2 testing periods, and did
not correlate with cortisol secretion, suggesting that these effects of endotoxin
are not mediated by hypothalamic-pituitary-adrenal system activation. This
notion is further supported by the finding that the decrease in memory performance
was present before increases in cortisol levels. Although in previous studies
stress and glucocorticoids were associated with decreased memory performance
in humans,51, 52, 53, 54, 55, 56, 57, 58, 59
the levels of cortisol in these studies were higher than those measured in
the present experiment. Furthermore, a recent study59
reported that after cortisol administration memory functions (as measured
by the Story Recall test) were impaired. However, in that study the decrease
in memory performance did not parallel the rise in plasma cortisol levels,
and appeared only after 4 days of administration. Thus, whereas cortisol secretion
does not seem to contribute to the decrease in memory performance that is
associated with acute host defense activation, it may still be detrimental
in more chronic conditions of immune activation.
The endotoxin-induced memory decrement, approximating 0.5- to 1.0-SD
reductions from placebo level performance, is clinically relevant. For example,
similar 1-SD changes in performance on the story recall test on the Wechsler
Memory Scale would lower an individual's age-normalized classification by
1 level.60 Although the endotoxin-induced increase
in anxiety and depression also had a 0.5-SD magnitude, the absolute severity
of negative mood did not reach clinical levels.
Our study has several limitations. First, the finding of a correlation
between cytokine secretion and psychological measures does not provide conclusive
evidence that cytokines directly mediate the psychological changes. Second,
because the levels of cytokines are highly correlated, it is difficult to
draw any conclusion with respect to the specific role of each cytokine in
mediating the observed psychological effects. Finally, in the present experiment
endotoxin was given acutely, whereas most infectious conditions have a more
chronic nature. In future studies, it will be necessary to gather direct evidence
for a causative role of cytokines, using cytokine antagonists, such as soluble
TNF receptors, which very recently have become available.61
The use of such compounds should also clarify the role of specific cytokines
in the psychological effects of endotoxin. Finally, other experimental models
of immune activation and cytokine secretion should be used to demonstrate
chronic effects.
The results of this study indicate that activation of the immune system
by low doses of endotoxin can produce significant emotional and memory disturbances,
which are positively correlated with endotoxin-induced cytokine secretion.
Elevation of cytokine secretion, both in the periphery and within the brain,
is associated not only with infectious diseases, but also with autoimmune
diseases (eg, multiple sclerosis, rheumatoid arthritis), stroke, brain trauma,
and neurodegenerative disease, such as Alzheimer disease.62
Depression and anxiety are highly prevalent in all of these conditions.41 Memory impairments are also commonly associated with
infectious1 and autoimmune diseases,63 and are particularly evident in conditions that involve
central inflammatory processes, including stroke and neurodegenerative diseases.24 Obviously, in such conditions several pathophysiological
mechanisms are involved in producing the emotional and the memory deficits,
but the results of the present study suggest that at least some of the illness-induced
behavioral pathology may be directly caused by cytokine secretion. This hypothesis
has important implications for the development of new psychopharmacological
approaches that should target the negative psychological effects of cytokines
in various medical conditions.
AUTHOR INFORMATION
Accepted for publication November 17, 2000.
Supported by a grant from the German-Israeli Foundation for Scientific
Research and Development, Jerusalem, Israel (Drs Yirmiya and Pollmächer).
We note with sorrow the death of Abraham Morag, MD.
Dr Yirmiya is a member of the Eric Roland Center for Neurodegenerative
Diseases at the Hebrew University of Jerusalem.
We thank Chris Galanos, PhD (Max Planck Institute for Immunobiology,
Freiburg), for kindly providing the endotoxin preparation used in this study.
From the Department of Psychology, the Hebrew University, Jerusalem,
Israel (Drs Reichenberg and Yirmiya); Max Planck Institute of Psychiatry,
Munich, Germany (Drs Schuld, Kraus, and Pollmächer and Ms Haack); and
the Clinical Virology Unit, Hadassah-Hebrew University Medical Center, Jerusalem
(Dr Morag). Dr Morag is deceased.
Corresponding author: Raz Yirmiya, PhD, Department of Psychology,
the Hebrew University of Jerusalem, Jerusalem, Israel (e-mail: msrazy{at}mscc.huji.ac.il).
REFERENCES
| |
1. Capuron L, Lamarque D, Dantzer R, Goodall G. Attentional and mnemonic deficit associated with infectious disease
in humans. Psychol Med. 1999;29:291-297.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
2. Maier SF, Watkins LR. Cytokines for psychologists: implications of bi-directional immune-to-brain
communication for understanding behavior, mood, and cognition. Psychol Rev. 1998;105:83-107. Review.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
3. Yirmiya R, Weidenfeld J, Pollak Y, Morag M, Morag A, Avitsur R, Barak O, 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.
4. Dantzer R, Aubert A, Bluthé RM, Gheusi G, Cremona S, Layé 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.
5. Kent S, Bluthe RM, Kelley KW, Dantzer R. Sickness behavior as a new target for drug development. Trends Pharmacol Sci. 1992;13:24-28.
FULL TEXT
| PUBMED
6. Fent K, Zbinden G. Toxicity of interferon and interleukin. Trends Pharmacol Sci. 1987;8:100-105.
FULL TEXT
7. 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.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
8. Smith A, Tyrrell D, Coyle K, Higgins P. Effects of interferon alpha on performance in man: a preliminary report. Psychopharmacology. 1988;96:414-416.
FULL TEXT
| PUBMED
9. Meyers CA, Valentine AD. Neurologic and psychiatric adverse effects of immunological therapy. CNS Drugs. 1995;3:56-68.
FULL TEXT
|
WEB OF SCIENCE
10. 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.
WEB OF SCIENCE
| PUBMED
11. Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, Ulmer AJ, Zahringer U, Seydel U, Di Padova F. Bacterial endotoxin: molecular relationships of structure to activity
and function. FASEB J. 1994;8:217-225.
ABSTRACT
12. Burrell R. Human responses to bacterial endotoxin. Circ Shock. 1994;43:137-153.
WEB OF SCIENCE
| PUBMED
13. 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.
ABSTRACT
14. 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.
WEB OF SCIENCE
| PUBMED
15. Hermann DM, Mullington J, Hinze-Selch D, Schreiber W, Galanos C, Pollmächer T. Endotoxin-induced changes in sleep and sleepiness during the day. Psychoneuroendocrinology. 1998;23:427-437.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
16. Korth C, Mullington J, Schreiber W, Pollmächer T. Influence of endotoxin on daytime sleep in humans. Infect Immun. 1996;64:1110-1115.
FREE FULL TEXT
17. Pollmächer 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.
WEB OF SCIENCE
| PUBMED
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition. Washington, DC: American Psychiatric Association; 1994.
19. McCaffrey RJ, Ortega A, Orsillo SM, Nelles WB, Haase RF. Practice effects in repeated neuropsychological assessments. Clin Neuropsychol. 1992;6:32-42.
FULL TEXT
20. Galanos C, Lüderitz O, Westphal O. Isolation and purification of a standardized lipopolysaccharide from Salmonella abortus equi. In: Homma JY, Kanegasaki S, Lüderitz O, Shitsa T, Westphal O,
eds. Bacterial Endotoxins. Weinheim, Germany: Verlag
Chemie; 1984:409-420.
21. Green P, Allen LM. Manual for the CogniSyst Story Recall Test. Durham, NC: CogniSyst Inc; 1995.
22. Meador KJ, Taylor HS, Loring DW. Medical College of Georgia (MCG) Complex Figures. Augusta: Medical College of Georgia; 1991.
23. Spreen O, Strauss E. A Compendium of Neuropsychological Tests. 2nd ed. New York, NY: Oxford University Press; 1998.
24. Lezak MD. Neuropsychological Assessment. 3rd ed. New York, NY: Oxford University Press; 1995.
25. Ruff RM, Allen CC. Ruff 2 & 7 Selective Attention Test: Professional
Manual. Lutz, Fla: Psychological Assessment Resources Inc; 1996.
26. Wechsler D. WAIS-R Manual. New York, NY: Psychological Corp; 1981.
27. Miller EN. California Computerized Assessment Package. Los Angeles: University of California at Los Angeles; 1993.
28. D'Elia LF, Satz P. Manual for the Color Trail Making Test. Lutz, Fla, Psychological Assessment Resources Inc; 1996.
29. Borkowski JG, Benton AL, Spreen O. Word fluency and brain damage. Neuropsychologia. 1967;5:135-140.
30. Lubin B. Depression Adjectives Check List: Manual. San Diego, Calif: Educational and Industrial Testing Service; 1981.
31. Spielberger CA, Gorsuch RL, Lushene RE. Manual for the State-Trait Anxiety Inventory. Palo Alto, Calif: Psychologists Press; 1970.
32. Mullington J, Korth C, Hermann DM, Orth A, Galanos C, Holsboer F, Pollmächer T. Dose-dependent effects of endotoxin on human sleep. Am J Physiol Regul Integr Comp Physiol. 2000;278:R947-R955.
33. 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 Edition. 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.
WEB OF SCIENCE
| PUBMED
38. Smith AP, Tyrrell DA, Barrow GI. Mood and experimentally induced respiratory virus infections and illness. Psychol 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.
WEB OF SCIENCE
| PUBMED
40. Morag M, Yirmiya R, Lerer B, Morag A. Influence of socioeconomic status on behavioral, emotional and cognitive
effects of rubella vaccination: a prospective, double blind study. Psychoneuroendocrinology. 1998;23:337-351.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
41. Yirmiya R. Behavioral and psychological effects of immune activation: implications
for "depression due to a general medical condition." Curr Opin Psychiatry. 1997;10:470-476.
FULL TEXT
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.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
43. Ferrari R. The role of TNF in cardiovascular disease. Pharmacol Res. 1999;40:97-105.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
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.
FREE FULL TEXT
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.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
46. Meyers C. Mood and cognitive disorders in cancer patients receiving cytokine
therapy. In: Dantzer R, Wollman EE, Yirmiya R, eds. Cytokines,
Stress and Depression. 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.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
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.
PUBMED
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.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
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 Behav Immun. 1998;12:212-229.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
51. Bender BG, Lerner JA, Poland JE. Association between corticosteroids and psychological change in hospitalized
asthmatic children. Ann Allergy. 1991;66:414-419.
WEB OF SCIENCE
| PUBMED
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.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
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.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
54. Newcomer JW, Craft S, Hershey T, Askins K, Bardgett ME. Glucocorticoid-induced impairment in declarative memory performance
in adult humans. J Neurosci. 1994;14:2047-2053.
ABSTRACT
55. Plihal W., Born J. Memory consolidation in human sleep depends on inhibition of glucocorticoid
release. Neuroreport. 1999;10:2741-2747.
WEB OF SCIENCE
| PUBMED
56. de Quervain DJ, Roozendaal B, McGaugh JL. Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature. 1998;394:787-790.
FULL TEXT
| PUBMED
57. Roozendaal B, Nguyen BT, Power AE, McGaugh JL. Basolateral amygdala noradrenergic influence enables enhancement of
memory consolidation induced by hippocampal glucocorticoid receptor activation. Proc Natl Acad Sci U S A. 1999;96:11642-11647.
FREE FULL TEXT
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.
FREE FULL TEXT
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.
FREE FULL TEXT
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.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
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.
FULL TEXT
| PUBMED
63. Thornton AE, Raz N. Memory impairments in multiple sclerosis: a quantitative review. Neuropsychology. 1997;11:357-366.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Course of Cognitive Decline in Hematopoietic Stem Cell Transplantation: A Within-subjects Design
Friedman et al.
Arch Clin Neuropsychol 2009;24:689-698.
ABSTRACT
| FULL TEXT
Fatigue in Psychiatric HIV Patients: A Pilot Study of Psychological Correlates
Paddison et al.
Psychosomatics 2009;50:455-460.
ABSTRACT
| FULL TEXT
Peripheral tumors induce depressive-like behaviors and cytokine production and alter hypothalamic-pituitary-adrenal axis regulation
Pyter et al.
Proc. Natl. Acad. Sci. USA 2009;106:9069-9074.
ABSTRACT
| FULL TEXT
Common Genetic Contributions to Depressive Symptoms and Inflammatory Markers in Middle-Aged Men: The Twins Heart Study
Su et al.
Psychosom. Med. 2009;71:152-158.
ABSTRACT
| FULL TEXT
Review: Psychopathology in multiple sclerosis: diagnosis, prevalence and treatment
Haussleiter et al.
Therapeutic Advances in Neurological Disorders 2009;2:13-29.
ABSTRACT
Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system
Dilger and Johnson
J. Leukoc. Biol. 2008;84:932-939.
ABSTRACT
| FULL TEXT
Does chronic stress lead to increased rates of recurrences of genital herpes - a review of the psychoneuroimmunological evidence?
Goldmeier et al.
Int J STD AIDS 2008;19:359-362.
ABSTRACT
| FULL TEXT
The alcohol hangover-a puzzling phenomenon
Verster
Alcohol Alcohol 2008;43:124-126.
FULL TEXT
Review: From therapy to experimental model: a hundred years of endotoxin administration to human subjects
Bahador and Cross
Innate Immunity 2007;13:251-279.
ABSTRACT
Genetic Variants in P-Selectin and C-Reactive Protein Influence Susceptibility to Cognitive Decline After Cardiac Surgery
Mathew et al.
J Am Coll Cardiol 2007;49:1934-1942.
ABSTRACT
| FULL TEXT
Human Models of Low-Grade Inflammation: Bolus versus Continuous Infusion of Endotoxin
Taudorf et al.
CVI 2007;14:250-255.
ABSTRACT
| FULL TEXT
Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers.
Sparkman et al.
J. Neurosci. 2006;26:10709-10716.
ABSTRACT
| FULL TEXT
Depression and Risk for Alzheimer Disease: Systematic Review, Meta-analysis, and Metaregression Analysis.
Ownby et al.
Arch Gen Psychiatry 2006;63:530-538.
ABSTRACT
| FULL TEXT
HELMINTH INFECTION AND COGNITIVE IMPAIRMENT AMONG FILIPINO CHILDREN
EZEAMAMA et al.
Am J Trop Med Hyg 2005;72:540-548.
ABSTRACT
| FULL TEXT
Two-Year Cognitive, Emotional, and Quality-of-Life Outcomes in Acute Respiratory Distress Syndrome
Hopkins et al.
Am. J. Respir. Crit. Care Med. 2005;171:340-347.
ABSTRACT
| FULL TEXT
Brain-Derived Tumor Necrosis Factor-{alpha} and Its Involvement in Noradrenergic Neuron Functioning Involved in the Mechanism of Action of an Antidepressant
Reynolds et al.
J. Pharmacol. Exp. Ther. 2004;310:1216-1225.
ABSTRACT
| FULL TEXT
Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS
Huijbregts et al.
Neurology 2004;63:335-339.
ABSTRACT
| FULL TEXT
Association of Fear of Terror With Low-Grade Inflammation Among Apparently Healthy Employed Adults
Melamed et al.
Psychosom. Med. 2004;66:484-491.
ABSTRACT
| FULL TEXT
Self-rated Health Is Related to Levels of Circulating Cytokines
Lekander et al.
Psychosom. Med. 2004;66:559-563.
ABSTRACT
| FULL TEXT
Effect of hyperglycemia and hyperinsulinemia on the response of IL-6, TNF-{alpha}, and FFAs to low-dose endotoxemia in humans
Krogh-Madsen et al.
Am. J. Physiol. Endocrinol. Metab. 2004;286:E766-E772.
ABSTRACT
| FULL TEXT
Integrated evolutionary, immunological, and neuroendocrine framework for the pathogenesis of chronic disabling inflammatory diseases
STRAUB and BESEDOVSKY
FASEB J. 2003;17:2176-2183.
ABSTRACT
| FULL TEXT
Cognitive Function, Fatigue, and Menopausal Symptoms in Women Receiving Adjuvant Chemotherapy for Breast Cancer
Tchen et al.
JCO 2003;21:4175-4183.
ABSTRACT
| FULL TEXT
Dietary Modifications and Fibromyalgia
Logan
Complementary Health Practice Review 2003;8:234-245.
ABSTRACT
Tryptophan as a Link between Psychopathology and Somatic States
Russo et al.
Psychosom. Med. 2003;65:665-671.
ABSTRACT
| FULL TEXT
The Relation of Severity of Depressive Symptoms to Monocyte-Associated Proinflammatory Cytokines and Chemokines in Apparently Healthy Men
Suarez et al.
Psychosom. Med. 2003;65:362-368.
ABSTRACT
| FULL TEXT
An Integrative Approach to Depression: Part 2--Assessment and Treatment
Zuess
Complementary Health Practice Review 2003;8:99-115.
ABSTRACT
Cytokines in Depression and Heart Failure
Pasic et al.
Psychosom. Med. 2003;65:181-193.
ABSTRACT
| FULL TEXT
Heart failure and depression
Miller
Eur J Heart Fail 2002;4:401-402.
FULL TEXT
Fatigue and Proinflammatory Cytokine Activity in Breast Cancer Survivors
Bower et al.
Psychosom. Med. 2002;64:604-611.
ABSTRACT
| FULL TEXT
Effects of Seasonal Allergic Rhinitis on Fatigue Levels and Mood
Marshall et al.
Psychosom. Med. 2002;64:684-691.
ABSTRACT
| FULL TEXT
Interleukin-6 (IL-6): A Possible Neuromodulator Induced by Neuronal Activity
Juttler et al.
Neuroscientist 2002;8:268-275.
ABSTRACT
Randomised trial of thyroxine to prevent postnatal depression in thyroid-antibody-positive women
HARRIS et al.
Br. J. Psychiatry 2002;180:327-330.
ABSTRACT
| FULL TEXT
|
)
in anxiety in the first testing period (A), depressed mood in the second testing
period (B), delayed Story Recall in the first testing period (C), and delayed
Figure Recall in the first testing period (D). The associations between these
psychological changes and the secretion of interleukin 6 and interleukin 1
receptor antagonist were very similar. The numbers at the top right of each
graph represent the correlation coefficient between the change in psychological
measures and TNF-