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This chapter presents individual cytokines and inflammatory markers and their neurophysiological and behavioral effects.
Pro-inflammatory cytokines are shown to have considerable influence on dopamine, norepinephrine, and serotonin balance, thereby exhibiting neurophysiological effects very similar to those found in ADHD.
Overall, the evidence suggests that the cause of IFN-α-induced dopamine deficiency in the striatum is different from that in ADHD, as it, as well as the symptoms it mediates, can be reduced by L-dopa, whereas in ADHD L-dopa is known not to improve symptoms.
The differences are also reflected in the fact that the dopaminergic-mediated symptoms of IFN-α administration (here: fatigue) respond only weakly to treatment by the stimulants that are well effective in ADHD and act as reuptake inhibitors of dopamine and norepinephrine, or, in the case of amphetamine, probably also increase dopamine release to a small extent.
Both IFN-α and IFN-β bind to the interferon type 1 receptor with its subtypes IFNAR-1 and IFNAR-2, whereas IFN-γ binds to the interferon type 2 receptor (IFNGR).1
The studies on effects of IFN-α on dopamine levels show inconsistent results. This is partly due to the fact that rodents were treated with human IFN-α, whereas rodents do not possess IFN type 1 receptors, so the conclusions are of limited value.2 Inconsistent results for IFN-α exist not only for dopamine, but also with respect to norepinephrine and serotonin.1
1.1.1.1.1. Influence on dopamine, serotonin, norepinephrine by IFN-α¶
IFN-α decreases striatal dopaminergic activation, which is associated with anhedonia, fatigue, and depression 345
This correlates with changes in motivation at the same time.6
IFN-α decreases dopamine levels and tetrahydrobiopterin (BH4) in the amygdala and raphe nuclei (muscularly given IFN-α).7 Cardiotrophin-1 (CT-1) and IN-6 likewise decrease BH4 levels8
It is unclear whether this is mediated by nitrogen oxide. This was partly affirmed,7 partly denied.9
IFN-α in the brain by microglia and astrocytes IFN-α occurs in lower quantities than IL-6 and MCP-1, IFN-α in the brain again increased
IL-6 in the brain
IL-1 in the brain by microglia
TNF-α in the brain
MCP-1 (monocyte chemoattractant protein-1) in the brain
Oxidative stress (superoxidants) in the brain by microglia
Hepatitis C-infected subjects received IFN-α and a radioactivity-measurable L-dopa (F-dopa). IFN-α caused significantly increased uptake of F-dopa and decreased turnover of F-dopa in caudate nucleus, putamen, and those areas of the ventral striatum that were diminished activated by IFN-α. The changes in F-dopa uptake and turnover correlated with depression and fatigue3
In contrast, in Parkinson’s disease, it is observed:
Decreased F-dopa uptake and increased turnover of F-dopa10
Decreased F-dopa uptake in the putamen and increased uptake in the PFC11
Decreased activity and dopamine storage in the striatum12
Norepinephrine and dopamine levels and tyrosine hydroxylase in rats were induced by IFN-α by 7-day administration13
Significantly increased in
PFC
Hypothalamus
Medulla oblongata
Unchanged in
Thalamus
Hippocampus
Injection of IFN-α into the brain induced within 2 hours14 in rats
Serotonin decreased
Significant dose-dependent reduction in the PFC
Reduction in the middle brain
Reduction in the striatum
5-hydroxyindoleacetic acid (5-HIAA) reduced
Reduction in the middle brain
Reduction in the striatum
Norepinephrine decreased
Significant dose-dependent reduction in the PFC
IFN-α decreases tryptophan levels (although more weakly than IFN-γ), suggesting an inhibitory effect on serotonin.1
IFN-α injected into the abdomen over 14 days induced in rats9
Dopamine decreased
Decreased after 1 day in the cortex
Reversible after end of IFN-α administration
Norepinephrine decreased
Reduced in most brain regions after 4 days
Reversible after end of IFN-α administration
Serotonin increased
After 14 days at 20,000 U/kg each increased in
PFC
Hippocampus
After 14 days at 200,000 U/kg each increased in
PFC
Hippocampus
Amygdala
Thalamus
Hypothalamus
After 14 days at 2,000,000 U/kg each increased in
Thalamus
Hypothalamus
No change in serotonin transporter mRNA levels
IFN-α injected once into the peritoneum at 1,500,000 U/kg, 3,000,000 U/KG, or 6,000,000 U/kg did not significantly alter monoamines, monoamine metabolites, or monoamine turnover in rats15
IFN-α of 1,500,000 U/kg injected into the peritoneum for 5 consecutive days induced in rats15
Significantly suppressed dopamine degradation induced by α-methyl-p-tyrosine.
IFN-α over 4 weeks in monkeys caused a decreased increase in dopamine in the striatum by amphetamines. This correlated with anhedonia.
This striatal dopamine reduction caused by IFN-α was completely reversed by L-dopa,16 suggesting that IFN-α impairs the synthesis of dopamine.
The ratio of 3,4-dihydroxyphenylacetic acid to dopamine, which increases when unpackaged dopamine is metabolized via monoamine oxidase, remained unchanged, suggesting that IFN-α does not affect dopamine levels via monoamine oxidase.16
Further, binding of the D2 dopamine receptor was decreased, but not that of the dopamine transporter.17
MPH showed no effect on fatigue in cancer.181920 Amantadine also showed little effect on fatigue in multiple sclerosis, as did modafinil. A very large and comprehensive metastudy of 113 studies with n = 11,525 subjects found no better effect on fatigue in cancer for either amphetamines or drugs overall than for exercise and psychotherapy. The metastudy’s supporting material provides a very good overview.212223
An increase in evening cortisol minimum levels correlated significantly with increased depression scores of the MADRS and increased fatigue scores of the MFI and all its subscales (general fatigue, physical fatigue, decreased activity, decreased motivation, mental fatigue)
Elevated evening cortisol levels correlated with stress experienced that day26
A single administration of 5 million IU IFN-α activates the HPA axis
After daily administration of 5 million IU IFN-α for 3 weeks, no elevated ACTH and cortisol blood levels were observed. In contrast, supramaximal doses of CRH significantly increased ACTH and cortisol levels.
In the laboratory, IFN-α stimulates CRF production in the hypothalamus and corticoid secretion from the adrenal cortex (of rats), but not ACTH secretion from the pituitary gland.
IFN-α increased glucose metabolism in the basal ganglia and cerebellum (cerebellum), whereas it decreased it in the dorsal PFC. It caused exhaustion, alexithymia (lack of emotion), and fatigue.28
This increased glucose metabolism in basal ganglia nuclei is similar to that seen in Parkinson’s disease patients, where it maps to increased oscillatory burst activity due to loss of inhibitory nigral dopamine input.2
IFN-α potentiates the dopaminergic effect of D-amphetamine. The mu opioid receptor antagonist naloxone suppressed this increase in effect, so it may be mediated via opioid receptors.292
IFN-α reduces pain perception in rats. This effect can be suppressed by mu opioid receptor antagonists (e.g., naloxone) but not by delta or kappa opioid receptor antagonists.30
Anhedonia, fatigue and depression induced by IFN-α
Due to reduced dopaminergic activation of the striatum3245
This correlates at the same time with changes in motivation.6
Depression and fatigue correlated with increased F-dopa uptake and decreased L-dopa turnover on long-term IFN-α administration.33
Depressive behavior (huddling) correlated with decreased homovanillic acid in cerebrospinal fluid, a metabolite of dopamine, suggesting decreased dopamine turnover.2
Fatigue correlated with decreased homovanillic acid in cerebrospinal fluid, a metabolite of dopamine, suggesting decreased dopamine turnover.34
IFN-α decreased motor activity in rats (7-day administration).13 The decreased motor activity correlated with decreased homovanillic acid in cerebrospinal fluid, a metabolite of dopamine, suggesting decreased dopamine turnover.34
Pretreatment with an antidepressant (here: paroxetine) prevented IFN-α-induced depression, anxiety, cognitive impairment, and pain better than anorexia and fatigue.3940
In a double-blind study, paroxetine showed no effect on ADHD.41 Pegylated IFN-α with a reduced half-life leads to lower depressive symptoms than non-pegylated IFN-α.42
The triggering of depressive symptoms (but not the other symptoms) by IFN-α could be mediated by the reduction of tryptophan (TRP) due to its conversion to kynurenine (KYN) by the enzyme indoleamine 2,3-dioxygenase.43 IFN-α 2 b, as a drug for hepaptitis C or malignant melanoma, induces severe depression in 40 to 50% of affected individuals in a dose-dependent manner and fatigue, loss of energy, and motor slowing in up to 80%.44 Plasma levels of IFN-α correlate highly with depression features according to the MADRS and fatigue scores according to the MFI.25
Anorexia, fatigue, and pain did not occur immediately but within 14 days after IFN-α treatment initiation. In contrast, depressed mood, anxiety, and cognitive impairment occurred later and mainly in patients who met DSM-IV criteria for major depression.
Alterations in dopamine metabolism in the basal ganglia
Does not respond to antidepressants
Late onset: depressive syndrome
Depressive symptoms
Activation of neuroendocrine pathways
Altered serotonin metabolism
Responds to antidepressants
Title
Different pathways of action in different depression subtypes? We wonder whether the different depressive consequences of the neurovegetative system (dopaminergic) and depressive syndrome (serotonergic) might also explain some differences between melancholic and atypical depression. Whereas atypical depression is more associated with a flattened endocrine stress response and increased daytime sleepiness, melancholic depression is typically associated with an increased endocrine stress response without increased daytime sleepiness. If there is a link here, atypical depression, which is more strongly linked to daytime sleepiness, should respond better to dopaminergic treatment.
IFN-α-induced depression and “naturally” occurring depression show46
Identical symptom severity of
Anxiety
Depressed mood
Impaired work activity
Deviant in IFN-α induced depression
Greater psychomotor slowdown
Higher weight loss
Lower feelings of guilt
Parameters that make depression more likely after antiviral treatment with interferon are:47
High initial levels of IL-6
Female sex
Previous depressions
Subthreshold depression symptoms
Low educational level
Antidepressants cause the production of pro-inflammatory cytokines (such as IFN-α) to be decreased and the production of anti-inflammatory cytokines to be increased.48
Both IFN-α and IFN-β bind to the interferon type 1 receptor with its subtypes IFNAR-1 and IFNAR-2, whereas IFN-γ binds to the interferon type 2 receptor (IFNGR).1
Both IFN-α and IFN-β bind to the interferon type 1 receptor with its subtypes IFNAR-1 and IFNAR-2, whereas IFN-γ binds to the interferon type 2 receptor (IFNGR).1
IFN-γ and IL-12 inhibit the activity of TH-2 cells.49
IL-6, IL-10, IL-17, IFN-γ, and TNF-α Are little affected by alcohol consumption (at 1.2 per mille).50
Behaviorally more active rats showed higher peripheral blood levels of proinflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the nonstressed condition. Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in pro-inflammatory IL-1β and anti-inflammatory IL-4 in peripheral blood in more passive animals.51
IFN-α reduces tryptophan5248 (more strongly than IFN-α), suggesting an inhibitory effect on serotonin.1
The only cerebrospinal fluid study to date found IFN-γ in 60% of children with ADHD.53
One study found no changes in serum levels of IL-2, IL-4, IL-17, TNF-α and IFN-γ in children with ADHD.54
Blood serum levels often have inconclusive information regarding neuropsychological effects of cytokines. See for this: Measurement of cytokines
IL-1α and IL-1β appear to have very similar effects. IL-1β is thought to be more potent with respect to activation of the HPA axis.1 IL-1α and IL-1β both bind to the IL-1 type 1 receptor, which mediates their action.
The IL-1 type 2 receptor appears to merely bind IL-1 without mediating its own effects. It thus acts as a kind of IL-1 antagonist. IL-4 and dexamethasone increase the formation of IL-1 type 2 receptors.55
Human IL-1 receptors differ significantly from animal variants.1
Behaviorally more active rats showed higher peripheral blood levels of proinflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the nonstressed condition. Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in pro-inflammatory IL-1β and anti-inflammatory IL-4 in peripheral blood in more passive animals.51
IL-1, TNF-α, and IL-6 trigger different responses:56
1.2.1.1.1.1. Increased turnover of norepinephrine, dopamine, serotonin¶
IL-1 increases norepinephrine turnover in the hypothalamus (which activates the HPA axis) as well as ACTH and blood cortisol levels and tryptophan levels. The maximum occurred after 4 hours.57IL-1, in addition to norepinephrine in the hypothalamus, also increases serotonin turnover throughout the brain1
The IL-1-mediated norepinephrine turnover increase is lower in brain regions innervated by the dorsal noradrenergic bundle57
PFC
Hippocampus
Cerebellum
The noradrenergic effect of IL-1 appears to be mediated by cyclooxygenase 2 (COX2). COX2 antagonists (diclofenac) suppress increased norepinephrine turnover indicated by IL-1, but COX-1 antagonists (indomethacin, ibuprofen) or lipoxygenase antagonists do not.58 Indomethacin, however, was able to suppress the norepinephrine increase on IL-1 given intravenously but not on IL-1 given intraperitoneally (into the peritoneum). Intravenously given IL-1 also resulted in a more rapid HPA axis activation than IL-1 given into the peritoneum.
IL-1 causes increase in the turnover (leading to decrease in the level) of59
Norepinephrine in the hypothalamus and hippocampus
Serotonin in the hippocampus and PFC
Dopamine in the PFC
IL-1 causes cortisol elevation in blood, but this did not correlate significantly with noradrenaline elevation
The sometimes increased dopamine consumption in mice by IL-1 did not resemble the usual pattern of increased dopamine turnover in the PFC relative to other brain areas during stress1
Activation of the HPA axis60 by IL-1 occurs primarily through increased norepinephrine. IL-1β is thought to be more potent with respect to activation of the HPA axis1
1.2.1.2.1.1. Influences on norepinephrine, dopamine, serotonin¶
An increase in tyrosine hydroxylase by IL-1-beta indicates increased dopamine turnover in the hypothalamus. The change correlated with increased ACTH levels with unchanged prolactin levels.64
IL-1-β potentiated the dopamine increase induced by mild stress in the PFC.65
IL-1-β increases the activity of the serotonin transporter, leading to increased degradation of serotonin.6667
IL-1 causes increase in the turnover (leading to decrease in the level) of59
Norepinephrine in hypothalamus and hippocampus
Serotonin in the hippocampus and PFC
Dopamine in the PFC
IL-1 causes cortisol elevation in blood, but this did not correlate significantly with noradrenaline elevation
For IL-1β, the effects in rats depend significantly on the mode of application (into the brain = intracerebroventricular or injected into the peritoneum = intraperitoneal = peripheral)68
Norepinephrine
Reduced in limbic regions due to prolonged administration
Serotonin
Increased in limbic regions due to prolonged administration
Dopamine
Increased in limbic regions due to prolonged administration
Stress sensitivity
Increased
Blood cortisol elevation
By acute as well as long-lasting IL-1β administration
IL-10 reduction
By acute as well as long-lasting IL-1β administration
Neurogenesis with the maturation of neural stem cells in the hippocampus has central importance for cognitive function.707169 One of the pathways of action of antidepressants is the suppression of mechanisms that impair neurogenesis.72
1.2.1.2.1.3. Inhibition of long-term potentiation¶
IL-1β administration prevents long-term potentiation (LTP), which is essential for long-term memory. 74 LTP inhibition is prevented by administration of antioxidant vitamins E and vitamin C.
Inhibition of LTP correlates with:
IL-1β increase in the dentate gyrus
Decrease in KCl-stimulated glutamate release in synaptosomes from dentate gyrus
LTP is associated with increased glutamate release
Decrease in KCl-stimulated glutamate release is prevented by administration of antioxidant vitamins E and vitamin C
Increase in unstimulated glutamate release
Increased activity of stress-activated kinases
Increased activity of c-Jun N-terminal kinase (JNK)
Increased activity of p38 mitogen-activated protein kinase
Intracerebroventricular (= given into the brain) injection of IL-1β increased oxygen radicals in the hippocampus.
Is prevented by administration of antioxidant vitamins E and vitamin C
IL-1β and H²O² increase the activities of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase
Is prevented by administration of antioxidant vitamins E and vitamin C
The higher the IL-1β, IL-6, and IL-8 stress response to an emotionally stressful movie, the greater the stress-related impairment in cognitive control/performance on the Stroop test.76
Spatial memory is impaired only with long-term IL-1β administration to the brain, not with short-term administration or with peripheral administration to the peritoneum.68
Neonatal rats treated with endotoxin respond to repeat endotoxin treatment in adulthood:77
Increased gene expression for microglia cell markers in the hippocampus
A greater increase in gene expression of glial cell markers in the hippocampus
This increase remained elevated for 24 h longer
A more rapid increase in IL-1beta in hippocampus and PFC
A prolonged IL-1-beta increase in the PFC
Peripheral cytokines or basal corticosterone were unchanged
Limited memory
This could be prevented by administration of a caspase-1 inhibitor to the adult animals 1 hour before the learning event and subsequent endotoxin administration.
A caspase-1 inhibitor prevents the synthesis of IL-1beta
Peripheral administration of IL-1β reduced the effort shown for sugar rewards versus freely available food. Thereby, the preference for sugar over freely available food was not reduced. This suggests that IL-1β reduces the magnitude of reward stimuli (anhedonia). This is similar to the effect of IFN-α.78
For IL-1β, behavioral effects in rats depend significantly on the mode of delivery (into the brain = intracerebroventricular or injected into the peritoneum = intraperitoneal = peripheral).68
For IL-1β, behavioral effects in rats depend significantly on the mode of administration (into the brain = intracerebroventricular or injected into the peritoneum = intraperitoneal = peripheral).68 Anxiousness is increased even more after IL-1β administration into the brain than after IL-1β administration into the peritoneum.
1.2.1.2.3. Behavioral changes depending on application site and duration¶
For IL-1β, behavioral effects in rats depend significantly on the mode of delivery (into the brain = intracerebroventricular or injected into the peritoneum = intraperitoneal = peripheral).68
Movement activity:
Elevated (into the peritoneum)
Reduced (to the brain)
Anxiety
Increased after administration into the peritoneum
More elevated when administered to the brain
Spatial memory
Only impaired by prolonged administration to the brain
Blood cortisol elevation
By acute as well as long-lasting IL-1β administration
IL-10 reduction
By acute as well as long-lasting IL-1β administration
PGE2 release
Increased by IL-1β- given into brain
Reduced by peripheral administration
Norepinephrine
Reduced in limbic regions due to prolonged administration
Serotonin
Increased in limbic regions due to prolonged administration
Dopamine
Increased in limbic regions due to prolonged administration
Psychological stress (on TSST as on Angry memory retrieval) leads to an increase in IL-1β, TNF-α, and IL-6 in terms of a stress response. The stress-induced increase in IL-1β, TNF-α, and IL-6 correlates with negative emotions.79
Another study confirms this for IL-1-b and TNF-a and, to a lesser extent, for CRP.80
The higher the IL-1β, IL-6, and IL-8 stress response to an emotionally stressful movie, the greater the stress-related impairment in cognitive control/performance on the Stroop test.76
In women, interview stress caused an increase in81
Plasma cortisol
Norepinephrine
IL-1β
IL-10
TNF-a
Number and activity of natural killer cells
In women, stress from sleep deprivation caused an increase in82
IL-1β
TNF-α
Natural killer cells.
Behaviorally more active rats showed higher peripheral blood levels of proinflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the nonstressed condition. Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in pro-inflammatory IL-1β and anti-inflammatory IL-4 in peripheral blood in more passive animals.51
IL-1Ra (as well as anti-inflammatory cytokines such as IL-10) suppresses symptoms mediated by IL-1. IL-1-Ra avoids the reduction of social behavior by IL-1beta, but not the reduction of body weight by IL-1beta in rats.84
Alcohol consumption (to 1.2 per mille) increased IL-1Ra levels within 2 hours and for at least another 10 hours, whereas alcohol was completely cleared within 10 hours.50
High IL-6, IL-1beta, and IL-1-RA levels correlate with decreased connectivity between
To mild stress, healthy subjects with a low cortisol stress response showed higher stress responses of IL-6 and IL-1ra in blood than those with a high cortisol stress response. At the same time, subjects with a low cortisol stress response showed lower heart rate variability, indicating poorer stress processing by the autonomic nervous system.85ADHD-HI is often associated with a flattened cortisol stress response, and ADHD-I is very often associated with an exaggerated cortisol stress response.
Behaviorally more active rats showed higher peripheral blood levels of proinflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the nonstressed condition. Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in pro-inflammatory IL-1β and anti-inflammatory IL-4 in peripheral blood in more passive animals.51
IL-2 and IL-4 combined induce glucocorticoid resistance in T cells by significantly decreasing the affinity of the glucocorticoid receptor for its ligand.8889 In addition, conversion of cortisol to less active or inactive metabolites decreases glucocorticoid sensitivity of immune system cells to glucocorticoids.90
IL-2 chronically given impairs working memory62 and memory function because IL-2 increases dopamine release and there are particularly large numbers of IL-2 receptors in the hippocampus.61
The only cerebrospinal fluid study to date found IL-2 in 90% of children with ADHD.53 One study found no changes in blood serum levels of IL-2, IL-4, IL-17, TNF-α and IFN-gamma in ADHD.54Brain fluid levels are likely to be critical for behavioral effects.
Within a group of children with ADHD, decreased TNF-α and IL-2 plasma levels correlated with higher levels of oppositional defiant behavior, while higher IL-2 plasma levels correlated with decreased reaction time.93
Activation of effector T cells (TH cells) during stress can have inhibitory effects on depressive and anxiety behaviors in mice by activating IL-4. TH cells in the meninges produce IL-4, which has anti-inflammatory effects and stimulates the production of growth factors in the brain that support neuronal plasticity and resilience.94
IL-4 and IL-10 inhibit the activity of TH-1 cells and macrophages.49
IL-2 and IL-4 combined induce glucocorticoid resistance in T cells by significantly decreasing the affinity of the glucocorticoid receptor for its ligand.8889 In addition, conversion of cortisol to less active or inactive metabolites decreases glucocorticoid sensitivity of immune system cells to glucocorticoids.90
Behaviorally more active rats showed higher peripheral blood levels of proinflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the nonstressed condition. Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in pro-inflammatory IL-1β and anti-inflammatory IL-4 in peripheral blood in more passive animals.51
1.2.3.4. Serum IL-4 probably not elevated in ADHD¶
One study found no changes in serum levels of IL-2, IL-4, IL-17, TNF-α, and IFNG in ADHD.54
IL-6 (and even more so IL-6-related cardiotrophin-1, CT-1) decrease BH4 levels.8 BH4 is an enzyme required for the synthesis of serotonin, dopamine, and norepinephrine. A decrease in BH4 causes decreased serotonin and dopamine levels.
IL-6 and sIL-6R (on an administration of interferon alpha) did not correlate with increased depression scores according to the MADRS. Changes in IL-6 day course had no effect on behavior.25
A strong IL-6 elevation is neurophysiologically associated with95
Increased activity within the subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotion appraisal
The stress response of TNF-α, IL-6, and CRP is higher in depressed than in nondepressed individuals.96
The strong IL-6 elevation is neurophysiologically associated with95
Reduced connectivity of sACC with amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus, which was modulated by peripheral interleukin-6
High IL-6, IL-1beta, and IL-1-RA levels correlate with decreased connectivity between
IL-6 mediates impairment of cognitive performance under stress. The higher the IL-1β, IL-6, and IL-8 stress response to an emotionally stressful movie, the greater the stress-related impairment of cognitive control/performance in the Stroop test.76
1.2.5.2.3. Social behavior more competitive and negative¶
IL-6 causes increased competitive social interactions. Basal blood levels of IL-6 and soluble TNF receptor correlate with the level of competitive social interactions.103 Competitive social interactions are the opposite of cooperation.
IL-6 causes increased negative social interactions. IL-6 and soluble TNF receptor stress response correlated positively with the measure of negative social interactions. The basal blood level of soluble TNF receptor correlated positively with the measure of negative social interactions.103 Aggression is an example of negative social interaction.
Psychological stress (through TSST such as Angry memory retrieval) leads to an increase in IL-6 (as well as IL-1β and TNF-α) in terms of a stress response. The stress-induced increase in IL-6, IL-1β, and TNF-α correlated with negative emotions.79
1.2.5.3. IL-6 in serum: correlation to ADHD questionable¶
A study of 135 unmedicated adults found no differences in blood IL-6 between ADHD-HI sufferers, ADHD-I sufferers, and unaffected individuals.104 Another investigation on 2307 participants of a Dutch study came to the same conclusion.105
Another study of 120 children with and without ADHD found an average of 4-fold higher serum IL-6 levels in the children with ADHD, with no correlation with IQ or symptom severity.106
Compared to the other studies, the same analytical technique was used, only from a different manufacturer.
Another study also found elevated serum IL-6 and IL-10 levels in children with ADHD.54
The difference in results could possibly be because the levels of IL-6 in blood and cerebrospinal fluid need not correlate and neuropsychological effects of cytokines are not represented by blood levels of the same.73
1.2.5.4. Causes of an IL-6 increase: stress / infections¶
Norepinephrine, which (like cortisol) is part of the endocrine stress response, stimulates IL-6 mRNA expression and IL-6 production in astrocytes via β2- and α1-adrenoceptors in a dose-dependent manner.108 Because norepinephrine release occurs temporally before activation of the HPA axis, inhibition of IL-6 by cortisol could represent a negative feedback loop, comparable to inhibition of the HPA axis after the stress response has occurred.
Maternal stress that causes damage to the unborn is thought to be mediated to the unborn primarily by IL-6. The deficient development of GABAergic cells in the unborn child caused by prenatal stress in the mother can apparently be prevented by IL-6 antagonists.109
Psychological stress (TSST as well as Angry memory retrieval) led to an increase in IL-1β, TNF-α, and IL-6 in terms of a stress response. The stress-induced increase of IL-1β, TNF-α and IL-6 correlated with negative emotions.79
When habituated to the stressor, the cortisol stress response decreased, but apparently not (or more slowly?) the IL-6 stress response.110
The stress response of TNF-α, IL-6, and CRP was higher in depressed than in nondepressed individuals.96
IL-6, IL-10, IL-17, IFN-γ, and TNF-α were little affected by alcohol consumption (at 1.2 per mille).50
To mild stress, healthy subjects with a low cortisol stress response showed higher stress responses of IL-6 and IL-1ra in blood than those with a high cortisol stress response. At the same time, subjects with a low cortisol stress response showed lower heart rate variability, indicating poorer stress processing by the autonomic nervous system.85ADHD-HI is associated with a flattened cortisol stress response, ADHD-I with an exaggerated cortisol stress response.
A thyphoid vaccination was followed by a 250% increase in IL-6, which correlated with a decrease in mood. The group not vaccinated against thyphoid but treated with placebo showed a slight IL-6 increase of 30%.100 This could be due to the stress associated with testing.
Particulate matter did not increase gene expression for IL-6.83
Administration of 635 mg eicosapentaenoic acid (EPA) and 195 mg docosahexaenoic acid (DHA) (unsaturated fatty acids) reduced serum CRP and IL-6 levels in children with ADHD and improved ADHD symptoms within 8 weeks in a double-blind placebo study.111
The higher the IL-8, IL-1β, and IL-6 stress response to an emotionally stressful movie, the greater the stress-related impairment in cognitive control/performance on the Stroop test.76
Behaviorally more active rats showed higher peripheral blood levels of proinflammatory cytokines (IL-1α, IL-1β, IL-2, IFN-γ, granulocyte-monocyte LSF) and anti-inflammatory cytokines (IL-4, IL-10) than more passive animals in the nonstressed condition. Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in pro-inflammatory IL-1β and anti-inflammatory IL-4 in peripheral blood in more passive animals.51
In women, interview stress caused an increase in81
Plasma Cortisol
Norepinephrine
IL-1β
IL-10
TNF-a
Number and activity of natural killer cells.
IL-10, IL-6, IL-17, IFN-γ, and TNF-α are little affected by alcohol consumption (at 1.2 per mille).50
Elevated plasma IL-10 levels correlate with higher ADHD symptomatology93 Another study also found elevated serum IL-6 and IL-10 levels in children with ADHD.54
The only screening of cerebrospinal fluid for cytokines in ADHD to date found IL-10 in 7% of children with ADHD.53
Increased TNF-α and TNFR2 levels after IFN-α administration correlated significantly with increased depression scores according to the MADRS.25 Treatment of sufferers with treatment-resistant depression with a TNF antagonist was helpful only in the presence of high basal hs-CRP levels above 5mg/L and high TNF-α levels.114
1.3.1.2.6. No influence on anhedonia and motivation¶
TNF-α has no known effect on reward processes/motivation (anhedonia), as does IL-1- beta, unlike IL-2 single dose.62
1.3.1.3. TNF-α in serum: no correlation with ADHD¶
A study of 135 unmedicated adults found no differences in blood TNF-α between ADHD-HI sufferers, ADHD-I sufferers, and unaffected individuals.104 An investigation of 2307 participants in a Dutch study reached the same conclusion.105 One study found no changes in serum levels of IL-2, IL-4, IL-17, TNF-α, and IFN-gamma in children with ADHD.54
Whether this could be because the levels of TNF-α in blood and cerebrospinal fluid may be different and neuropsychological effects of cytokines are represented by their levels in the brain rather than their blood levels73 is an open question.
Psychological stress (TSST such as Angry memory retrieval) leads to an increase in IL-1β, TNF-α, and IL-6 in terms of a stress response. The stress-induced increase in IL-1β, TNF-α, and IL-6 correlates with negative emotions.79 Likewise for TNF-α.110
Stress causes an increase in cortisol and TNF-α (stress response).96110 Another study confirms this for IL-1-b and TNF-α and, to a lesser extent, for CRP.80
The stress response of TNF-α, IL-6, and CRP is higher in depressed than in nondepressed individuals.96
In women, interview stress caused an increase in81
Plasma cortisol
Norepinephrine
IL-1β
IL-10
TNF-α
Number and activity of natural killer cells
In women, stress from sleep deprivation caused an increase in82
TFNR2 shows no diurnal rhythm.25 IFN-α 2a as well as IFN-α 2b lead to significantly increased TFNR2 levels.25
Increasing TNF-α and TNFR2 to IFN-α significantly correlated with increased depression scores according to the MADRS.25
MCP-1 (monocyte chemoattractant protein 1) decreased performance on psychomotor tasks such as a finger tapping task and the DSST (digit symbol substitution task).102
Alcohol consumption (to 1.2 per mille) initially acutely decreased the level of the chemokine MCP-1, which steadily increased over the next 12 hours and remained above baseline, whereas the alcohol was completely degraded within 10 hours.50
MCP-1 correlated with slowed psychomotor function.98
In ASD sufferers, significant associations were found between increased plasma levels of CCL5 (= RANTES) and CXCL8 (= IL-8, NAP-1, MDNCF, GCP-1) and more frequent abnormal behaviors and less adaptive behaviors.115116117
Decreased plasma levels of TGFβ1 (transforming growth factor beta1) correlated with more stereotypy, irritability, hyperactivity, and other behavioral symptoms and less adaptive behavior in a study of ASD sufferers.118
2.1. NF-kB (Nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells)¶
NF-kB is a specific transcription factor found in almost all animal cell types and tissues. By binding to regulatory sections of DNA, it can influence the transcription of dependent genes.
Psychosocial stress increased NF-kB levels in peripheral human blood cells via norepinephrine at alpha(1) and beta adrenoceptors. Stress also increased catecholamines and cortisol. NF-kB returned to baseline levels after one hour.119
Inhaled particulate matter was found in brain tissue of mice, where it increased NF-kB levels.63
In chronic autoimmune rheumatic diseases, adenosine A2A and A3 receptors are overexpressed in lymphocytes. A2A and A3 agonists inhibited NF-κB activation, the release of typical proinflammatory cytokines, and the concentration of metalloproteinases involved in the inflammatory responses in chronic autoimmune rheumatic diseases.120
MIF / MMIF (Macrophage migration inhibitory factor) is also called GIF (Glycosylation-inhibiting factor), L-dopachrome isomerase or phenylpyruvate tautomerase. It is a pro-inflammatory cytokine.
Elevated plasma levels of MIF correlate with more severe social impairments and less imaginative play in ASD sufferers, according to one study.121
Elevated CRP in cerebrospinal fluid significantly correlated with elevated glutamate levels in right basal ganglia, independent of age, sex, race, body mass index, smoking status, and depression severity.24
Increased glutamate in the right basal ganglia correlates with anhedonia and psychomotor slowing on various tests.24
Plasma CRP did not correlate with glutamate levels in the dorsal ACC.24
CRP in plasma and CSF correlate with CSI measurements of basal ganglia glutamate and the glial marker myoinositol.24
Acute stress increases blood levels of IL-1-b and TNF-a and, to a lesser extent, CRP.80
The stress response of TNF-α, IL-6, and CRP is higher in depressed than in nondepressed individuals.96
An investigation of 2307 participants in a Dutch study found no correlation between blood levels of C-reactive protein (CRP) and ADHD.105
Administration of 635 mg eicosapentaenoic acid (EPA) and 195 mg docosahexaenoic acid (DHA) (unsaturated fatty acids) reduced serum CRP and IL-6 levels in children with ADHD and improved ADHD symptoms within 8 weeks in a double-blind placebo study.111
found. No differences were found between ADHD-HI and ADHD-I.
NOS, XO, GST and PON-1 are important markers for oxidative stress. ADA is a marker for cellular immunity.122
Endotoxin / lipopolysaccharide (LPS) is a pathogen secreted by the bacterium Escherichia Coli (E. Coli). Infections with E. Coli are therefore a trigger of a severe immune reaction.
4.1.1.1. Norepinephrine, serotonin turnover increased by endotoxin¶
Endotoxin / lipopolysaccharide (LPS) increases norepinephrine and serotonin turnover and tryptophan levels as does IL-1. IL-1 antagonists partially suppress this effect.1
The same low dose of endotoxin that makes sugar rewards less interesting appears to decrease dopamine and serotonin in the nucleus accumbens123 and significantly increase metabolites of catecholamines, such as 5-HIAA, DOPAC, and HVA, in the nucleus accumbens and mPFC. That a reuptake inhibitor was able to suppress this effect suggests that endotoxin increases DAT activity.124
Both the short- and long-term effects of endotoxin on dopamine levels can be neutralized by inhibition or genetic blockade of inflammatory cytokines such as TNF-α (e.g., by catalpol).124125 This suggests that TNF-α (among others) may mediate anhedonia.
Endotoxin reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (a site of origin of dopamine)126
If sensitivity to HPA axis suppression by dexamethasone is reduced, endotoxin causes significantly more severe increases in IL-6.128
Increases IL-10
Cortisol administration immediately before endotoxin administration significantly enhanced IL-10 increase. Cortisol administration more than 6 hours before endotoxin administration did not affect the IL-10 increase. In the laboratory, cortisol decreased the IL-10 increase caused by endotoxin and reversed the IL-10 increase increased by epinephrine to an IL-10 decrease on endotoxin administration.129
Increases TNF-α
Cortisol administration immediately before endotoxin administration suppresses TNF-α release. Cortisol administration more than 12 hours before endotoxin administration increases endotoxin-induced TNF-α increase.1291
A single administration of endotoxin in mice immediately increased TNF-α levels (except in mice with deactivated TNFα receptor). While peripheral TNF-α levels decreased in serum after 9 h and in liver after 1 week, they were still elevated in brain after 10 months.127
If sensitivity to HPA axis suppression by dexamethasone is reduced, endotoxin causes significantly greater increases in TNFα.128
Increases MCP-1
Endotoxin increases the expression of MCP-1 (except in mice with deactivated TNFα receptor):127
Increases NF-κB p65
Endotoxin increases NF-κB p65 expression (except in mice with deactivated TNFα receptor):127
Endotoxin-activated microglia (as well as those activated by TNF-α)126 (except in mice with deactivated TNFα receptor)127microglia can increase the expression of inducible nitric oxide synthase (iNOS) and release significant amounts of nitric oxide (NO) and TNF-α, which can damage dopaminergic neurons.125
Endotoxin increases depressed mood1301 within 24 hours.131 Peripheral endotoxin triggers depressive behavior via indoleamine 2,3-dioxygenase (IDO) by increasing tryptophan turnover. The degradative of tryptophan, L-kynurenine, triggers depressive behavior in a dose-dependent manner.132
An IDO blockade before endotox input
Prevents depressive behaviors.
Normalizes the kynurenine/tryptophan ratio in plasma and brain
Does not prevent the increase of serotonin turnover in the brain
IDO can be blocked
Indirectly by anti-inflammatory drugs that attenuate endotoxin-induced expression of proinflammatory cytokines, e.g., minocycline (a broad-spectrum antibiotic that increases COX-2)133
Directly by IDO antagonists, e.g. 1-methyltryptophan (1-MT)
Endotoxin decreased striatum activity to offered rewards (anhedonia).130 It decreased the motivation to develop activities to obtain sugar rewards, while the preference for sugar over other food was not itself decreased.134123
decreased motor activity still after 6 hours, but no longer after 24 hours
Increased depressive and anhedonic behavior even after 24 and 48 hours
4.1.2.4. Lifetime behavioral changes associated with endotoxin in neonates¶
4.1.2.4.1. Decreased depression symptoms to stress with unchanged serotonin levels¶
Neonatal rats treated with endotoxin showed lower depressive symptoms to inescapable pain stress than adult animals.135 Thereby, the serotonin level in the amygdala did not differ before, during or after stress from the animals that were not treated with endotoxin as neonates.
While basal cortisol levels of newborn rats before endotoxin treatment and also of adult animals of both groups did not differ, adult animals treated with endotoxin as newborns showed a markedly blunted cortisol stress response during and after stress.135
4.1.2.4.3. Memory problems with renewed immune activation in adulthood¶
Neonatal rats treated with endotoxin show a response to renewed endotoxin treatment in adulthood77
Increased gene expression for microglia cell markers in the hippocampus
A greater increase in gene expression of glial cell markers in the hippocampus
This increase remained elevated for 24 h longer
A more rapid increase in IL-1beta in hippocampus and PFC
A prolonged IL-1-beta increase in the PFC
Peripheral cytokines or basal corticosterone were unchanged
Limited memory
This could be prevented by administration of a caspase-1 inhibitor to the adult animals 1 hour before the learning event and subsequent endotoxin administration.
A caspase-1 inhibitor prevents the synthesis of IL-1beta
4.1.2.4.4. Reduced immunological effect of amphetamine¶
Endotoxin in newborn rats at day 4 of life causes altered responses to amphetamines in juvenile animals. The effects on:136
GFAP (glial fibrillic acid protein, an astroglial marker)
The changes induced by a single non-toxic amphetamine administration in juvenile animals differed by brain region:
Changes in PFC:
In the mPFC, amphetamine increased gene expression for
IL1β
IL6
TNFα
CD200
Arc
GFAP
in rats not treated neonatally with endotoxin, but not in animals treated with endotoxin on day 4 of life.
There were no relevant differences for CD11b and IL-10.
Changes in the nucleus accumbens:
In the NAcc, amphetamine increased gene expression for
IL1β
CD200
only in rats not treated with endotoxin,
while gene expression decreased from
CD200
only in animals treated with endotoxin.
In all animals, amphetamine increased gene expression of
IL1β
Arc
Unchanged
IL6
GFAP
CD11b
IL-10
TNFα
Changes in the hippocampus (CA1):
Amphetamine increased gene expression for
Arc
GFAP
only in rats not treated with endotoxin
Amphetamine increased the gene expression of
IL1β
in all animals.
Unchanged
IL6
CD200
CD11b
IL-10
TNFα.
Thus, these results are more similar to the effects of neonatal E. coli infection on adult responses to psychological stress that were blunted than to adult responses to LPS that were amplified.
5. Other elements inside and outside the immune response¶
5.1.1. BDNF in serum: rather no correlation to ADHD¶
BDNF is not an inflammatory marker but is relevant to neurogenesis.
One study found significantly decreased blood BDNF (brain-derived neurotrophic factor) levels in adults with ADHD, and these levels tended to be even lower in ADHD-HI than in ADHD-I.137 In contrast, another study found increased BDNF levels in children with ADHD.138
In contrast, a study of 2307 participants in a Dutch study139 and another study140 found no correlation between blood levels of the growth factor BDNF and ADHD.
Cell adhesion molecules (CAM) are proteins that mediate contacts between cells in tissue. They bring about the cohesion of tissues and the communication between cells.
In extremely preterm infants, a one-day increase in intercellular adhesion molecule-3 increased the risk of attention problems.141
In extremely preterm infants, the risk of attention problems increased when permanent or recurrent elevations of141
Anti-Yo antibodies are immunoglobulin G (IgG) autoantibodies that react with a 62 kDa Purkinje cell cytoplasmic protein. They impair the function of the cerebellum (cerebellum).142 The cerebellum is responsible for motor coordination. Motor problems are common in ADHD.143
One study found anti-Yo antibodies in 77.5% of children with ADHD. In these children, plasma IL-6 and IL-10 levels were also elevated.144
S100B is a cytokine-related neurotrophin. Diagnostically, S-100B is a marker for brain damage (e.g. stroke, traumatic brain injury).
Children with ADHD and predominantly internalizing symptoms (ADHD-I) showed lower plasma S100B levels than ADHD children with externalizing symptoms (ADHD-HI).93
Reduced C4BP blood levels have been found in ADHD sufferers and their mothers (but not their fathers). C4BP is a protein that is important for the immunological defense against viral and bacterial infections by the complement system.145
Antibodies to glutamic acid decarboxylase 65 (GAD65) were found in the serum of 15% of children with autism (N = 20), 27% of children with ADHD (N = 15), and none of the controls (N = 14). The serum of 60% of the autistic children and 53% of the children with ADHD reacted with Purkinje neurons in the mouse cerebellum. The serum of 20% of the children with ADHD also reacted with cells in the molecular and granular cell layers and cells near the Purkinje neurons. Reactions of serum antibodies with the cells in the cerebellum indicate direct effects on brain function.146
Nisticò, De Sarro (1991): Is interleukin 2 a neuromodulator in the brain? Trends in Neurosciences, Volume 14, Issue 4, 1991, Pages 146-150, ISSN 0166-2236, https://doi.org/10.1016/0166-2236(91)90086-A. ↥