Dear readers of ADxS.org, please forgive the disruption.

ADxS.org needs about $19740 in 2023. In 2022 we received donations from third parties of about $ 13870. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2023 would be over after a few days. This donation request is displayed 12,000 times a week, but only 140 people donate. If you find ADxS.org useful, please take a minute and support ADxS.org with your donation. Thank you!

Since 01.06.2021 ADxS.org is supported by the non-profit ADxS e.V..

$0 of $19740 - as of 2023-01-03
0%
Header Image
Effect of individual cytokines and inflammatory markers

Effect of individual cytokines and inflammatory markers

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 because 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 dopaminergically mediated symptoms of IFN-α administration (here: fatigue) respond only weakly to treatment with 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.

1. Cytokines

1.1. Interferons

1.1.1. Interferon alpha (IFN-α)

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

1.1.1.1. Neurophysiological effects of IFN-α

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.34 5
    • 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 levels.8
    • It is unclear whether this is mediated by nitrogen oxide. This was partly affirmed,7 partly denied.9
  • IFN-α, peripherally given, increased2
    • 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 fatigue.3
    • 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
    • Dopamine level significantly reduced
    • 3,4-Dihydroxyphenylacetic acid levels significantly reduced
    • 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 could be 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

1.1.1.1.2. Influence on glutamate by IFN-α

IFN-α increases glutamate in basal ganglia and dorsal anterior cingulate cortex (dACC) in nondepressed subjects.24

1.1.1.1.3. Influence on the HPA axis by IFN-α

IFN activates the HPA axis in humans, but hardly at all in rodents.1 HPA axis changes observed were:

  • Cortisol
    • The changes in cortisol levels correlated with depression25
    • Flattened cortisol diurnal profile25
      • This correlated significantly with
        • Reduced activity
        • Reduced motivation
        • Physical exhaustion (fatigue)
        • Mental exhaustion
        • But not with general fatigue
      • Morning cortisol increase did not correlate with behavioral changes
    • Elevated evening cortisol25
      • 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
  • ACTH
    • Flattened ACTH diurnal profile25
      • ACTH changes did not correlate with behavioral changes
    • Elevated evening ACTH level25
      • ACTH changes did not correlate with behavioral changes
  • HPA axis stimulation27
    • 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.
    • IFN-α stimulates CRF production in the hypothalamus and corticoid secretion from the adrenal cortex (of rats) in the laboratory, but not ACTH secretion from the pituitary gland.
1.1.1.1.4. Other effects of IFN-α
  • 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
1.1.1.2. Behavioral effects of IFN-α
1.1.1.2.1. Fever

IFN-α increases fever in humans but hardly in rodents.1

1.1.1.2.2. Cognitive impairment

Cognitive impairment by IFN-α correlates significantly with prolonged latency of P300.31

1.1.1.2.3. Depression, Anhedonia, Fatigue
  • 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
    • Anhedonia16
      • Correlated with a decreased increase in dopamine in the striatum by amphetamines after IFN-α administration for 4 weeks in 8 monkeys.
      • This striatal dopamine reduction caused by IFN-α could be completely reversed by L-dopa, suggesting that IFN-α impairs the synthesis of dopamine.
1.1.1.2.4. Fear

Rhesus monkeys permanently treated with IFN-α showed2 in 3 of 8 animals35

  • Increasing anxiety behavior
  • A decrease in psychomotor activity
  • An increase in depressive-like huddling (huddling)
  • Signs of depression were present only in the 3 animals that had
    • Had significantly decreased dopamine metabolites in cerebrospinal fluid
      • Homovanillic acid (HVA)
      • 3,4-Dihydroxyphenylacetyl acid (DOPAC)
    • Which correlated with decreased motor activity
  • Increased values of
    • ACTH
    • Cortisol
    • IL-6
  • Anhedonia36
1.1.1.2.5. Sleep impaired
  • IFN-α impairs sleep372
    • Increased nocturnal awakening
      • Correlates with increased evening cortisol levels
    • Impaired REM sleep
      • This is mediated via the dopamine level38
      • Correlates with increased fatigue
    • Increased Stage 2 sleep (intermediate non-REM sleep)
    • Reduced deep sleep
      • Correlates with increased fatigue
    • Worse sleep efficiency
      • Correlates with slowed motor speed
    • No increased daytime sleepiness
      • Reduced frequency of power naps
1.1.1.2.6. Motor activity decreased

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

1.1.1.2.7. No effects of IFN-α
  • Response time6
  • Executive functions6
  • Accuracy in the concentration test6
1.1.1.2.1. IFN-α and depression

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.

IFN-α has two pathways of action45

  • Rapid consequence: neurovegetative syndrome
    • Psychomotor slowdown
    • Fatigue
    • Alterations in dopamine metabolism in the basal ganglia
    • Does not respond to antidepressants
  • Late-onset consequence: 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

1.1.2. IFN-β

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

1.1.3. IFN-γ

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

1.1.3.1. IFN-γ in ADHD

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

1.2. Interleukins

1.2.1. IL-1

1.2.1.1. IL-

IL-1α and IL-1β seem 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. Neurophysiological effect of IL-
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.57 IL-1, in addition to norepinephrine in the hypothalamus, also increases serotonin turnover throughout the brain.1
    • The IL-1-mediated norepinephrine turnover increase is lower in brain regions innervated by the dorsal noradrenergic bundle:57
      • 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
1.2.1.1.1.2. HPA axis activation
  • 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 axis.1
    • IL-1 increases ACTH secretion61
1.2.1.1.1.3. Acute phase proteins increased
  • Increase of acute phase proteins60
1.2.1.1.2. Behavioral changes
1.2.1.1.2.1. Fever
1.2.1.1.2.2. Sickness behaviour
  • As well as TNF-α, other than IL-2 single dose62
  • Reduced food intake60
  • Reduced water absorption
  • Trembling
  • Increased sleepiness
  • Reduced social interest.
1.2.1.1.2.3. Anxiety symptoms
  • As well as TNF-α, other than IL-2 single dose62
1.2.1.1.2.4. Anorexia
  • As well as TNF-α, other than IL-2 single dose62
1.2.1.1.2.5. Sleep
  • IL-1 induces sleep61
1.2.1.1.2.6. No influence by IL-1
  • No influence on reward processes / motivation (anhedonia)
    • As well as TNF-α, other than IL-2 single dose62
1.2.1.1.2. Effects on IL-

Inhaled particulate matter was found in brain tissue of mice, where it increased the level of IL-1α.63

1.2.1.2. IL-
1.2.1.2.1. Neurophysiological effect of IL-
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
    • PGE2 release
      • Increased by IL-1β given into brain
      • Reduced by peripheral IL-1β administration
1.2.1.2.1.2. Inhibition of neurogenesis
  • IL-1-β inhibits neurogenesis in the hippocampus69
    • 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
    • Cortisol also inhibits neurogenesis.73
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 the 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
1.2.1.2.1.3. HPA axis activation

IL-1 increases ACTH secretion.61

1.2.1.2.1.4. Connectivity striatum - vmPFC

High IL-6, IL-1β, and IL-1-RA levels correlate with decreased connectivity between striatum and vmPFC.75

1.2.1.2.2. Behavioral change through IL-
1.2.1.2.2.1. Cognitive performance

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
1.2.1.2.2.2. Anhedonia / reward motivation reduced

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

1.2.1.2.2.3. Sleep stimulating

IL-1 induces sleep.61

1.2.1.2.2.4. Movement activity

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)
1.2.1.2.2.5. Anxiety

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
  • Stress sensitivity
    • Increased
1.2.1.2.4. Effects on IL-
1.2.1.2.4.1. Stress increases IL-
  • 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-
    • IL-10
    • TNF-a
    • Number and activity of natural killer cells
  • In women, stress from sleep deprivation caused an increase in82
    • IL-
    • TNF
    • 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
1.2.1.2.4.2. Particulate matter increases IL-

Inhaled particulate matter increased gene expression for IL-1β in mice.83

1.2.1.3. IL-1-Ra

Interleukin 1 receptor antagonist

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

  • Striatum and vmPFC 75

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.85 ADHD-HI is often associated with a flattened cortisol stress response, and ADHD-I is very often associated with an exaggerated cortisol stress response.

1.2.2. IL-2

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

1.2.2.1. Neurophysiological effects of IL-2
1.2.2.1.1. IL-2 increases turnover of norepinephrine and dopamine

IL-2 causes an increase in the turnover (leading to a decrease in the level) of

  • Norepinephrine in the hypothalamus59
  • Norepinephrine in the hippocampus61
  • Dopamine in the PFC5961
  • Dopamine in the striatum86
  • IL-2 at low doses in newborn mice causes decreased levels of dopamine in the hypothalamus in adulthood.87
  • Because IL-2 increases dopamine release and IL-2 receptors are particularly abundant in the hippocampus, IL-2 has implications for memory function.61
  • The effects of IL-2 on dopamine and norepinephrine are weaker than those of IL-1 and IL-6.1
1.2.2.1.2. No increase in serotonin or cortisol by IL-2
  • No increase in
    • Serotonin59. Different: moderate serotonin increase.1
    • Cortisol in blood59
1.2.2.1.3. IL-2 induces glucocorticoid resistance
  • IL-2 and IL-4 combined induce glucocorticoid resistance in T cells by significantly decreasing the affinity of the glucocorticoid receptor for its ligand.88 89 In addition, conversion of cortisol to less active or inactive metabolites decreases glucocorticoid sensitivity of immune system cells to glucocorticoids.90
1.2.2.1.4. IL-2 decreases acetylcholine

IL-2 decreases acetylcholine release

  • In the hippocampus61
  • In PFC61
1.2.2.2. Behavioral effects of IL-2

Typical behavioral effects of IL-2 are:61

1.2.2.2.1. Sedating
  • IL-2 has a sedative effect
    • Presumably via the locus coeruleus91
1.2.2.2.2. Motor effects on posture
  • Has motor effects on posture
  • May cause schizophrenia symptoms in a dose-dependent manner92
1.2.2.2.3. Memory impairment
  • 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
1.2.2.2.4. Anhedonia, motivation impairment
  • IL-2 single dose affects reward processes/motivation (anhedonia), unlike IL-1 beta and TNF alpha62
1.2.2.2.5. Not caused: Anxiety, Anorexia, Sickness behaviour
  • IL-2 single dose does not induce anxiety symptoms, unlike IL-1 beta and TNF alpha, which act synergistically62
  • IL-2 does not induce sickness behavior, unlike IL-1 beta and TNF alpha, which act synergistically62
  • IL-2 does not induce anorexia, unlike IL-1 beta and TNF alpha, which act synergistically62
1.2.2.3. IL-2 and ADHD

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.54 Brain fluid levels are likely to be critical for behavioral effects.

1.2.2.2.3. IL-2 reduces oppositional defiant behavior, prolongs reaction time

Within a group of children with ADHD, decreased TNF-α and IL-2 plasma levels correlated with higher levels of oppositional defiant behavior, whereas higher IL-2 plasma levels correlated with decreased reaction time.93

1.2.3. IL-4

1.2.3.1. IL-4 inhibits cytokine-induced depression

Activation of effector T cells (TH cells) during stress can have inhibitory effects on depressive and anxious behavior 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

1.2.3.2. Induces glucocorticoid resistance

IL-2 and IL-4 combined induce glucocorticoid resistance in T cells by significantly decreasing the affinity of the glucocorticoid receptor for its ligand.88 89 In addition, conversion of cortisol to less active or inactive metabolites decreases glucocorticoid sensitivity of immune system cells to glucocorticoids.90

1.2.3.3. IL-4, stress and behavior

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

1.2.4. IL-5

1.2.4.1. IL-5 in cerebrospinal fluid often elevated in ADHD

The only cerebrospinal fluid screening for cytokines in ADHD to date found IL-5 in 62% of children with ADHD.53

1.2.5. IL-6

1.2.5.1. Neurophysiological effects of IL-6
1.2.5.1.1. Increased dopamine and serotonin turnover, norepinephrine and cortisol unchanged
  • IL-6 causes increase in the turnover (leading to decrease in the level) of59
    • Serotonin in the hippocampus and PFC
    • Dopamine in the PFC
    • But not of noradrenaline in hypothalamus or hippocampus
    • No increase of cortisol in the blood
  • IL-6 increases tryptophan levels and serotonin turnover in the brain (but more weakly than IL-1), but not norepinephrine.1
  • IL-6 (and TNF-alpha) do not decrease norepinephrine uptake, but IL-6-related CT-1 does.8
1.2.5.1.1.1. IL-6 and depression
  • 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 with:95
    • 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
1.2.5.1.2. Activation of the HPA axis
  • Activation of the HPA axis60 but weaker than by IL-1.1
1.2.5.1.3. Increases acute phase proteins
  • Increase in acute phase proteins97
  • Slowed psychomotor activity98
1.2.5.1.4. Reduced connectivity
  • 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
    • Striatum and vmPFC 75
1.2.5.1.5. IL-6 decreases Il-1 and TNF
  • IL-6 decreases the production of IL-1 and TNF-α in the blood by phagocytes.99
1.2.5.2. Behavioral changes due to IL-6
1.2.5.2.1. Fever, Sickness Behavior
  • Fever
    • As well as IL-1 and TNF56
  • Sickness behaviour
    • Reduced food intake97
    • Reduced water absorption
    • Trembling
    • Increased sleepiness
    • Reduced social interest
1.2.5.2.2. Anhedonia, increased fear of loss
  • Decreased response to rewards (anhedonia), increased fear of loss/punishment100
1.2.5.2.3. Mood drop

IL-6 mediates mood deterioration.95100

1.2.5.2.3. Reaction speed reduced

IL-6 causes prolonged reaction times.101102

1.2.5.2.3. Cognitive performance under stress

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
  • Stress hormones increase IL-6:107
    • Norepinephrine
    • CRH
  • 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.85 ADHD-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
1.2.5.5. Influence of IL-6

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

1.2.6. Cardiotrophin-1 (CT-1)

Cardiotrophin-1 is a cytokine of the IL-6 protein family.

  • CT-1 (and, to a lesser extent, IL-6) decreases BH4 levels.8
  • CT-1 (but not IL-6 or TNF-alpha) decreases norepinephrine uptake.8

1.2.7. IL-8

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

1.2.8. IL-10

  • IL-10 causes an increase in performance during DSST (Digit Symbol Substitution Task).102
  • Elevated IL-10 levels correlate with allergic tendencies.112
  • IL-10 and IL-4 inhibit the activity of TH-1 cells.49
1.2.8.1. Causes of IL-10: Stress
  • 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-
    • 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
1.2.8.1. IL-10 in ADHD

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 cerebrospinal fluid screening for cytokines in ADHD to date found IL-10 in 7% of children with ADHD.53

1.2.9. IL-12

IL-12 and IFN-γ inhibit the activity of TH-2 cells.49
IL-12 strongly promotes IFN-γ.49
IL-12 strongly inhibits IL-4 production by T cells.49

1.2.10. IL-13

1.2.10.1. IL-13 in ADHD

IL-13 is an anti-inflammatory cytokine. Elevated plasma IL-13 levels tend to correlate with increased inattention.93

1.2.12. IL-16

Elevated IL-16 levels correlate with allergy susceptibility112

1.2.12.1. IL-16 in ADHD

Elevated plasma IL-16 levels correlate with higher ADHD symptomatology and increased hyperactivity/impulsivity.93 Higher IL-16 plasma levels also correlate with higher commission errors.93

1.2.13. IL-17

IL-6, IL-10, IL-17, IFN-γ, and TNF-α Are little affected by alcohol consumption (at 1.2 per mille).50

1.2.13.1. IL-17 - no known correlation to ADHD

One study found no changes in serum levels of IL-2, IL-4, IL-17, TNF-α and IFNG.54

1.3. Tumor necrosis factor

1.3.1. TNF

1.3.1.1. Neurophysiological effect of TNF
1.3.1.1.1. Only high doses decrease serotonin and norepinephrine

TNF-alpha increased the activity of the serotonin transporter, leading to increased degradation of serotonin.67

TNF-α addresses norepinephrine and tryptophan only at high doses.1

A single TNF-α or IL-1-b administration does not alter norepinephrine release in sympathetic cells.113

  • A new depolarization after 6 minutes reduced the release of norepinephrine
  • A new depolarization after 10 minutes restored the noradrenaline release
1.3.1.1.2. HPA axis activation

TNF-α activates the HPA axis97 as does IL-6.1

1.3.1.1.3. Acute phase proteins increased

TNF-α leads to increased acute phase proteins.97

  • TNF-α causes sensitization for subsequent renewed TNF-α administration62
1.3.1.1.3. TNF-α inhibits allergies

Decreased TNF-α levels correlated with allergies.112

1.3.1.2. Behavioral changes due to TNF
1.3.1.2.1. Fever and sickness behaviour
    • Fever56
      • Sickness behaviour
        • As well as IL-1- beta, different from IL-2 single dose62
        • Reduced food intake60
        • Reduced water absorption
        • Trembling
        • Increased sleepiness
        • Reduced social interest.
1.3.1.2.2. Fear

TNF-α elicits anxiety symptoms, as does IL-1- beta, unlike IL-2 single dose.62

1.3.1.2.3. Anorexia

TNF-α induces anorexia, as does IL-1- beta, unlike IL-2 single dose62

1.3.1.2.4. TNF-α inhibits oppositional defiant behavior

Within a group of children with ADHD, decreased TNF-α and IL-2 plasma levels correlated with higher levels of oppositional defiant behavior.112

1.3.1.2.5. Conditional influence on depression

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 to 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.

1.3.1.4. Effects on TNF
1.3.1.4.1. Stress increases TNF
  • 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-
    • IL-10
    • TNF
    • Number and activity of natural killer cells
  • In women, stress from sleep deprivation caused an increase in82
    • IL-
    • TNF
    • Natural killer cells.
1.3.1.4.2. Fine dust increases TNF

Inhaled particulate matter was found in the brain tissue of mice, where it increased the level of TNF63 by upregulating the gene responsible.83

1.3.1.4.3. Alcohol does not alter TNF

TNF-α, IL-6, IL-10, IL-17, and IFN-γ were little affected by alcohol consumption (to 1.2 per mille).50

1.3.1.4.4. TNF-α blocker

TNF-α blockers inhibit the inflammatory processes mediated by TNF-α.
The annual therapy costs of a treatment are around €40,000 (as of 2019).

  • Etanercept
    • Receptor fusion protein, first approved in 2003.
  • Adalimumab
    • Fully human monoclonal antibody, first approved in 2006.

1.3.2. TNF

1.3.2.1. TNF-β in cerebrospinal fluid: high correlation with ADHD

The only study to date of cerebrospinal fluid in children with ADHD found TNF-β in 70%.53

1.3.3. TNFR2

TFNR2 does not show a 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

1.4. Chemokines

1.4.1. MCP-1

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 cleared within 10 hours.50
MCP-1 correlated with slowed psychomotor function.98

1.4.2. CCL5 (RANTES), CXCL8 (= IL-8, NAP-1, MDNCF, GCP-1)

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

1.5. TGFβ1 (transforming growth factor)

TGF is a cytokine.

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. Other inflammatory markers

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

2.2. MIF / MMIF / GIF

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

2.3. C-reactive protein (CRP)

CRP is an acute phase protein. It activates the complement system.
High CRP values

  • Correlate with reduced connectivity between75
    • Ventral striatum and ventromedial prefrontal cortex (vmPFC),
      • This correlated with
        • Increased anhedonia
    • Between dorsal striatum, vmPFC and presupplementary motor cortex
      • This correlated with
        • Reduced motor activity
        • Increased psychomotor slowing down
    • Striatum and vmPFC are parts of the (mesocorticolimbic) dopaminergically controlled reward system.10
  • High IL-6, IL-1beta, and IL-1-RA levels also correlate with decreased connectivity between
    • Striatum and vmPFC 75
  • Elevated CRP in cerebrospinal fluid correlated significantly with elevated glutamate levels in the 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

2.3.1. CRP in serum: no correlation to ADHD

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

2.4. Natural killer cells

In women, stress from sleep deprivation caused an increase in82

  • Natural killer cells
  • IL-
  • TNF

3. Oxidative stress

3.1. Oxidative stress in ADHD

In ADHD, the serum was found to contain

  • Significantly increased values of
    • Nitric oxide synthase (NOS),
    • Xanthine oxidase (XO),
    • Adenosine deaminase (ADA)
  • As well as significantly reduced values of
    • Glutathione S-transferase (GST)
    • Paraoxonase-1 (PON-1)

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

4. Consequences of infection

4.1. Endotoxin / Lipopolysaccharide (LPS)

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. Neurophysiological effects of endotoxin

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

4.1.1.2. Dopamine reduced by endotoxin
  • 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
    • 7 months after treatment by 23127
    • 10 months after treatment by 47127
4.1.1.3. Effects of endotoxin on cytokines
  • Increases IL-1-1
    • Increases the expression of IL-1-beta (except in mice with deactivated TNFα receptor):127
  • Increases IL-61
    • 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
    • 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
4.1.1.3. Endotoxin activates microglia

Endotoxin-activated microglia (as well as those activated by TNF-α)126 (except in mice with deactivated TNFα receptor)127 microglia 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

4.1.1.4. Endotoxin increases cortisol

If sensitivity to HPA axis suppression by dexamethasone is reduced, endotoxin causes significantly greater increases in cortisol.128

4.1.2. Behavioral changes due to endotoxin

4.1.2.1. Endotoxin increases depressed mood

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)

Endotoxin131

    • decreased motor activity still after 6 hours, but no longer after 24 hours
      • Increased depressive and anhedonic behavior even after 24 and 48 hours
      • After 6 hours, c-Fos was significantly reduced in all brain areas
      • After 24 hours, depressive behavior correlated with delayed cellular activity (FosB/ΔFosB) especially in amygdala, hippocampus, and hypothalamus
4.1.2.2. Anhedonia increased

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

4.1.2.3. Motor activity decreased

Endotoxin131

    • 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.

4.1.2.4.2. Flattened cortisol stress responses

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 on day 4 of life causes altered responses to amphetamines in juvenile animals. The effects on:136

  • Proinflammatory cytokines
    • IL-
    • IL-6
    • TNFα
  • Anti-inflammatory cytokines
    • IL-10
  • CD200 (anti-inflammatory neuroimmune regulatory molecule)
  • ARC (Activity-Regulated Cytoskeleton-Associated Protein)
  • CD11b (a microglial membrane protein)
  • 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. BDNF

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 BDNF (brain-derived neurotrophic factor) levels in the blood of 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.

5.2. Intercellular adhesion molecule-3

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

  • Myeloperoxidase
  • Interleukin-6
  • TNF-RI
  • IL-8
  • Intercellular adhesion molecule-3
  • Vascular endothelial growth factor-R1
  • Vascular endothelial growth factor-R2

5.3. Anti-Yo Antibody

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

5.4. S 100 B

5.4.1. S 100 B reduced for ADHD-I

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

5.5. C4B-binding protein (C4BP)

C4BP is an (inhibitory) regulator of the complement system.

5.5.1. C4BP in ADHD

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

5.6. GAD65 antibody

5.6.1. GAD65 antibodies in ADHD and ASD

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 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


  1. Dunn (2006): Effects of cytokines and infections on brain neurochemistry. Clin Neurosci Res. 2006 Aug;6(1-2):52-68.

  2. Felger, Miller (2012): Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol. 2012 Aug;33(3):315-27. doi: 10.1016/j.yfrne.2012.09.003.

  3. Capuron, Pagnoni, Drake, Woolwine, Spivey, Crowe, Votaw, Goodman, Miller (2012): Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch Gen Psychiatry. 2012 Oct;69(10):1044-53. doi: 10.1001/archgenpsychiatry.2011.2094.

  4. Miller AH, Jones, Drake, Tian, Unger, Pagnoni (2014): Decreased Basal Ganglia Activation in Subjects with Chronic Fatigue Syndrome: Association with Symptoms of Fatigue. PLoS ONE 9(5): e98156. https://doi.org/10.1371/journal.pone.0098156

  5. Sammut, Goodall, Muscat (2001): Acute interferon-alpha administration modulates sucrose consumption in the rat. Psychoneuroendocrinology. 2001 Apr;26(3):261-72.

  6. Majer, Welberg, Capuron, Pagnoni, Raison, Miller (2008): IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C. Brain Behav Immun. 2008 Aug;22(6):870-80. doi: 10.1016/j.bbi.2007.12.009

  7. Kitagami, Yamada, Miura, Hashimoto, Nabeshima, Ohta (2003): Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood–brain barrier, Brain Research, Volume 978, Issues 1–2, 2003, Pages 104-114, ISSN 0006-8993, https://doi.org/10.1016/S0006-8993(03)02776-8.

  8. Li, Knowlton, Woodward, Habecker (2003): Regulation of noradrenergic function by inflammatory cytokines and depolarization. Journal of Neurochemistry, 86: 774-783. doi:10.1046/j.1471-4159.2003.01890.x

  9. Sato, Suzuki, Yokoyama , Semba , Watanabe, Miyaoka (2006): Chronic intraperitoneal injection of interferon‐α reduces serotonin levels in various regions of rat brain, but does not change levels of serotonin transporter mRNA, nitrite or nitrate. Psychiatry and Clinical Neurosciences, 60: 499-506. doi:10.1111/j.1440-1819.2006.01538.x

  10. Felger (2017): The Role of Dopamine in Inflammation-Associated Depression: Mechanisms and Therapeutic Implications. Curr Top Behav Neurosci. 2017;31:199-219. doi: 10.1007/7854_2016_13.

  11. Kaasinen, Nurmi, Brück, Eskola, Bergman, Solin, Rinne (2001): Increased frontal [18F]fluorodopa uptake in early Parkinson’s disease: sex differences in the prefrontal cortex, Brain, Volume 124, Issue 6, June 2001, Pages 1125–1130, https://doi.org/10.1093/brain/124.6.1125

  12. Leenders, Palmer, Quinn, Clark, Firnau, Garnett, Nahmias, Jones, Marsden (1986): Brain dopamine metabolism in patients with Parkinson’s disease measured with positron emission tomography. Journal of Neurology, Neurosurgery, and Psychiatry 1986;49:853-860

  13. Kumai, Tateishi, Tanaka, Watanabe, Shimizu, Kobayashi (2000): Effect of interferon-α on tyrosine hydroxylase and catecholamine levels in the brain of rats, Life Sciences, Volume 67, Issue 6, 2000, Pages 663-669, ISSN 0024-3205, https://doi.org/10.1016/S0024-3205(00)00660-3.

  14. Kamata, Higuchi, Yoshimoto, Yoshida, Shimizu (2000): Effect of single intracerebroventricular injection of α-interferon on monoamine concentrations in the rat brain, European Neuropsychopharmacology, Volume 10, Issue 2, 2000, Pages 129-132, ISSN 0924-977X, https://doi.org/10.1016/S0924-977X(99)00067-X.

  15. Shuto, Kataoka, Horikawa, Fujihara, Oishi (1997): Repeated interferon-α administration inhibits dopaminergic neural activity in the mouse brain, Brain Research, Volume 747, Issue 2, 1997, Pages 348-351, ISSN 0006-8993, https://doi.org/10.1016/S0006-8993(96)01371-6.

  16. Felger, Hernandez, Miller (2015): Levodopa Reverses Cytokine-Induced Reductions in Striatal Dopamine Release. International Journal of Neuropsychopharmacology, Volume 18, Issue 4, February 2015, pyu084, https://doi.org/10.1093/ijnp/pyu084

  17. Felger, Mun, Kimmel, Nye, Drake, Hernandez, Freeman, Rye, Goodman, Howell, Miller (2013): Chronic Interferon-α Decreases Dopamine 2 Receptor Binding and Striatal Dopamine Release in Association with Anhedonia-Like Behavior in Nonhuman Primates, Neuropsychopharmacology volume 38, pages 2179–2187, 2013

  18. Moraska, Sood, Dakhil, Sloan, Barton, Atherton, Suh, Griffin, Johnson, Ali, Silberstein, Duane, Loprinzi (2010): Phase III, randomized, double-blind, placebo-controlled study of long-acting methylphenidate for cancer-related fatigue: North Central Cancer Treatment Group NCCTG-N05C7 trial. J Clin Oncol. 2010 Aug 10;28(23):3673-9. doi: 10.1200/JCO.2010.28.1444. n = 148

  19. Mar Fan, Clemons, Xu, Chemerynsky, Breunis, Braganza, Tannock (2008): A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Support Care Cancer. 2008 Jun;16(6):577-83.

  20. Butler, Case, Atkins, Frizzell, Sanders, Griffin, Lesser, McMullen, McQuellon, Naughton, Rapp, Stieber, Shaw (2007): A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumor patients receiving radiation therapy. Int J Radiat Oncol Biol Phys. 2007 Dec 1;69(5):1496-501. n = 68

  21. Pucci, Branãs, D’Amico, Giuliani, Solari, Taus (2007): Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD002818. n = 272

  22. Stankoff, Waubant, Confavreux, Edan, Debouverie, Rumbach, Moreau, Pelletier, Lubetzki, Clanet; French Modafinil Study Group. (2005): Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology. 2005 Apr 12;64(7):1139-43.

  23. Mustian, Alfano, Heckler, Kleckner, Kleckner, Leach, Mohr, Palesh, Peppone, Piper, Scarpato, Smith, Sprod, Miller (2017): Comparison of Pharmaceutical, Psychological, and Exercise Treatments for Cancer-Related Fatigue: A Meta-analysis. JAMA Oncol. 2017 Jul 1;3(7):961-968. doi: 10.1001/jamaoncol.2016.6914.

  24. Haroon, Fleischer, Felger, Chen, Woolwine, Patel, Hu, Miller (2016): Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Molecular Psychiatry volume 21, pages 1351–1357, 2016

  25. Raison, Borisov, Woolwine, Massung, Vogt, Miller (2010): Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry. 2010 May;15(5):535-47. doi: 10.1038/mp.2008.58.

  26. Dahlgren, Kecklund, Theorell, Akerstedt (2009): Day-to-day variation in saliva cortisol–relation with sleep, stress and self-rated health. Biol Psychol. 2009 Oct;82(2):149-55. doi: 10.1016/j.biopsycho.2009.07.001.

  27. Gisslinger, Svoboda, Clodi, Gilly, Ludwig, Havelec, Luger (1993): Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro. Neuroendocrinology. 1993 Mar;57(3):489-95.

  28. Capuron, Pagnoni, Demetrashvili, Lawson, Fornwalt, Woolwine, Berns, Nemeroff, Miller (2007): Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy. Neuropsychopharmacology. 2007 Nov;32(11):2384-92.

  29. Ho, Huo, Lu, Tansey, Levin (1992): Opioid-dopaminergic mechanisms in the potentiation of d-amphetamine discrimination by interferon-alpha. Pharmacol Biochem Behav. 1992 May;42(1):57-60.

  30. Wang, Zeng, Fan, Yuan, Tang (2006): mu- but not delta- and kappa-opioid receptor mediates the nucleus submedius interferon-alpha-evoked antinociception in the rat. Neurosci Lett. 2006 Apr 24;397(3):254-8.

  31. Tanaka, Sasaki (2017): Cognitive impairment with interferon treatment in patients with chronic hepatitis C. Biomed Res. 2017;38(6):371-374. doi: 10.2220/biomedres.38.371.

  32. Capuron, Pagnoni, Drake, Woolwine, Spivey, Crowe, Votaw, Goodman, Miller (2012): Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch Gen Psychiatry. 2012 Oct;69(10):1044-53. doi: 10.1001/archgenpsychiatry.2011.2094. n = 14

  33. Capuron, Pagnoni, Drake, Woolwine, Spivey, Crowe, Votaw, Goodman, Miller (2012): Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch Gen Psychiatry. 2012 Oct;69(10):1044-53. doi: 10.1001/archgenpsychiatry.2011.2094. n = 12

  34. di Rocco, Bottiglieri, Dorfman, Werner, Morrison, Simpson (2000): Decreased homovanilic acid in cerebrospinal fluid correlates with impaired neuropsychologic function in HIV-1-infected patients. Clin Neuropharmacol. 2000 Jul-Aug;23(4):190-4.

  35. Felger, Alagbe, Hu, Mook, Freeman, Sanchez, Kalin, Ratti, Nemeroff, Miller (2007): Effects of Interferon-Alpha on Rhesus Monkeys: A Nonhuman Primate Model of Cytokine-Induced Depression, Biological Psychiatry, Volume 62, Issue 11, 2007, Pages 1324-1333, ISSN 0006-3223, https://doi.org/10.1016/j.biopsych.2007.05.026. n = 8

  36. Felger, Mun, Kimmel, Nye, Drake, Hernandez, Freeman, Rye, Goodman, Howell, Miller (2013): Chronic Interferon-α Decreases Dopamine 2 Receptor Binding and Striatal Dopamine Release in Association with Anhedonia-Like Behavior in Nonhuman Primates, Neuropsychopharmacology volume 38, pages 2179–2187, 2013, n = 8

  37. Raison, Rye, Woolwine, Vogt, Bautista, Spivey, Miller (2010): Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with hepatitis C: association with fatigue, motor slowing, and increased evening cortisol. Biol Psychiatry. 2010 Nov 15;68(10):942-9. doi: 10.1016/j.biopsych.2010.04.019.

  38. Reite, Laudenslager, Jones, Crnic, Kaemingk (1987): Interferon decreases REM latency. Biol Psychiatry. 1987 Jan;22(1):104-7.

  39. Capuron, Gumnick, Musselman, Lawson, Reemsnyder, Nemeroff, Miller (2002): Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002 May;26(5):643-52.

  40. Musselman, Lawson, Gumnick, Manatunga, Penna, Goodkin, Greiner, Nemeroff, Miller (2001): Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001 Mar 29;344(13):961-6

  41. Weiss, Hechtman (2006): A randomized double-blind trial of paroxetine and/or dextroamphetamine and problem-focused therapy for attention-deficit/hyperactivity disorder in adults. J Clin Psychiatry. 2006 Apr;67(4):611-9.

  42. Raison, Borisov, Broadwell, Capuron, Woolwine, Jacobson, Nemeroff, Miller (2005): Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry. 2005 Jan;66(1):41-8.

  43. Capuron, Neurauter, Musselman, Lawson, Nemeroff, Fuchs, Miller (2003): Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry. 2003 Nov 1;54(9):906-14.

  44. Felger (2018): Imaging the Role of Inflammation in Mood and Anxiety-related Disorders, Curr Neuropharmacol. 2018 Jun; 16(5): 533–558. doi: 10.2174/1570159X15666171123201142

  45. Capuron, Miller (2004): Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry. 2004 Dec 1;56(11):819-24.

  46. Capuron, Fornwalt, Knight, Harvey, Ninan, Miller (2009): Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals? J Affect Disord. 2009 Dec;119(1-3):181-5. doi: 10.1016/j.jad.2009.02.017.

  47. Udina, Castellví, Moreno-España, Navinés, Valdés, Forns, Langohr, Solà, Vieta, Martín-Santos (2012): Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2012 Aug;73(8):1128-38. doi: 10.4088/JCP.12r07694.

  48. Capuron, Hauser, Hinze-Selch, Miller, Neveu (2002): Treatment of cytokine-induced depression. Brain Behav Immun. 2002 Oct;16(5):575-80.

  49. Elenkov (2004): Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci. 2004 Jun;1024:138-46.

  50. Neupane, Skulberg, Skulberg, Aass, Bramness (2016): Cytokine Changes following Acute Ethanol Intoxication in Healthy Men: A Crossover Study. Mediators Inflamm. 2016;2016:3758590. doi: 10.1155/2016/3758590. n = 20

  51. Kalinichenko, Koplik, Pertsov (2014): Cytokine profile of peripheral blood in rats with various behavioral characteristics during acute emotional stress. Bull Exp Biol Med. 2014 Feb;156(4):441-4. doi: 10.1007/s10517-014-2369-4.

  52. Schroecksnadel, Winkler, Werner, Sarcletti, Romani, Ebner, Schennach, Fuchs, Zangerle (2008): Interferon-γ-mediated pathways and in vitro PBMC proliferation in HIV-infected patients, Biological Chemistry, 2008, Band 390, Heft 2, Seiten 115–123, DOI: https://doi.org/10.1515/BC.2009.018.

  53. Anand, Colpo, Zeni, Zeni, Teixeira (2017): Attention-Deficit/Hyperactivity Disorder And Inflammation: What Does Current Knowledge Tell Us? A Systematic Review. Front Psychiatry. 2017 Nov 9;8:228. doi: 10.3389/fpsyt.2017.00228. eCollection 2017.

  54. Donfrancesco, Nativio, Borrelli, Giua, Andriola, Villa, DI Trani (2016): Serum cytokines in paediatric neuropsychiatric syndromes: focus on Attention Deficit Hyperactivity Disorder. Minerva Pediatr. 2016 Dec 22. n = 60

  55. Colotta, Re, Muzio, Bertini, Polentarutti, Sironi, Giri, Dower, Sims, Mantovani (1993): Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science. 1993 Jul 23;261(5120):472-5.

  56. Lopes (2017): Why are behavioral and immune traits linked? Horm Behav. 2017 Feb;88:52-59. doi: 10.1016/j.yhbeh.2016.09.008.

  57. Dunn (1988): Systemic interleukin-1 administration stimulates hypothalamic norepinephrine metabolism parallelling the increased plasma corticosterone. Life Sci. 1988;43(5):429-35.

  58. Dunn, Chuluyan (1992): The role of cyclo-oxygenase and lipoxygenase in the interleukin-1-induced activation of the HPA axis: dependence on the route of injection. Life Sci. 1992;51(3):219-25.

  59. Zalcman, Green-Johnson, Murray, Nance, Dyck, Anisman, Greenberg (1994): Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6, Brain Research, Volume 643, Issues 1–2, 1994, Pages 40-49, ISSN 0006-8993, https://doi.org/10.1016/0006-8993(94)90006-X.

  60. Gruys, Toussaint, Niewold, Koopmans (2005): Acute phase reaction and acute phase proteins. J Zhejiang Univ Sci B. 2005 Nov;6(11):1045-56.

  61. Müller: Psychoneuroimmunologische Grundlagen psychischer Erkrankungen, in: Möller, Laux, Kapfhammer (Hrsg.) (2017): Psychiatrie, Psychosomatik, Psychotherapie, Band 1, 5. Auflage, Kapitel 11, S. 291 – 310

  62. Anisman, Merali (1999): Anhedonic and anxiogenic effects of cytokine exposure. Adv Exp Med Biol. 1999;461:199-233.

  63. Campbell, Oldham, Becaria, Bondy, Meacher, Sioutas, Misra, Mendez, Kleinman (2005): Particulate Matter in Polluted Air May Increase Biomarkers of Inflammation in Mouse Brain. NeuroToxicology, Volume 26, Issue 1, 2005, Pages 133-140, ISSN 0161-813X, https://doi.org/10.1016/j.neuro.2004.08.003.

  64. Abreu, Llorente, Hernández, González (1994): Interleukin-1 beta stimulates tyrosine hydroxylase activity in the median eminence. Neuroreport. 1994 Jun 27;5(11):1356-8.

  65. Merali, Lacosta, Anisman (1997): Effects of interleukin-1beta and mild stress on alterations of norepinephrine, dopamine and serotonin neurotransmission: a regional microdialysis study. Brain Res. 1997 Jul 4;761(2):225-35.

  66. Zhu, Lindler, Owens, Daws, Blakely, Hewlett (2010): Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology. 2010 Dec;35(13):2510-20. doi: 10.1038/npp.2010.116.

  67. Zhu, Blakely, Hewlett (2006): The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology. 2006 Oct;31(10):2121-31.

  68. Song, Horrobin, Leonard (2006): The comparison of changes in behavior, neurochemistry, endocrine, and immune functions after different routes, doses and durations of administrations of IL-1beta in rats. Pharmacopsychiatry. 2006 May;39(3):88-99.

  69. Koo, Duman (2008): IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):751-6. doi: 10.1073/pnas.0708092105.

  70. O’Léime, Cryan, Nolan (2017): Nuclear deterrents: Intrinsic regulators of IL-1β-induced effects on hippocampal neurogenesis, Brain, Behavior, and Immunity, Volume 66, 2017, Pages 394-412, ISSN 0889-1591, https://doi.org/10.1016/j.bbi.2017.07.153.

  71. Goshen, Kreisel, Ben-Menachem-Zidon, Licht, Weidenfeld, Ben-Hur, Yirmiya (2008): Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry. 2008 Jul;13(7):717-28.

  72. Perera, Dwork, Keegan, Thirumangalakudi, Lipira, Joyce, Lange, Higley, Rosoklija, Hen, Sackeim, Coplan (2011): Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates. PLoS One. 2011 Apr 15;6(4):e17600. doi: 10.1371/journal.pone.0017600.

  73. Bieger: ME/CFS – die unbekannte Krankheit, symptome.ch

  74. Vereker, O’Donnell, Lynch (2000): The inhibitory effect of interleukin-1beta on long-term potentiation is coupled with increased activity of stress-activated protein kinases. J Neurosci. 2000 Sep 15;20(18):6811-9.

  75. Felger, Li, Haroon, Woolwine, Jung, Hu, Miller (2016): Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. Molecular Psychiatry volume 21, pages 1358–1365, 2016

  76. Shields, Kuchenbecker, Pressman, Sumida, Slavich (2016): Better cognitive control of emotional information is associated with reduced pro-inflammatory cytokine reactivity to emotional stress. Stress. 2016;19(1):63-8. doi: 10.3109/10253890.2015.1121983.

  77. Bilbo, Biedenkapp, Der-Avakian, Watkins, Rudy, Maier (2005): Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition. J Neurosci. 2005 Aug 31;25(35):8000-9.

  78. Nunes, Randall, Estrada, Epling, Hart, Lee, Baqi, Müller, Correa, Salamone (2014): Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task. Psychopharmacology (2014) 231: 727. https://doi.org/10.1007/s00213-013-3285-4

  79. Newton, Fernandez-Botran, Lyle, Szabo, Miller, Warnecke (2017): Salivary cytokine response in the aftermath of stress: An emotion regulation perspective. Emotion. 2017 Sep;17(6):1007-1020. doi: 10.1037/emo0000156.

  80. Steptoe, Hamer, Chida (2007): The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun. 2007 Oct;21(7):901-12.

  81. Altemus, Rao, Dhabhar, Ding, Granstein (2001): Stress-Induced Changes in Skin Barrier Function in Healthy Women, Journal of Investigative Dermatology, Volume 117, Issue 2, 2001, Pages 309-317, ISSN 0022-202X, https://doi.org/10.1046/j.1523-1747.2001.01373.x. n = 25

  82. Altemus, Rao, Dhabhar, Ding, Granstein (2001): Stress-Induced Changes in Skin Barrier Function in Healthy Women, Journal of Investigative Dermatology, Volume 117, Issue 2, 2001, Pages 309-317, ISSN 0022-202X, https://doi.org/10.1046/j.1523-1747.2001.01373.x. n = 11

  83. Fonken, Xu, Weil, Chen, Sun, Rajagopalan, Nelson (2011): Air pollution impairs cognition, provokes depressive-like behaviors and alters hippocampal cytokine expression and morphology. Molecular Psychiatry volume 16, pages 987–995 2011

  84. Bluthé, Beaudu, Kelley, Dantzer (1995): Differential effects of IL-1ra on sickness behavior and weight loss induced by IL-1 in rats. Brain Res. 1995 Apr 17;677(1):171-6.

  85. Kunz-Ebrecht, Mohamed-Ali, Feldman, Kirschbaum, Steptoe (2003): Cortisol responses to mild psychological stress are inversely associated with proinflammatory cytokines, Brain, Behavior, and Immunity, Volume 17, Issue 5, 2003, Pages 373-383, ISSN 0889-1591, https://doi.org/10.1016/S0889-1591(03)00029-1. n = 199

  86. Lapchak (1992): A role for interleukin-2 in the regulation of striatal dopaminergic function. Neuroreport. 1992 Feb;3(2) 165-168. PMID: 1623167.

  87. Kabiersch, Furukawa, del Rey, Besedovsky (1998): Administration of interleukin-1 at birth affects dopaminergic neurons in adult mice. Ann N Y Acad Sci. 1998 May 1;840:123-7.

  88. Kam, Szefler, Surs, Sher, Leung (1993): Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol October 1, 1993, 151 (7) 3460-3466

  89. Chrousos (1995): The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995 May 18;332(20):1351-62.

  90. Klein, Buskila, Gladman, Bruser, Malkin (1990): Cortisol catabolism by lymphocytes of patients with systemic lupus erythematosus and rheumatoid arthritis. (PMID:2313669) The Journal of Rheumatology [01 Jan 1990, 17(1):30-33]

  91. 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.

  92. Denicoff, Rubinow, Papa, Simpson, Seipp, Lotze, Chang, Rosenstein, Rosenberg (1987): The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med. 1987 Sep;107(3):293-300.

  93. Oades, Myint, Dauvermann, Schimmelmann, Schwarz (2010): Attention-deficit hyperactivity disorder (ADHD) and glial integrity: an exploration of associations of cytokines and kynurenine metabolites with symptoms and attention. Behav Brain Funct. 2010 Jun 9;6:32. doi: 10.1186/1744-9081-6-32.

  94. Miller, Raison (2016): The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature Rev Immunol 2016; 16: 22-34

  95. Harrison, Brydon, Walker, Gray, Steptoe, Critchley (2009): Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry. 2009 Sep 1;66(5):407-14. doi: 10.1016/j.biopsych.2009.03.015.

  96. Weinstein, Deuster, Francis, Bonsall, Tracy, Kop (2010): Neurohormonal and inflammatory hyper-responsiveness to acute mental stress in depression, Biological Psychology, Volume 84, Issue 2, 2010, Pages 228-234, ISSN 0301-0511, https://doi.org/10.1016/j.biopsycho.2010.01.016. n = 28

  97. Gruys E1, Toussaint MJ, Niewold TA, Koopmans (2005): Acute phase reaction and acute phase proteins. J Zhejiang Univ Sci B. 2005 Nov;6(11):1045-56.

  98. Goldsmith, Haroon, Woolwine, Jung, Wommack, Harvey, Treadway, Felger, Miller (2016): Inflammatory markers are sociated with decreased psychomotor speed in patients with major depressive disorder, Brain, Behavior, and Immunity, Volume 56, 2016, Pages 281-288, ISSN 0889-1591, https://doi.org/10.1016/j.bbi.2016.03.025.

  99. Schindler, Mancilla, Endres, Ghorbani, Clark, Dinarello (1990): Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood. 1990 Jan 1;75(1):40-7.

  100. Harrison, Voon, Cercignani, Cooper, Pessiglione, Critchley (2016): A Neurocomputational Account of How Inflammation Enhances Sensitivity to Punishments Versus Rewards, Biological Psychiatry, Volume 80, Issue 1, 2016, Pages 73-81, ISSN 0006-3223, https://doi.org/10.1016/j.biopsych.2015.07.018.

  101. Brydon, Harrison, Walker, Steptoe, Critchley (2008): Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry. 2008 Jun 1;63(11):1022-9. doi: 10.1016/j.biopsych.2007.12.007.

  102. Goldsmith, Haroon, Woolwine, Jung, Wommack, Harvey, Treadway, Felger, Miller (2016): Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder. Brain Behav Immun. 2016 Aug;56:281-8. doi: 10.1016/j.bbi.2016.03.025. n = 93

  103. Chiang, Eisenberger, Seeman, Taylor (2012): Negative and competitive social interactions are related to heightened proinflammatory cytokine activity. PNAS February 7, 2012 109 (6) 1878-1882; https://doi.org/10.1073/pnas.1120972109, n = 122

  104. Corominas-Roso, Armario, Palomar, Corrales, Carrasco, Richarte, Ferrer, Casas, Ramos-Quiroga (2017): IL-6 and TNF-α in unmedicated adults with ADHD: Relationship to cortisol awakening response. Psychoneuroendocrinology. 2017 May;79:67-73. doi: 10.1016/j.psyneuen.2017.02.017.

  105. Vogel, Bijlenga, Verduijn, Bron, Beekman, Kooij, Penninx (2017): Attention-deficit/hyperactivity disorder symptoms and stress-related biomarkers. Psychoneuroendocrinology. 2017 May;79:31-39. doi: 10.1016/j.psyneuen.2017.02.009.

  106. Darwish, Elgohary, Nosair (2019): Serum Interleukin-6 Level in Children With Attention-Deficit Hyperactivity Disorder (ADHD). J Child Neurol. 2019 Feb;34(2):61-67. doi: 10.1177/0883073818809831. n = 120

  107. Chrousos (2009): Stress and disorders of the stress system. Nat Rev Endocrinol. 2009 Jul;5(7):374-81. doi: 10.1038/nrendo.2009.106. PMID: 19488073. REVIEW

  108. Norris, Benveniste (1993): Interleukin-6 production by astrocytes: Induction by the neurotransmitter norepinephrine, Journal of Neuroimmunology, Volume 45, Issues 1–2, 1993, Pages 137-145, ISSN 0165-5728, https://doi.org/10.1016/0165-5728(93)90174-W.

  109. Gumusoglu, Fine, Murray, Bittle, Stevens (1995): The role of IL-6 in neurodevelopment after prenatal stress. Brain Behav Immun. 2017 Oct;65:274-283. doi: 10.1016/j.bbi.2017.05.015.

  110. von Känel, Kudielka, Preckel, Hanebuth, Fischer (2006): Delayed response and lack of habituation in plasma interleukin-6 to acute mental stress in men, Brain, Behavior, and Immunity, Volume 20, Issue 1, 2006, Pages 40-48, ISSN 0889-1591, https://doi.org/10.1016/j.bbi.2005.03.013.

  111. Hariri, Djazayery, Djalali, Saedisomeolia, Rahimi, Abdolahian (2012): Effect of n-3 supplementation on hyperactivity, oxidative stress and inflammatory mediators in children with attention-deficit-hyperactivity disorder. Malays J Nutr. 2012 Dec;18(3):329-35. n = 103

  112. Oades, Dauvermann, Schimmelmann, Schwarz, Myint (2010): Attention-deficit hyperactivity disorder (ADHD) and glial integrity: S100B, cytokines and kynurenine metabolism–effects of medication. Behav Brain Funct. 2010 May 28;6:29. doi: 10.1186/1744-9081-6-29.

  113. Soliven, Albert (1992): Tumor Necrosis Factor Modulates the Inactivation of Catecholamine Secretion in Cultured Sympathetic Neurons. Journal of Neurochemistry, 58: 1073-1079. https://doi.org/10.1111/j.1471-4159.1992.tb09364.x

  114. Raison, Rutherford, Woolwine, Shuo, Schettler, Drake, Haroon, Miller (2013): A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013 Jan;70(1):31-41. doi: 10.1001/2013.jamapsychiatry.4.

  115. Han, Cheung, Wong, Sze, Cheng, Yeung, Chan (2017): Distinct Cytokine and Chemokine Profiles in Autism Spectrum Disorders. Front Immunol. 2017 Jan 23;8:11. doi: 10.3389/fimmu.2017.00011. eCollection 2017.

  116. Ashwood, Krakowiak, Hertz-Picciotto, Hansen, Pessah, Van de Water (2010): Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J Neuroimmunol. 2011 Mar;232(1-2):196-9. doi: 10.1016/j.jneuroim.2010.10.025.

  117. Ashwood, Krakowiak, Hertz-Picciotto, Pessah, Van de Water (2011): Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011 Jan;25(1):40-5. doi: 10.1016/j.bbi.2010.08.003. n = 229

  118. Ashwood, Enstrom, Krakowiak, Hertz-Picciotto, Hansen, Croen, Ozonoff, Pessah, Van de Water (2008): Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol. 2008 Nov 15;204(1-2):149-53. doi: 10.1016/j.jneuroim.2008.07.006.

  119. Bierhaus, Wolf, Andrassy, Rohleder, Humpert, Petrov, Ferstl, von Eynatten, Wendt, Rudofsky, Joswig, Morcos, Schwaninger, McEwen, Kirschbaum, Nawroth (2003): A mechanism converting psychosocial stress into mononu clear cell activation. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1920-5.

  120. Ravani, Vincenzi, Bortoluzzi, Padovan, Pasquini, Gessi, Merighi, Borea, Govoni, Varani (2017): Role and Function of A2A and A₃ Adenosine Receptors in Patients with Ankylosing Spondylitis, Psoriatic Arthritis and Rheumatoid Arthritis. Int J Mol Sci. 2017 Mar 24;18(4):697. doi: 10.3390/ijms18040697. PMID: 28338619; PMCID: PMC5412283.

  121. Grigorenko, Han, Yrigollen, Leng, Mizue, Anderson, Mulder, de Bildt, Minderaa, Volkmar, Chang, Bucala (2008): Macrophage migration inhibitory factor and autism spectrum disorders. Pediatrics. 2008 Aug;122(2):e438-45. doi: 10.1542/peds.2007-3604.

  122. Ceylan, Sener, Bayraktar, Kavutcu (2012): Changes in oxidative stress and cellular immunity serum markers in attention‐deficit/hyperactivity disorder. Psychiatry and Clinical NeurosciencesVolume 66, Issue 3, https://doi.org/10.1111/j.1440-1819.2012.02330.x, n = 70

  123. Yeh, Shou, Lin, Chen, Chiang, Yeh (2015): Effect of Ginkgo Biloba Extract on Lipopolysaccharide‐induced Anhedonic Depressive‐like Behavior in Male Rats, Phytother. Res.,29, 260– 266, doi: 10.1002/ptr.5247.

  124. van Heesch, Prins, Konsman, Korte-Bouws, Westphal, Rybka, Olivier, Kraneveld, Korte (2014): Lipopolysaccharide increases degradation of central monoamines: An in vivo microdialysis study in the nucleus accumbens and medial prefrontal cortex of mice, European Journal of Pharmacology, Volume 725, 2014, Pages 55-63, ISSN 0014-2999, https://doi.org/10.1016/j.ejphar.2014.01.014.

  125. Tian, An, Jiang, Duan, Chen, Jiang (2006): Catalpol protects dopaminergic neurons from LPS-induced neurotoxicity in mesencephalic neuron-glia cultures. Life Sciences, Volume 80, Issue 3, 2006, Pages 193-199, ISSN 0024-3205, https://doi.org/10.1016/j.lfs.2006.09.010.

  126. Reinert, Umphlet, Quattlebaum, Boger (2014): Short-term effects of an endotoxin on substantia nigra dopamine neurons, Brain Research, Volume 1557, 2014, Pages 164-170, ISSN 0006-8993, https://doi.org/10.1016/j.brainres.2014.02.005.

  127. Qin, Wu, Block, Liu, Breese, Hong, Knapp, Crews (2007): Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia, 55: 453-462. doi:10.1002/glia.20467

  128. Vedder, Schreiber, Schuld, Kainz, Lauer, Krieg, Holsboer, Pollmächer (2007): Immune–endocrine host response to endotoxin in major depression, Journal of Psychiatric Research, Volume 41, Issues 3–4, 2007, Pages 280-289, ISSN 0022-3956, https://doi.org/10.1016/j.jpsychires.2006.07.014.

  129. van der Poll, Barber, Coyle, Lowry (1996): Hypercortisolemia increases plasma interleukin-10 concentrations during human endotoxemia–a clinical research center study. The Journal of Clinical Endocrinology & Metabolism, Volume 81, Issue 10, 1 October 1996, Pages 3604–3606, https://doi.org/10.1210/jcem.81.10.8855809

  130. Eisenberger, Berkman, Inagaki, Rameson, Mashal, Irwin (2010): Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010 Oct 15;68(8):748-54. doi: 10.1016/j.biopsych.2010.06.010.

  131. Frenois, Moreau, O’Connor, Lawson, Micon, Lestage, Kelley, Dantzer, Castanon (2007): Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology. 2007 Jun;32(5):516-31.

  132. O’Connor, Lawson, André, Moreau, Lestage, Castanon, Kelley, Dantzer (2009): Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry. 2009 May;14(5):511-22. doi: 10.1038/sj.mp.4002148.

  133. Attur, Patel, Patel, Abramson, Amin (1999): Tetracycline up-regulates COX-2 expression and prostaglandin E2 production independent of its effect on nitric oxide. J Immunol. 1999 Mar 15;162(6):3160-7

  134. Vichaya, Hunt, Dantzer (2014): Lipopolysaccharide Reduces Incentive Motivation While Boosting Preference for High Reward in Mice. Neuropsychopharmacology volume 39, pages 2884–2890, 2014

  135. Bilbo, Yirmiya, Amat, Paul, Watkins, Maier (2008): Bacterial infection early in life protects against stressor-induced depressive-like symptoms in adult rats. Psychoneuroendocrinology. 2008 Apr;33(3):261-9. doi: 10.1016/j.psyneuen.2007.11.008.

  136. Bland, Beckley, Watkins, Maier, Bilbo (2010): Neonatal Escherichia coli infection alters glial, cytokine, and neuronal gene expression in response to acute amphetamine in adolescent rats. Neuroscience Letters, Volume 474, Issue 1, 2010, Pages 52-57, ISSN 0304-3940, https://doi.org/10.1016/j.neulet.2010.03.006.

  137. Corominas-Roso, Ramos-Quiroga, Ribases, Sanchez-Mora, Palomar, Valero, Bosch, Casas (2013): Decreased serum levels of brain-derived neurotrophic factor in adults with attention-deficit hyperactivity disorder. International Journal of Neuropsychopharmacology, Volume 16, Issue 6, July 2013, Pages 1267–1275, https://doi.org/10.1017/S1461145712001629, n = 113

  138. Shim, Hwangbo, Kwon, Jeong, Lee, Lee, Kim (2008): Increased levels of plasma brain-derived neurotrophic factor (BDNF) in children with attention deficit-hyperactivity disorder (ADHD), Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 32, Issue 8, 2008, Pages 1824-1828, ISSN 0278-5846, https://doi.org/10.1016/j.pnpbp.2008.08.005. n = 148

  139. Vogel, Bijlenga, Verduijn, Bron, Beekman, Kooij, Penninx (2017): Attention-deficit/hyperactivity disorder symptoms and stress-related biomarkers. Psychoneuroendocrinology. 2017 May;79:31-39. doi: 10.1016/j.psyneuen.2017.02.009. n = 2307

  140. Scassellati, Zanardini, Tiberti, Pezzani, Valenti, Effedri, Filippini, Conte, Ottolini, Gennarelli, Bocchio-Chiavetto (2014): Serum brain-derived neurotrophic factor (BDNF) levels in attention deficit–hyperactivity disorder (ADHD). European Child & Adolescent Psychiatry; March 2014, Volume 23, Issue 3, pp 173–177, n = 90

  141. O’Shea, Joseph, Kuban, Allred, Ware, Coster, Fichorova, Dammann, Leviton (2014): Elevated blood levels of inflammation-related proteins are associated with an attention problem at age 24 mo in extremely preterm infants. Pediatr Res. 2014 Jun;75(6):781-7. doi: 10.1038/pr.2014.41.

  142. Greenlee, Clawson, Hill, Wood, Clardy, Tsunoda, Carlson (2015): Anti-Yo Antibody Uptake and Interaction with Its Intracellular Target Antigen Causes Purkinje Cell Death in Rat Cerebellar Slice Cultures: A Possible Mechanism for Paraneoplastic Cerebellar Degeneration in Humans with Gynecological or Breast Cancers; https://doi.org/10.1371/journal.pone.0123446

  143. Buderath, Gärtner, Frings, Christiansen, Schoch, Konczak, Gizewski, Hebebrand, Timmann (2009): Postural and gait performance in children with attention deficit/hyperactivity disorder. Gait Posture. 2009 Feb;29(2):249-54. doi: 10.1016/j.gaitpost.2008.08.016.

  144. Donfrancesco, Nativio, Di Benedetto, Villa, Andriola, Melegari, Cipriano, Di Trani (2016): Anti-Yo Antibodies in Children With ADHD: First Results About Serum Cytokines. J Atten Disord. 2016 Apr 19. pii: 1087054716643387.

  145. Warren, Odell, Warren, Burger, Maciulis, Torres (1995): Is Decreased Blood Plasma Concentration of the Complement C4B Protein Associated with Attention-Deficit Hyperactivity Disorder? Journal of the American Academy of Child & Adolescent Psychiatry, Volume 34, Issue 8, 1995, Pages 1009-1014, ISSN 0890-8567, https://doi.org/10.1097/00004583-199508000-00010.

  146. Rout, Mungan, Dhossche (2012): Presence of GAD65 autoantibodies in the serum of children with autism or ADHD, D.M. Eur Child Adolesc Psychiatry, 2012, 21: 141. https://doi.org/10.1007/s00787-012-0245-1

Diese Seite wurde am 08.08.2022 zuletzt aktualisiert.