Effect of individual cytokines and inflammatory markers

This article presents individual cytokines and inflammatory markers as well as their neurophysiological and behavioral effects.
Proinflammatory cytokines have a considerable influence on the dopamine, noradrenaline and serotonin balance, cause an activation of the HPA axis and an increase in acute-phase proteins. They thus have neurophysiological effects similar to those of ADHD.
Some cytokines, such as IL-6 and IL-10, appear to be directly related to ADHD. IFN-α can cause dopamine deficiency in the striatum, as occurs in ADHD. However, the associated symptoms can be reduced by L-dopa, whereas in ADHD L-dopa is not known to improve symptoms. At the same time, the dopaminergic-mediated symptoms of IFN-α administration (here: fatigue) respond only weakly to treatment with the stimulants that are effective in ADHD, which act as reuptake inhibitors of dopamine and noradrenaline and increase extracellular dopamine levels through DAT efflux.

• 1. Cytokines
  • 1.1. Interferons
    • 1.1.1. Interferon alpha (IFN-α)
      • 1.1.1.1. Neurophysiological effects of IFN-α
        • 1.1.1.1.1. Influence of IFN-α on dopamine, serotonin and noradrenaline
        • 1.1.1.1.2. Influence on glutamate through IFN-α
        • 1.1.1.1.3. Influence of IFN-α on the HPA axis
        • 1.1.1.1.4. Further effects of IFN-α
      • 1.1.1.2. Behavioral effects of IFN-α
        • 1.1.1.2.1. Fever
        • 1.1.1.2.2. Cognitive impairments
        • 1.1.1.2.3. Depression, anhedonia, fatigue
        • 1.1.1.2.4. Fear
        • 1.1.1.2.5. Sleep impaired
        • 1.1.1.2.6. Reduced motor activity
        • 1.1.1.2.7. No effects of IFN-α
        • 1.1.1.2.1. IFN-α and depression
    • 1.1.2. IFN-β
    • 1.1.3. IFN-γ
      • 1.1.3.1. IFN-γ for ADHD
  • 1.2. Interleukins
    • 1.2.1. IL-1
      • 1.2.1.1. IL-1α
        • 1.2.1.1.1. Neurophysiological effect of IL-1α
        • 1.2.1.1.1.1. Increased turnover of noradrenaline, dopamine, serotonin
        • 1.2.1.1.1.2. HPA axis activation
        • 1.2.1.1.1.3. Acute phase proteins increased
        • 1.2.1.1.2. Behavioral changes
        • 1.2.1.1.2.1. Fever
        • 1.2.1.1.2.2. Sickness behavior
        • 1.2.1.1.2.3. Anxiety symptoms
        • 1.2.1.1.2.4. Anorexia
        • 1.2.1.1.2.5. Sleep
        • 1.2.1.1.2.6. No influence of IL-1
      • 1.2.1.1.2. Effects on IL-1α
      • 1.2.1.2. IL-1ß
        • 1.2.1.2.1. Neurophysiological effect of IL-1ß
        • 1.2.1.2.1.1. Influences on noradrenaline, dopamine, serotonin
        • 1.2.1.2.1.2. Inhibition of neurogenesis
        • 1.2.1.2.1.3. Inhibition of long-term potentiation
        • 1.2.1.2.1.3. HPA axis activation
        • 1.2.1.2.1.4. Striatum connectivity - vmPFC
        • 1.2.1.2.2. Behavioral change through IL-1ß
        • 1.2.1.2.2.1. Cognitive performance
        • 1.2.1.2.2.2. Anhedonia / reward motivation reduced
        • 1.2.1.2.2.3. Stimulating sleep
        • 1.2.1.2.2.4. Movement activity
        • 1.2.1.2.2.5. Anxiety
        • 1.2.1.2.3. Behavioral changes depending on application location and duration
        • 1.2.1.2.4. Effects on IL-1β
        • 1.2.1.2.4.1. Stress increases IL-1β
        • 1.2.1.2.4.2. Particulate matter increases IL-1β
      • 1.2.1.3. IL-1-Ra
    • 1.2.2. IL-2
      • 1.2.2.1. Neurophysiological effects of IL-2
        • 1.2.2.1.1. IL-2 increases the turnover of noradrenaline and dopamine
        • 1.2.2.1.2. No increase in serotonin or cortisol due to IL-2
        • 1.2.2.1.3. IL-2 induces glucocorticoid resistance
        • 1.2.2.1.4. IL-2 reduces acetylcholine
      • 1.2.2.2. Behavioral effects of IL-2
        • 1.2.2.2.1. Sedating
        • 1.2.2.2.2. Motor effects on posture
        • 1.2.2.2.3. Memory impairment
        • 1.2.2.2.4. Anhedonia, impaired motivation
        • 1.2.2.2.5. Not caused: Anxiety, Anorexia, Sickness behavior
      • 1.2.2.3. IL-2 and ADHD
        • 1.2.2.2.3. IL-2 reduces oppositional defiant behavior, prolongs reaction time
    • 1.2.3. IL-4
      • 1.2.3.1. IL-4 inhibits cytokine-induced depression
      • 1.2.3.2. Induces glucocorticoid resistance
      • 1.2.3.3. IL-4, stress and behavior
      • 1.2.3.4. Serum IL-4 probably not elevated in ADHD
    • 1.2.4. IL-5
      • 1.2.4.1. IL-5 in cerebrospinal fluid often elevated in ADHD
    • 1.2.5. IL-6
      • 1.2.5.1. Neurophysiological effects of IL-6
        • 1.2.5.1.1. Increased dopamine and serotonin turnover, noradrenaline and cortisol unchanged
        • 1.2.5.1.1.1. IL-6 and depression
        • 1.2.5.1.2. Activation of the HPA axis
        • 1.2.5.1.3. Increases acute-phase proteins
        • 1.2.5.1.4. Reduced connectivity
        • 1.2.5.1.5. IL-6 reduces Il-1 and TNF-α
      • 1.2.5.2. Behavioral changes due to IL-6
        • 1.2.5.2.1. Fever, Sickness Behavior
        • 1.2.5.2.2. Anhedonia, increased fear of loss
        • 1.2.5.2.3. Drop in mood
        • 1.2.5.2.3. Reduced reaction speed
        • 1.2.5.2.3. Cognitive performance under stress
        • 1.2.5.2.3. Competitive and negative social behavior
      • 1.2.5.3. IL-6 in serum: correlation to ADHD questionable
      • 1.2.5.4. Causes of an increase in IL-6: stress / infections
      • 1.2.5.5. Influencing IL-6
    • 1.2.6. Cardiotrophin-1 (CT-1)
    • 1.2.7. IL-8
    • 1.2.8. IL-10
      • 1.2.8.1. Causes of IL-10: Stress
      • 1.2.8.1. IL-10 for ADHD
    • 1.2.9. IL-12
    • 1.2.10. IL-13
      • 1.2.10.1. IL-13 in ADHD
    • 1.2.12. IL-16
      • 1.2.12.1. IL-16 for ADHD
    • 1.2.13. IL-17
      • 1.2.13.1. IL-17 - no known correlation to ADHD
  • 1.3. Tumor necrosis factor
    • 1.3.1. TNF-α
      • 1.3.1.1. Neurophysiological effect of TNF-α
        • 1.3.1.1.1. Only high doses reduce serotonin and noradrenaline
        • 1.3.1.1.2. HPA axis activation
        • 1.3.1.1.3. Acute phase proteins increased
        • 1.3.1.1.3. TNF-α inhibits allergies
      • 1.3.1.2. Behavioral changes due to TNF-α
        • 1.3.1.2.1. Fever and sickness behavior
        • 1.3.1.2.2. Fear
        • 1.3.1.2.3. Anorexia
        • 1.3.1.2.4. TNF-α inhibits oppositional defiant behavior
        • 1.3.1.2.5. Conditional influence on depression
        • 1.3.1.2.6. No influence on anhedonia and motivation
      • 1.3.1.3. TNF-α in serum: no correlation to ADHD
      • 1.3.1.4. Effects on TNF-α
        • 1.3.1.4.1. Stress increases TNF-α
        • 1.3.1.4.2. Particulate matter increases TNF-α
        • 1.3.1.4.3. Alcohol does not change TNF-α
        • 1.3.1.4.4. TNF-α - blocker
    • 1.3.2. TNF-β
      • 1.3.2.1. TNF-β in cerebrospinal fluid: high correlation to ADHD
    • 1.3.3. TNFR2
  • 1.4. Chemokines
    • 1.4.1. MCP-1
    • 1.4.2. CCL5 (RANTES), CXCL8 (= IL-8, NAP-1, MDNCF, GCP-1)
  • 1.5. TGFβ1 (transforming growth factor)
• 2. Other inflammatory markers
  • 2.1. NF-kB (Nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells)
  • 2.2. MIF / MMIF / GIF
  • 2.3. C-reactive protein (CRP)
    • 2.3.1. CRP in serum: no correlation to ADHD
  • 2.4. Natural killer cells
• 3. Oxidative stress
  • 3.1. Oxidative stress in ADHD
• 4. Consequences of infection
  • 4.1. Endotoxin / lipopolysaccharide (LPS)
    • 4.1.1. Neurophysiological effects of endotoxin
      • 4.1.1.1. Noradrenaline, serotonin turnover increased by endotoxin
      • 4.1.1.2. Dopamine reduced by endotoxin
      • 4.1.1.3. Effects of endotoxin on cytokines
      • 4.1.1.3. Endotoxin activates microglia
      • 4.1.1.4. Endotoxin increases cortisol
    • 4.1.2. Behavioral changes due to endotoxin
      • 4.1.2.1. Endotoxin increases depressive mood
      • 4.1.2.2. Anhedonia increased
      • 4.1.2.3. Reduced motor activity
      • 4.1.2.4. Lifelong behavioral changes with endotoxin in newborns
        • 4.1.2.4.1. Reduced depression symptoms in response to stress with unchanged serotonin levels
        • 4.1.2.4.2. Flattened cortisol stress responses
        • 4.1.2.4.3. Memory problems with renewed immune activation in adulthood
        • 4.1.2.4.4. Reduced immunological effect of amphetamine
• 5. Other elements inside and outside the immune response
  • 5.1. BDNF
    • 5.1.1. BDNF in serum: rather no correlation to ADHD
  • 5.2. Intercellular adhesion molecule-3
  • 5.3. Anti-Yo antibody
  • 5.4. S 100 B
    • 5.4.1. S 100 B reduced for ADHD-I
  • 5.5. C4B-binding protein (C4BP)
    • 5.5.1. C4BP for ADHD
  • 5.6. GAD65 antibody
    • 5.6.1. GAD65 antibodies in ADHD and ASD

1. Cytokines¶

1.1. Interferons¶

1.1.1. Interferon alpha (IFN-α)¶

IFN-α and IFN-β bind to the interferon type 1 receptor with its subtypes IFNAR-1 and IFNAR-2, while IFN-γ binds to the interferon type 2 receptor (IFNGR).¹

1.1.1.1. Neurophysiological effects of IFN-α¶

The studies on the 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, although rodents do not have IFN type 1 receptors, so that the statements are only of limited significance.² Inconsistent results for IFN-α exist not only for dopamine, but also in relation to noradrenaline and serotonin.¹

1.1.1.1.1. Influence of IFN-α on dopamine, serotonin and noradrenaline¶

• IFN-α reduces dopaminergic activation of the striatum, which is associated with anhedonia, fatigue and depression ^{3 45}
  • This also correlates with changes in motivation.⁶
• IFN-α reduces dopamine and tetrahydrobiopterin (BH4) levels in the amygdala and raphe nuclei (IFN-α given to muscles).⁷ Cardiotrophin-1 (CT-1) and IN-6 also reduce BH4 levels⁸
  • It is unclear whether this is mediated by nitrogen oxide. This was partly affirmed,⁷ partly denied.⁹
• IFN-α, given peripherally, increased²
  • IFN-α in the brain through microglia and astrocytes
    IFN-α occurs in lower quantities than IL-6 and MCP-1, IFN-α in the brain in turn increases
  • IL-6 in the brain
  • IL-1 in the brain through microglia
  • TNF-α in the brain
  • MCP-1 (monocyte chemoattractant protein-1) in the brain
  • Oxidative stress (superoxidants) in the brain due to microglia
• Hepatitis C-infected persons with ADHD received IFN-α and L-dopa (F-dopa) measurable by radioactivity. IFN-α significantly increased F-dopa uptake and decreased F-dopa turnover in the caudate nucleus, putamen and those areas of the ventral striatum that were less activated by IFN-α. The changes in F-dopa uptake and turnover correlated with depression and fatigue³
  • Parkinson’s disease, on the other hand, is observed:
    • Reduced F-dopa uptake and increased turnover of F-dopa¹⁰
    • Reduced F-dopa uptake in the putamen and increased uptake in the PFC¹¹
    • Reduced activity and dopamine storage in the striatum¹²
• Noradrenaline and dopamine levels and tyrosine hydroxylase in rats were increased by IFN-α administered for 7 days¹³
  • Significantly increased in
    • PFC
    • Hypothalamus
    • Medulla oblongata
  • Unchanged in
    • Thalamus
    • Hippocampus
• An injection of IFN-α into the brain in rats within 2 hours¹⁴
  • Serotonin reduced
    • Significant dose-dependent reduction in PFC
    • Reduction in the middle brain
    • Reduction in the striatum
  • 5-Hydroxyindoleacetic acid (5-HIAA) reduces
    • Reduction in the middle brain
    • Reduction in the striatum
  • Noradrenaline reduced
    • Significant dose-dependent reduction in PFC
• IFN-α reduces tryptophan levels (albeit to a lesser extent than IFN-γ), which suggests an inhibitory effect on serotonin.¹
• IFN-α injected into the abdomen over 14 days in rats⁹
  • Dopamine reduced
    • Reduced after 1 day in the cortex
    • Reversible after the end of IFN-α administration
  • Noradrenaline reduced
    • Reduced in most brain regions after 4 days
    • Reversible after the end of IFN-α administration
  • Increased serotonin
    • After 14 days at 20,000 U/kg increased in
      • PFC
      • Hippocampus
    • After 14 days at 200,000 U/kg increased in
      • PFC
      • Hippocampus
      • Amygdala
      • Thalamus
      • Hypothalamus
    • After 14 days at 2,000,000 U/kg 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 in rats¹⁵
  • Dopamine levels significantly reduced
  • 3,4-Dihydroxyphenylacetic acid levels significantly reduced
  • Dopamine degradation induced by α-methyl-p-tyrosine is significantly suppressed.
• IFN-α over 4 weeks in monkeys caused a reduced increase in dopamine in the striatum due to amphetamines. This correlated with anhedonia.
  • This IFN-α-induced striatal dopamine reduction was completely reversed by L-dopa,¹⁶ suggesting that IFN-α impairs the synthesis of dopamine.
  • The ratio of 3,4-dihydroxyphenylacetic acid to dopamine, which increases when unpackaged dopamine is metabolized via monoamine oxidase, remained unchanged, suggesting that IFN-α does not affect dopamine levels via monoamine oxidase.¹⁶
  • Furthermore, the binding of the D2 dopamine receptor was reduced, but not that of the dopamine transporter.¹⁷

MPH shows 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 meta-analysis of 113 studies with n = 11,525 subjects found that neither amphetamines nor medication had a better overall effect on fatigue in cancer than exercise and psychotherapy. The accompanying material of the meta-analysis provides a very good overview.²¹²²²³

1.1.1.1.2. Influence on glutamate through IFN-α¶

IFN-α increases glutamate in the basal ganglia and dorsal ACC (dACC) in non-depressed individuals.²⁴

1.1.1.1.3. Influence of IFN-α on the HPA axis¶

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

• Cortisol
  • The changes in cortisol levels correlated with depression²⁵
  • Flattened daily course of cortisol²⁵
    • This correlated significantly with
      • Reduced activity
      • Reduced motivation
      • Physical exhaustion (fatigue)
      • Mental exhaustion
      • But not with general fatigue
    • The morning cortisol increase did not correlate with behavioral changes
  • Elevated evening cortisol level²⁵
    • An increase in evening cortisol minimums correlated significantly with increased depression scores on the MADRS and increased fatigue scores on 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 daily ACTH curve²⁵
    • ACTH changes did not correlate with behavioral changes
  • Elevated evening ACTH value²⁵
    • ACTH changes did not correlate with behavioral changes
• Stimulation of the HPA axis²⁷
  • A single administration of 5 million IU IFN-α activates the HPA axis
  • After a daily administration of 5 million IU IFN-α over 3 weeks, no increased ACTH and cortisol blood levels were detected. However, supramaximal doses of CRH triggered significantly increased ACTH and cortisol levels.
  • In the laboratory, IFN-α stimulates CRF production in the hypothalamus and corticoid secretion in the adrenal cortex (in rats), but not ACTH secretion by the pituitary gland.

1.1.1.1.4. Further effects of IFN-α¶

• IFN-α increased glucose metabolism in the basal ganglia and cerebellum, while decreasing it in the dorsal PFC. It caused exhaustion, alexithymia (lack of emotion) and fatigue.²⁸
• This increased glucose metabolism in the basal ganglia nuclei is similar to that of Parkinson’s patients, where it reflects 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, which is why it is possibly mediated via opioid receptors.²⁹²
• IFN-α reduces the perception of pain in rats. This effect can be prevented 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 barely in rodents.¹

1.1.1.2.2. Cognitive impairments¶

Cognitive impairments caused by IFN-α correlate significantly with a prolonged latency of P300.³¹

1.1.1.2.3. Depression, anhedonia, fatigue¶

• Anhedonia, fatigue and depression due to IFN-α
  • Due to reduced dopaminergic activation of the striatum³²⁴⁵
  • This also correlates with a change 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, huddling) correlated with reduced homovanillic acid in the cerebrospinal fluid, a metabolic product of dopamine, indicating reduced dopamine turnover.²
  • Fatigue correlated with reduced homovanillic acid in the cerebrospinal fluid, a metabolic product of dopamine, indicating reduced dopamine turnover.³⁴
  • Anhedonia¹⁶
    • Correlated with a reduced increase of dopamine in the striatum by amphetamines after IFN-α administration for 4 weeks in 8 monkeys.
    • This IFN-α-induced striatal dopamine reduction was completely reversed by L-dopa, suggesting that IFN-α impairs the synthesis of dopamine.

1.1.1.2.4. Fear¶

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

• Increasing anxiety behavior
• A decrease in psychomotor activity
• An increase in depressive-like huddling (huddling)
• Signs of depression were only present in the 3 animals that
  • Had significantly reduced dopamine metabolites in the cerebrospinal fluid:
    • Homovanillic acid (HVA)
    • 3,4-Dihydroxyphenylacetic acid (DOPAC)
  • Which correlated with reduced 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 elevated evening cortisol levels
  • Impaired REM sleep
    • This is mediated via the dopamine level³⁸
    • Correlates with increased fatigue
  • Increased stage 2 sleep (medium non-REM sleep)
  • Reduced deep sleep
    • Correlates with increased fatigue
  • Poorer sleep efficiency
    • Correlates with slower motor speed
  • No increased daytime tiredness
    • Reduced frequency of power naps

1.1.1.2.6. Reduced motor activity¶

IFN-α decreased motor activity in rats (7-day administration).¹³ The decreased motor activity correlated with decreased cerebrospinal fluid homovanillic acid, a metabolite of dopamine, indicating 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 fewer 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
As a drug against hepatitis C or malignant melanoma, IFN-α 2 b triggers severe depression in 40 to 50 % of people with ADHD in a dose-dependent manner and fatigue, loss of energy and motor slowdown in up to 80 %.⁴⁴ Plasma levels of IFN-α correlate highly with depression characteristics according to the MADRS and fatigue values according to the MFI.²⁵

Anorexia, fatigue and pain do not occur immediately, but only within 14 days of starting IFN-α treatment. Depressed mood, anxiety and cognitive impairment, on the other hand, only occurred later and mainly in patients who met the DSM-IV criteria for major depression.

IFN-α has two pathways of action⁴⁵

• Consequences occur quickly: neurovegetative syndrome
  • Psychomotor deceleration
  • Tiredness
  • Changes in the dopamine metabolism of the basal ganglia
  • Does not respond to antidepressants
• Consequences occurring late: depressive syndrome
  • Depressive symptoms
  • Activation of neuroendocrine pathways
  • Altered serotonin metabolism
  • Responds to antidepressants

IFN-α-induced depression and “naturally” occurring depression show⁴⁶

• Identical symptom severity of
  • States of anxiety
  • Depressive mood
  • Impaired work activity
• Deviating in IFN-α-induced depression
  • Stronger psychomotor deceleration
  • Higher weight loss
  • Feeling less guilty

Parameters that make depression more likely after antiviral treatment with interferon are:⁴⁷

• High baseline levels of IL-6
• Female gender
• Previous depression
• Subliminal symptoms of depression
• Low level of education

Antidepressants have the effect of reducing the production of pro-inflammatory cytokines (such as IFN-α) and increasing the production of anti-inflammatory cytokines.⁴⁸

1.1.2. IFN-β¶

IFN-α and IFN-β bind to the interferon type 1 receptor with its subtypes IFNAR-1 and IFNAR-2, while IFN-γ binds to the interferon type 2 receptor (IFNGR).¹

1.1.3. IFN-γ¶

IFN-α and IFN-β bind to the interferon type 1 receptor with its subtypes IFNAR-1 and IFNAR-2, while 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 (to 1.2 per mille).⁵⁰

Behaviorally more active rats showed higher peripheral blood levels of pro-inflammatory 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 non-stressed state.
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 the peripheral blood of more passive animals.⁵¹

IFN-α reduces tryptophan⁵²⁴⁸ (more strongly than IFN-α), which suggests an inhibitory influence on serotonin.¹

1.1.3.1. IFN-γ for 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 values are often inconclusive with regard to the neuropsychological effects of cytokines. See here: Measurement of cytokines

1.2. Interleukins¶

1.2.1. IL-1¶

1.2.1.1. IL-1α¶

IL-1α and IL-1β appear to have very similar effects. IL-1β is said to be more potent in activating the HPA axis.¹
IL-1α and IL-1β both bind to the IL-1 type 1 receptor, which mediates their effect.
The IL-1 type 2 receptor only appears to 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
The IL-1 receptors in humans differ considerably from animal variants.¹

Behaviorally more active rats showed higher peripheral blood levels of pro-inflammatory 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 non-stressed state.
Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in proinflammatory IL-1β and anti-inflammatory IL-4 in the peripheral blood of more passive animals.⁵¹

IL-1, TNF-α and IL-6 trigger various reactions:⁵⁶

1.2.1.1.1. Neurophysiological effect of IL-1α¶

1.2.1.1.1.1. Increased turnover of noradrenaline, dopamine, serotonin¶

• IL-1 increases noradrenaline 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 In addition to noradrenaline in the hypothalamus, IL-1 also increases serotonin turnover in the entire brain¹
  • The IL-1-mediated increase in noradrenaline turnover is lower in the brain regions innervated by the dorsal noradrenergic bundle⁵⁷
    • PFC
    • Hippocampus
    • Cerebellum
  • The noradrenergic effect of IL-1 appears to be mediated by cyclooxygenase 2 (COX2). COX2 antagonists (diclofenac) prevent increased noradrenaline turnover induced by IL-1, but not COX-1 antagonists (indomethacin, ibuprofen) or lipoxygenase antagonists.⁵⁸ However, indomethacin was able to prevent the increase in noradrenaline in response to intravenously administered IL-1, but not the increase in response to IL-1 administered intraperitoneally (into the peritoneum). Intravenously administered IL-1 also led to faster HPA axis activation than IL-1 administered into the peritoneum.
• IL-1 causes an increase in the turnover (which leads to a reduction in the level) of⁵⁹
  • Noradrenaline in the hypothalamus and hippocampus
  • Serotonin in the hippocampus and PFC
  • Dopamine in the PFC
• IL-1 causes cortisol elevation in the blood, but this did not correlate significantly with the noradrenaline elevation
• The sometimes increased dopamine consumption by IL-1 in mice 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 is primarily due to the increased noradrenaline level. IL-1β is thought to be more potent in terms of activating the HPA axis¹
  • IL-1 increases the release of ACTH⁶¹

1.2.1.1.1.3. Acute phase proteins increased¶

• Increase in acute phase proteins⁶⁰

1.2.1.1.2. Behavioral changes¶

1.2.1.1.2.1. Fever¶

1.2.1.1.2.2. Sickness behavior¶

• As well as TNF-α, unlike IL-2 single dose⁶²
• Reduced food intake⁶⁰
• Reduced water absorption
• Trembling
• Increased drowsiness
• Reduced social interest.

1.2.1.1.2.3. Anxiety symptoms¶

• As well as TNF-α, unlike IL-2 single dose⁶²

1.2.1.1.2.4. Anorexia¶

• As well as TNF-α, unlike IL-2 single dose⁶²

1.2.1.1.2.5. Sleep¶

• IL-1 induces sleep⁶¹

1.2.1.1.2.6. No influence of IL-1¶

• No influence on reward processes / motivation (anhedonia)
  • As well as TNF-α, unlike IL-2 single dose⁶²

1.2.1.1.2. Effects on IL-1α¶

Inhaled particulate matter was found in the brain tissue of mice and increased the level of IL-1α there.⁶³

1.2.1.2. IL-1߶

1.2.1.2.1. Neurophysiological effect of IL-1߶

1.2.1.2.1.1. Influences on noradrenaline, dopamine, serotonin¶

• An increase in tyrosine hydroxylase due to 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 mild stress-induced dopamine increase by mild stress in the PFC.⁶⁵
• IL-1-β increases the activity of the serotonin transporter, which leads to increased degradation of serotonin.⁶⁶⁶⁷
• IL-1 causes an increase in the turnover (which leads to a reduction in the level) of⁵⁹
  • Noradrenaline in the hypothalamus and hippocampus
  • Serotonin in the hippocampus and PFC
  • Dopamine in the PFC
• IL-1 causes cortisol elevation in the blood, but this did not correlate significantly with the noradrenaline elevation
• The effects of IL-1β in rats depend considerably on the type of application (injected into the brain = intracerebroventricular or into the peritoneum = intraperitoneal = peripheral)⁶⁸
  • Noradrenaline
    • Reduced in limbic regions due to prolonged administration
  • Serotonin
    • Increased in limbic regions through prolonged administration
  • Dopamine
    • Increased in limbic regions through prolonged administration
  • Sensitivity to stress
    • Increased
  • Increase in blood cortisol
    • Through acute and prolonged administration of IL-1β
  • Reduction of IL-10
    • Through acute and prolonged administration of IL-1β
  • PGE2 release
    • Increased by IL-1β released into the 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 neuronal stem cells in the hippocampus is of central importance for cognitive function.⁷⁰⁷¹⁶⁹ One of the modes 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 administering the antioxidant vitamins E and C.
  • The inhibition of LTP correlates with:
    • IL-1β increase in the dentate gyrus
    • Decrease in KCl-stimulated glutamate release in synaptosomes from the dentate gyrus
      • LTP is associated with increased glutamate release
      • Decrease in KCl-stimulated glutamate release is prevented by administration of the antioxidant vitamins E and vitamin C
    • Increase in unstimulated glutamate release
    • Increased activity of stress-activated kinases
    • Increased activity of the c-Jun N-terminal kinase (JNK)
    • Increased activity of the p38 mitogen-activated protein kinase
  • An intracerebroventricular (= given into the brain) injection of IL-1β increased oxygen radicals in the hippocampus.
    • Is prevented by the administration of the antioxidant vitamins E and C
  • IL-1β and H²O² increase the activities of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase
    • Is prevented by the administration of the antioxidant vitamins E and C

1.2.1.2.1.3. HPA axis activation¶

IL-1 increases the release of ACTH.⁶¹

1.2.1.2.1.4. Striatum connectivity - vmPFC¶

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

1.2.1.2.2. Behavioral change through IL-1߶

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 of cognitive control/performance in the Stroop test.⁷⁶

Spatial memory is only impaired by long-term administration of IL-1β into the brain, not by short-term administration or peripheral administration into the peritoneum.⁶⁸

Neonatal rats treated with endotoxin respond to repeated endotoxin treatment in adulthood:⁷⁷

• Increased gene expression for microglia cell markers in the hippocampus
• A stronger increase in the gene expression of glial cell markers in the hippocampus
  • This increase remained elevated for 24 h longer
• A faster increase in IL-1beta in the hippocampus and PFC
• A prolonged increase in IL-1-beta in the PFC
• Peripheral cytokines or basal corticosterone were unchanged
• Impaired memory
  • This could be prevented by administering a caspase-1 inhibitor to the adult animals 1 hour before the learning event and the 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 compared to freely available food. The preference for sugar over freely available food was not reduced. This suggests that IL-1β reduces the level of reward stimuli (anhedonia). This is similar to the effect of IFN-α.⁷⁸

1.2.1.2.2.3. Stimulating sleep¶

IL-1 induces sleep.⁶¹

1.2.1.2.2.4. Movement activity¶

The behavioral effects of IL-1β in rats depend considerably on the type of application (injected into the brain = intracerebroventricular or into the peritoneum = intraperitoneal = peripheral).⁶⁸

• Movement activity:
  • Elevated (into the peritoneum)
  • Reduced (into the brain)

1.2.1.2.2.5. Anxiety¶

The behavioral effects of IL-1β in rats depend significantly on the type of administration (into the brain = intracerebroventricular or into the peritoneum = intraperitoneal = peripheral).⁶⁸ Anxiety 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 location and duration¶

The behavioral effects of IL-1β in rats depend considerably on the type of application (injected into the brain = intracerebroventricular or into the peritoneum = intraperitoneal = peripheral).⁶⁸

• Movement activity:
  • Elevated (into the peritoneum)
  • Reduced (into the brain)
• Anxiety
  • Increased after administration into the peritoneum
  • More elevated when administered into the brain
• Spatial memory
  • Only impaired by prolonged administration into the brain
• Increase in blood cortisol
  • Through acute and prolonged administration of IL-1β
• Reduction of IL-10
  • Through acute and prolonged administration of IL-1β
• PGE2 release
  • Increased by IL-1β- released into the brain
  • Reduced by peripheral administration
• Noradrenaline
  • Reduced in limbic regions through prolonged administration
• Serotonin
  • Increased in limbic regions through prolonged administration
• Dopamine
  • Increased in limbic regions through prolonged administration
• Stress sensitivity
  • Increased

1.2.1.2.4. Effects on IL-1β¶

1.2.1.2.4.1. Stress increases IL-1β¶

• Psychological stress (on TSST as well as on angry memory retrieval) leads to an increase in IL-1β, TNF-α and IL-6 in the sense of a stress response. The stress-induced increase in IL-1β, TNF-α and IL-6 correlates with negative emotions.⁷⁹
• A further 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 of cognitive control/performance in the Stroop test.⁷⁶
• In women, stress caused by an interview led to an increase in⁸¹
  • Plasma cortisol
  • Noradrenaline
  • IL-1β
  • IL-10
  • TNF-a
  • Number and activity of natural killer cells
• In women, stress caused by sleep deprivation led to an increase in⁸²
  • IL-1β
  • TNF-α
  • Natural killer cells.
• Behaviorally more active rats showed higher peripheral blood levels of pro-inflammatory 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 non-stressed state.
  Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in proinflammatory IL-1β and anti-inflammatory IL-4 in the peripheral blood of more passive animals.⁵¹

1.2.1.2.4.2. Particulate matter increases IL-1β¶

Inhaled particulate matter increased gene expression for IL-1β in mice.⁸³
Particulate matter also increases the risk of ADHD.

1.2.1.3. IL-1-Ra¶

Interleukin 1 receptor antagonist

IL-1Ra (as well as anti-inflammatory cytokines such as IL-10) prevents the symptoms mediated by IL-1. IL-1-Ra prevents 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) increases the IL-1Ra values within 2 hours and for at least another 10 hours, while the alcohol was completely broken down within 10 hours.⁵⁰

High IL-6, IL-1beta and IL-1-RA levels correlate with reduced connectivity between

• Striatum and vmPFC ⁷⁵

In response to mild stress, healthy subjects with a low cortisol stress response showed higher stress responses of IL-6 and IL-1ra in the 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, while ADHD-I is very often associated with an elevated cortisol stress response.

1.2.2. IL-2¶

Behaviorally more active rats showed higher peripheral blood levels of pro-inflammatory 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 non-stressed state.
Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in proinflammatory IL-1β and anti-inflammatory IL-4 in the peripheral blood of more passive animals.⁵¹

1.2.2.1. Neurophysiological effects of IL-2¶

1.2.2.1.1. IL-2 increases the turnover of noradrenaline and dopamine¶

IL-2 causes an increase in the turnover (which leads to a reduction in the level) of

• Noradrenaline in the hypothalamus⁵⁹
• Noradrenaline in the hippocampus⁶¹
• Dopamine in the PFC⁵⁹⁶¹
• Dopamine in the striatum⁸⁶
• IL-2 in low doses in newborn mice causes reduced dopamine levels in the hypothalamus in adulthood.⁸⁷
• Since IL-2 increases the release of dopamine and there are particularly many IL-2 receptors in the hippocampus, IL-2 has an effect on memory function.⁶¹
• The effects of IL-2 on dopamine and noradrenaline are weaker than those of IL-1 and IL-6.¹

1.2.2.1.2. No increase in serotonin or cortisol due to IL-2¶

• No increase in
  • Serotonin⁵⁹. Different: moderate increase in serotonin.¹
  • Cortisol in the 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 reducing the affinity of the glucocorticoid receptor for its ligand.^{88 89} In addition, the conversion of cortisol into less active or inactive metabolites reduces the glucocorticoid sensitivity of immune system cells to glucocorticoids.⁹⁰

1.2.2.1.4. IL-2 reduces acetylcholine¶

IL-2 reduces the release of acetylcholine

• In the hippocampus⁶¹
• In the 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
• Can trigger schizophrenia symptoms depending on the dose⁹²

1.2.2.2.3. Memory impairment¶

• Chronic administration of IL-2 impairs working memory⁶² and memory function because IL-2 increases the release of dopamine and there are a particularly large number of IL-2 receptors in the hippocampus.⁶¹

1.2.2.2.4. Anhedonia, impaired motivation¶

• IL-2 single dose influences reward processes/motivation (anhedonia), unlike IL-1 beta and TNF alpha⁶²

1.2.2.2.5. Not caused: Anxiety, Anorexia, Sickness behavior¶

• Single-dose IL-2 does not trigger anxiety symptoms, unlike IL-1 beta and TNF alpha, which act synergistically⁶²
• IL-2 does not trigger sickness behavior, unlike IL-1 beta and TNF alpha, which act synergistically⁶²
• IL-2 does not trigger 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 Cerebrospinal fluid levels are likely to be crucial 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, while 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¶

The activation of effector T cells (TH cells) during stress can have an inhibitory effect on depressive and anxious behavior in mice by activating IL-4. TH cells in the meninges produce IL-4, which has an anti-inflammatory effect 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 reducing the affinity of the glucocorticoid receptor for its ligand.^{88 89} In addition, the conversion of cortisol into less active or inactive metabolites reduces the 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 pro-inflammatory 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 non-stressed state.
Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in proinflammatory IL-1β and anti-inflammatory IL-4 in the peripheral blood of 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 test 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, noradrenaline and cortisol unchanged¶

• IL-6 causes an increase in the turnover (which leads to a reduction in the level) of⁵⁹
  • Serotonin in the hippocampus and PFC
  • Dopamine in the PFC
  • But not of noradrenaline in the hypothalamus or hippocampus
  • No increase in cortisol in the blood
• IL-6 increases tryptophan levels and serotonin turnover in the brain (but less so than IL-1), but not noradrenaline.¹
• IL-6 (and TNF-alpha) do not reduce noradrenaline uptake, but the IL-6-related CT-1 does.⁸

1.2.5.1.1.1. IL-6 and depression¶

• IL-6 (and even more so the IL-6-related cardiotrophin-1, CT-1) reduce BH4 levels.⁸ BH4 is an enzyme required for the synthesis of serotonin, dopamine and noradrenaline. A reduction in BH4 results in reduced serotonin and dopamine levels.
• IL-6 and sIL-6R (following administration of interferon-alpha) did not correlate with increased depression levels according to the MADRS. Changes in daily IL-6 levels had no effect on behavior.²⁵
• A strong increase in IL-6 is neurophysiologically associated with⁹⁵
  • Increased activity within the subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotion appraisal
• The stress response of TNF-α, IL-6 and CRP is higher in people with depression than in those without.⁹⁶

1.2.5.1.2. Activation of the HPA axis¶

• However, activation of the HPA axis⁶⁰ is weaker than by IL-1.¹

1.2.5.1.3. Increases acute-phase proteins¶

• Increase in acute phase proteins⁹⁷
• Slowed psychomotor skills⁹⁸

1.2.5.1.4. Reduced connectivity¶

• The strong increase in IL-6 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 levels of IL-6, IL-1beta and IL-1-RA correlate with reduced connectivity between
  • Striatum and vmPFC ⁷⁵

1.2.5.1.5. IL-6 reduces Il-1 and TNF-α¶

• IL-6 reduces 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 TNF-α⁵⁶
• Sickness behavior
  • Reduced food intake⁹⁷
  • Reduced water absorption
  • Trembling
  • Increased drowsiness
  • Reduced social interest

1.2.5.2.2. Anhedonia, increased fear of loss¶

• Reduced response to rewards (anhedonia), increased fear of loss/punishment¹⁰⁰

1.2.5.2.3. Drop in mood¶

IL-6 mediates a deterioration in mood.⁹⁵¹⁰⁰

1.2.5.2.3. Reduced reaction speed¶

IL-6 causes prolonged reaction times.¹⁰¹¹⁰²

1.2.5.2.3. Cognitive performance under stress¶

IL-6 mediates impairment of cognitive performance during stress. The higher the IL-1β, IL-6, and IL-8 stress response to an emotionally stressful movie, the greater the stress-induced impairment of cognitive control/performance in the Stroop test.⁷⁶

1.2.5.2.3. Competitive and negative social behavior¶

IL-6 causes increased competitive social interactions. The basal blood levels of IL-6 and the 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. The IL-6 and soluble TNF receptor stress response correlated positively with the level of negative social interactions. The basal blood level of the soluble TNF receptor correlated positively with the level 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 the sense 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 IL-6 in the blood between people with ADHD-HI, people with ADHD-I and unaffected people.¹⁰⁴ Another study of 2307 participants in a Dutch study came to the same conclusion.¹⁰⁵

Another study of 120 children with and without ADHD found on average 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 analysis technique was used, only from a different manufacturer.
Another study also found elevated IL-6 and IL-10 serum levels in children with ADHD.⁵⁴

The different results could possibly be due to the fact that the levels of IL-6 in the blood and in the cerebrospinal fluid do not necessarily correlate and that neuropsychological effects of the cytokines are not represented by blood levels of the same.⁷³

1.2.5.4. Causes of an increase in IL-6: stress / infections¶

• Stress hormones increase IL-6:¹⁰⁷
  • Noradrenaline
  • CRH
• Noradrenaline, which (like cortisol) is part of the endocrine stress response, stimulates the expression of IL-6 mRNA and the production of IL-6 in astrocytes via β2 and α1 adrenoceptors in a dose-dependent manner.¹⁰⁸ Since the release of noradrenaline occurs before the activation of the HPA axis, the inhibition of IL-6 by cortisol could represent a negative feedback loop, comparable to the inhibition of the HPA axis after a stress response.
• Stress in the mother, which causes damage to the unborn child, is presumably primarily mediated by IL-6. The defective 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 the sense of a stress response. The stress-induced increase in IL-1β, TNF-α and IL-6 correlated with negative emotions.⁷⁹
• On habituation 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 people with depression than in those without.⁹⁶
• IL-6, IL-10, IL-17, IFN-γ and TNF-α were little affected by alcohol consumption (to 1.2 per mille).⁵⁰
• In response to mild stress, healthy subjects with a low cortisol stress response showed higher stress responses of IL-6 and IL-1ra in the 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 elevated cortisol stress response.
• A thyphoid vaccination led to a 250% increase in IL-6, which correlated with a drop in mood. The group that was not vaccinated against thyphoid but treated with placebo showed a slight increase in IL-6 of 30%.¹⁰⁰ This could be due to the stress associated with the test.
• Particulate matter did not increase the gene expression for IL-6.⁸³

1.2.5.5. Influencing IL-6¶

An 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 from the IL-6 protein family.

• CT-1 (and, to a lesser extent, IL-6) reduces BH4 levels.⁸
• CT-1 (but not IL-6 or TNF-alpha) reduces noradrenaline 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 of cognitive control/performance in the Stroop test.⁷⁶

1.2.8. IL-10¶

• IL-10 increases the performance of the DSST (Digit Symbol Substitution Task).¹⁰²
• Elevated IL-10 levels correlate with a tendency to allergies.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 pro-inflammatory 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 non-stressed state.
  Acute stress caused a decrease in plasma levels of these cytokines in more behaviorally active rats, but an increase in proinflammatory IL-1β and anti-inflammatory IL-4 in the peripheral blood of more passive animals.⁵¹
• In women, stress caused by an interview led to an increase in⁸¹
  • Plasma cortisol
  • Noradrenaline
  • IL-1β
  • IL-10
  • TNF-a
  • Number and activity of natural killer cells.
• IL-10, IL-6, IL-17, IFN-γ and TNF-α are little affected by alcohol consumption (to 1.2 per mille).⁵⁰

1.2.8.1. IL-10 for ADHD¶

Elevated plasma IL-10 levels correlate with higher ADHD symptoms⁹³ Another study also found elevated IL-6 and IL-10 serum levels in children with ADHD.⁵⁴
The only cerebrospinal fluid test 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 for 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 (to 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-α¶

1.3.1.1. Neurophysiological effect of TNF-α¶

1.3.1.1.1. Only high doses reduce serotonin and noradrenaline¶

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

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

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

• A renewed depolarization after 6 minutes reduced the release of noradrenaline
• A renewed depolarization after 10 minutes restored the release of noradrenaline

1.3.1.1.2. HPA axis activation¶

TNF-α activates the HPA axis⁹⁷ as well as 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 new TNF-α administration⁶²

1.3.1.1.3. TNF-α inhibits allergies¶

Reduced TNF-α levels correlated with allergies.¹¹²

1.3.1.2. Behavioral changes due to TNF-α¶

1.3.1.2.1. Fever and sickness behavior¶

• • Fever⁵⁶
    • Sickness behavior
      • As well as IL-1 beta, unlike IL-2 single dose⁶²
      • Reduced food intake⁶⁰
      • Reduced water absorption
      • Trembling
      • Increased drowsiness
      • Reduced social interest.

1.3.1.2.2. Fear¶

TNF-α triggers anxiety symptoms, as does IL-1- beta, unlike single-dose IL-2.⁶²

1.3.1.2.3. Anorexia¶

TNF-α triggers 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 plasma TNF-α and IL-2 levels correlated with higher levels of oppositional defiant behavior.¹¹²

1.3.1.2.5. Conditional influence on depression¶

Increased TNF-α and TNFR2 values after IFN-α administration correlated significantly with increased depression values according to the MADRS.²⁵ Treatment of persons with ADHD with a TNF antagonist was only helpful with 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 influence on reward processes / motivation (anhedonia), nor does IL-1 beta, unlike a single dose of IL-2.⁶²

1.3.1.3. TNF-α in serum: no correlation to ADHD¶

A study of 135 unmedicated adults found no differences in TNF-α in the blood between people with ADHD-HI, people with ADHD-I and unaffected people.¹⁰⁴ A study of 2307 participants in a Dutch study came to 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 due to the fact that the levels of TNF-α in the blood and in the cerebrospinal fluid can be different and neuropsychological effects of the cytokines are not represented by their blood levels but by their levels in the brain,⁷³ is an open question.

1.3.1.4. Effects on TNF-α¶

1.3.1.4.1. Stress increases TNF-α¶

• Psychological stress (TSST such as angry memory retrieval) leads to an increase in IL-1β, TNF-α and IL-6 in the sense of a stress response. The stress-related 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 people with depression than in those without.⁹⁶
• In women, stress caused by an interview led to an increase in⁸¹
  • Plasma cortisol
  • Noradrenaline
  • IL-1β
  • IL-10
  • TNF-α
  • Number and activity of natural killer cells
• In women, stress caused by sleep deprivation led to an increase in⁸²
  • IL-1β
  • TNF-α
  • Natural killer cells.

1.3.1.4.2. Particulate matter increases TNF-α¶

Inhaled particulate matter was found in the brain tissue of mice, where it increased the level of TNF-α⁶³ by upregulating the responsible gene.⁸³

1.3.1.4.3. Alcohol does not change TNF-α¶

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 amount to around €40,000 (as of 2019).

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

1.3.2. TNF-β¶

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

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

1.3.3. TNFR2¶

TFNR2 does not show a daily rhythm.²⁵
IFN-α 2a and IFN-α 2b lead to significantly increased TFNR2 levels.²⁵
The increase in TNF-α and TNFR2 to IFN-α correlated significantly with increased depression scores after the MADRS.²⁵

1.4. Chemokines¶

1.4.1. MCP-1¶

MCP-1 (monocyte chemoattractant protein 1) reduced 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 reduces the value of the chemokine MCP-1 acutely, whereby this increased steadily over the following 12 hours and remained above the initial value, while the alcohol was completely broken down within 10 hours.⁵⁰
MCP-1 correlated with slower psychomotor skills.⁹⁸

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

In persons with ADHD, 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.

A reduced plasma level of TGFβ1 (transforming growth factor beta1) correlated with more stereotypy, irritability, hyperactivity and other behavioral symptoms and less adaptive behavior in a study of people with ADHD.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 that occurs 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 increases NF-kB levels in peripheral human blood cells via noradrenaline at alpha(1) and beta adrenoceptors. The stress also increased catecholamines and cortisol. NF-kB returned to baseline levels after one hour.¹¹⁹
Inhaled particulate matter was found in the brain tissue of mice and increased the NF-kB level there.⁶³

In chronic autoimmune rheumatic diseases, adenosine A2A and A3 receptors are overexpressed in lymphocytes. A2A and A3 agonists inhibited the activation of NF-κB, the release of typical proinflammatory cytokines and the concentration of metalloproteinases, which are involved in the inflammatory reactions in chronic autoimmune rheumatic diseases.¹²⁰

2.2. MIF / MMIF / GIF¶

MIF / MMIF (macrophage migration inhibitory factor) is also known as 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 impairment and less imaginative play in people with ADHD, according to a 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 deceleration
  • Striatum and vmPFC are parts of the (mesocorticolimbic) dopaminergic-controlled reward system.¹⁰
• High IL-6, IL-1beta and IL-1-RA levels also correlate with reduced connectivity between
  • Striatum and vmPFC ⁷⁵
• Elevated cerebrospinal fluid CRP correlates significantly with elevated glutamate levels in the right basal ganglia, independent of age, gender, race, body mass index, smoking status, and depression severity.²⁴
• Increased glutamate in the right basal ganglia correlates with anhedonia and psychomotor slowing in 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 the 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 people with depression than in those without.⁹⁶

2.3.1. CRP in serum: no correlation to ADHD¶

A study of 2307 participants in a Dutch study found no correlation between blood levels of C-reactive protein (CRP) and ADHD.¹⁰⁵
An 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 caused by sleep deprivation led to an increase in⁸²

• Natural killer cells
• IL-1β
• TNF-α

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)
• And 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 excreted by the bacterium Escherichia coli (E. coli). Infections with E. coli are therefore a trigger for a severe immune reaction.

4.1.1. Neurophysiological effects of endotoxin¶

4.1.1.1. Noradrenaline, serotonin turnover increased by endotoxin¶

Endotoxin / lipopolysaccharide (LPS) increases noradrenaline and serotonin turnover and tryptophan levels, as does IL-1. IL-1 antagonists partially prevent 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. The fact that a reuptake inhibitor was able to prevent this effect indicates that endotoxin increases the activity of the DAT.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
  • By 23 % 7 months after treatment¹²⁷
  • By 47 % 10 months after treatment¹²⁷

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 the sensitivity for suppression of the HPA axis by dexamethasone is reduced, endotoxin causes significantly stronger increases in IL-6.¹²⁸
• Increases IL-10
  • Cortisol administration immediately before endotoxin administration significantly increased the IL-10 increase. Cortisol administration more than 6 hours before endotoxin administration did not affect the IL-10 increase. In the laboratory, cortisol reduced the endotoxin-induced IL-10 increase and reversed the adrenaline-induced IL-10 increase to an IL-10 decrease upon endotoxin administration.¹²⁹
• Increases TNF-α
  • Cortisol administration immediately before endotoxin administration prevents TNF-α release. Cortisol administration more than 12 hours before endotoxin administration increases the TNF-α increase caused by endotoxin.¹²⁹¹
  • A single administration of endotoxin in mice immediately increases the TNF-α level (except in mice with deactivated TNFα receptor). While the peripheral TNF-α level decreased in the serum after 9 h and in the liver after 1 week, it was still elevated in the brain after 10 months.¹²⁷
  • If the sensitivity for suppression of the HPA axis by dexamethasone is reduced, endotoxin causes significantly stronger 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 the expression of NF-κB p65 (except in mice with deactivated TNFα receptor):¹²⁷

4.1.1.3. Endotoxin activates microglia¶

Endotoxin-activated microglia (as well as 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 the sensitivity for suppression of the HPA axis by dexamethasone is reduced, endotoxin causes significantly stronger increases in cortisol.¹²⁸

4.1.2. Behavioral changes due to endotoxin¶

4.1.2.1. Endotoxin increases depressive mood¶

Endotoxin increases the depressive mood¹³⁰¹ within 24 hours.¹³¹
Peripheral endotoxin triggers depressive behavior via indoleamine 2,3-dioxygenase (IDO) by increasing tryptophan turnover. The degradation substance of tryptophan, L-kynurenine, triggers depressive behavior in a dose-dependent manner.¹³²

• An IDO blockade before endotoxin administration
  • Prevents depressive behavior.
  • Normalizes the kynurenine/tryptophan ratio in plasma and brain
  • Does not prevent the increase in serotonin turnover in the brain
• IDO can be blocked
  • Indirectly through anti-inflammatory drugs that attenuate the expression of pro-inflammatory cytokines induced by endotoxins, e.g. minocycline (a broad-spectrum antibiotic that increases COX-2)¹³³
  • Directly through IDO antagonists, e.g. 1-methyltryptophan (1-MT)

Endotoxin¹³¹

• • motor activity still decreased 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), particularly in the amygdala, hippocampus and hypothalamus

4.1.2.2. Anhedonia increased¶

Endotoxin reduces the activity of the striatum to offered rewards (anhedonia).¹³⁰ It reduced the motivation to develop activities to obtain sugar rewards, while the preference for sugar over other food itself was not reduced.¹³⁴¹²³

4.1.2.3. Reduced motor activity¶

Endotoxin¹³¹

• • motor activity still decreased after 6 hours, but no longer after 24 hours
    • Increased depressive and anhedonic behavior even after 24 and 48 hours

4.1.2.4. Lifelong behavioral changes with endotoxin in newborns¶

4.1.2.4.1. Reduced depression symptoms in response to stress with unchanged serotonin levels¶

Newborn rats treated with endotoxin showed lower depressive symptoms in response to inescapable pain stress than adult animals.¹³⁵ The serotonin level in the amygdala did not differ before, during or after the stress from the animals that were not treated with endotoxin as newborns.

4.1.2.4.2. Flattened cortisol stress responses¶

While the basal cortisol levels of the newborn rats before endotoxin treatment and also of the adult animals of both groups did not differ, adult animals treated with endotoxin as newborns showed a significantly flattened cortisol stress response during and after the stress.¹³⁵

4.1.2.4.3. Memory problems with renewed immune activation in adulthood¶

Neonatal rats treated with endotoxin respond to repeated endotoxin treatment in adulthood⁷⁷

• Increased gene expression for microglia cell markers in the hippocampus
• A stronger increase in the gene expression of glial cell markers in the hippocampus
  • This increase remained elevated for 24 h longer
• A faster increase in IL-1beta in the hippocampus and PFC
• A prolonged increase in IL-1-beta in the PFC
• Peripheral cytokines or basal corticosterone were unchanged
• Impaired memory
  • This could be prevented by administering 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 were investigated:¹³⁶

• Proinflammatory cytokines:
  • IL-1β
  • 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 fibrillary acid protein, an astroglia marker)

The changes caused by a single non-intoxicating dose of amphetamine in juvenile animals differed according to brain region:

Changes in the PFC:

In the mPFC, amphetamine increased the gene expression for

• IL1β
• IL6
• TNFα
• CD200
• Arc
• GFAP

in rats that were not treated neonatally with endotoxin, but not in animals that were 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 the 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 the gene expression of

• IL1β
• Arc

The following remained unchanged

• IL6
• GFAP
• CD11b
• IL-10
• TNFα

Changes in the hippocampus (CA1):

Amphetamine increased the gene expression for

• Arc
• GFAP

only in rats not treated with endotoxin

Amphetamine increased the gene expression of

• IL1β

for all animals.

The following remained unchanged

• IL6
• CD200
• CD11b
• IL-10
• TNFα.

Thus, these results are more similar to the effects of neonatal E. coli infection on the adults’ response to psychological stress, which were blunted, than on the adults’ response to LPS, which were enhanced.

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 for neurogenesis.

One study found significantly reduced levels of BDNF (brain-derived neurotrophic factor) in the blood of adults with ADHD, although 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
However, 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 contact between cells in tissue. They bring about the cohesion of tissues and communication between cells.

In extremely premature 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 with the detection of persistent 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 (small brain).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. The IL-6 and IL-10 plasma levels were also elevated in these children.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, craniocerebral trauma).

Children with ADHD and predominantly internalizing symptoms (ADHD-I) showed lower S100B plasma 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 for ADHD¶

Reduced blood levels of C4BP have been found in people with ADHD 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 against glutamic acid decarboxylase 65 (GAD65) were found in the serum of 15 % of the children with autism (N = 20), 27 % of the children with ADHD (N = 15) and none of the controls (N = 14). The serum of 60 % of the autistic children and 53 % of the children with ADHD reacted with Purkinje neurons in the mouse cerebellum. The serum of 20% of the children with ADHD also reacted with cells in the molecular and granular cell layers and cells near the Purkinje neurons. Reactions of serum antibodies with the cells in the cerebellum indicate direct effects on brain function.¹⁴⁶