Immune reactions and inflammation as the cause of ADHD?

The role of neuroinflammation in ADHD is becoming increasingly clear.¹ There is frequent comorbidity of ADHD with inflammatory and autoimmune disorders. Studies show an association of ADHD with elevated cytokine levels in serum and cerebrospinal fluid. Untreated ADHD is associated with elevated cytokine levels, which decrease with treatment. Studies suggest that the response of the immune system influences the occurrence of ADHD.²

ADHD-HI (predominantly hyperactive/impulsive) is often associated with a hyporeactivity of the HPA axis to acute stressors, which is reflected, among other things, in a flattened cortisol stress response, while ADHD-I (predominantly inattentive) very often shows a hyperreactivity of the HPA axis (stress axis) and the endocrine stress response. The stress systems and in particular cortisol as one of the hormones of the 3rd increment of the HPA axis have a decisive effect on the immune system. While the first increments of the HPA axis use CRH and ACTH to promote the intracellular fight against inflammation through proinflammatory cytokines (defense against viruses and internal disruptive factors), cortisol inhibits the fight against inflammation and instead increases anti-inflammatory cytokines, which switch the immune system to fighting extracellular foreign bodies (bacteria, foreign bodies). This cortisol effect is called TH1/TH2 shift. Growth hormone, on the other hand, causes a TH2/TH1 shift.
Bacterial and viral infections during pregnancy through to infancy increase the risk of ADHD.

To date, there have been few studies on inflammatory markers in ADHD. Blood tests have found elevated IL-6 and TNF-alpha levels in obese children with ADHD-HI and high hyperactivity/impulsivity scores. A meta-analysis found no clear correlation between cytokines and ADHD subtypes.
In animal models of ADHD-HI, increased levels of reactive oxygen species and decreased levels of TNF-α and IL-10 were found in the brain. Treatment with dexmedetomidine improved hyperactivity, memory deficits and altered the gut microbiota.

Parkinson’s and ADHD not only appear to share a lack of dopamine, but also have similarities in terms of neuroinflammation.

• 1. Neuroinflammation in ADHD
• 2. Studies on the immune system and cytokines in ADHD
  • 2.1. Inflammatory markers in people with ADHD
  • 2.2. Inflammatory markers in the animal model of ADHD
• 3. Prenatal stress and the immune system
• 4. Neuroinflammation and Parkinson’s disease

1. Neuroinflammation in ADHD¶

There is increasing evidence for a role of neuroinflammation in ADHD pathophysiology:³⁴⁵⁶⁷

• There is a frequent comorbidity of ADHD with inflammatory and autoimmune diseases:
  • Unaffected twins of persons with ADHD have a 19% increased risk of inflammatory diseases.⁸
  • The increased comorbidity of ADHD and asthma has been repeatedly studied.⁷ Successful treatment of asthma may improve ADHD symptoms.⁹ IL-6 was elevated in comorbid asthma and ADHD, but probably not C-reactive protein.¹⁰
• Studies show an association of ADHD with elevated inflammatory markers¹¹ or cytokine levels in serum and cerebrospinal fluid. Studies show increased cytokine levels in untreated ADHD, which decrease in treated ADHD.
• Studies show associations between polymorphisms in genes associated with inflammatory pathways and ADHD.
• Early stress increases the risk of ADHD through inflammatory mechanisms. Conversely, prenatal exposure to inflammation causes changes in brain development, e.g. a reduction in volume in the cortex, which also occurs in ADHD, as well as changes in the neurotransmitter system involved in ADHD.
• In animal models, offspring of mothers with immune activation show similarities with ADHD in behavior and neurophysiological changes.

The hypothesis that ADHD is a (non-)allergic high-sensitivity reaction¹² correctly recognizes that inflammation and / or allergies occur more frequently than average in ADHD and that high sensitivity is a central factor in ADHD. In our opinion, however, the increased tendency to inflammation and allergies is the consequence of the frequently flattened endocrine stress response in ADHD-HI and regularly increased endocrine stress response in ADHD-I, which leads to an imbalance of the immune system in the form of a TH1 overbalance in ADHD-HI and a TH2 overbalance in ADHD-I due to the correspondingly low or high cortisol stress response. We therefore do not consider the increased occurrence of inflammation and allergies to be causal, but rather a reaction of the immune system to the endocrine imbalance.

A meta-analysis of blood tests for ADHD found:¹⁶

• IL-6 tends to be elevated
• TNF-α reduced
• unchanged:
  • CRP
  • IL-1β
  • IL-10
  • Interferon-γ

Another study found that IL-6, but not CRP, modulated the correlation between sleep problems in early childhood and ADHD at age 10.¹⁷

2. Studies on the immune system and cytokines in ADHD¶

2.1. Inflammatory markers in people with ADHD¶

Unfortunately, there are very few studies that have treated cytokines in ADHD.¹⁸
One study compared children with schizophrenia, obsessive-compulsive disorder and ADHD for IL-2, IFN-gamma, TNF-betaLT, IL-4, IL-5, IL-10 and TNF-alpha in cerebrospinal fluid.
Obsessive-compulsive disorder correlated highly with TH-1 cytokines. IL-4 was rarely present, IL-10 not at all.
Schizophrenia correlated highly with TH-2 cytokines. IL-10 and IFN-gamma were rare.
ADHD did not have a clear TH1 or TH2 picture*.¹⁹ The children with ADHD were found to have¹⁸

• At 90 %: IL-2 detectable
• Detectable at 70 % TNF-β
• IL-5 detectable in 62
• Detectable at 60 % IFN-γ
• Detectable at 7 % IL-10

In a small study (n = 40), ADHD adolescents showed elevated blood plasma levels of:²⁰

• in total
  • Platelet distribution width
• for men
  • IL-1β
  • IL-6
  • TNF-α
  • M1 profile
• for women
  • TNF-α
  • pro-/anti-inflammatory ratio

*Unfortunately, the full text of the article by Mittleman et al. has not yet been made available to us, which is why we do not know the composition of the ADHD subject group. In our opinion, however, it is not surprising that ADHD cannot be clearly assigned to one camp, considering that ADHD-HI / ADHD-C is characterized more by hypocortisolism and ADHD-I more by hypercortisolism, and cortisol causes the TH-1/TH-2 shift, which is why ADHD-HI is likely to be TH1-heavy and ADHD-I TH2-heavy. However, other studies that differentiated according to subtypes have not yet found any clear correlations. However, these studies used blood serum, which may be misleading with regard to the neuropsychological effects of cytokines.

In blood serum, one study found elevated IL-6 and TNF-alpha levels in obese children with ADHD-HI and high hyperactivity/impulsivity scores.²¹

A small study of n = 13 children with ADHD-I and n = 18 children with ADHD-C examined the pro-inflammatory cytokines IL-1β, IL-5, IL-6, TNF-α and the anti-inflammatory cytokines IL-4, IL-10, IL-13.
Treatment with MPH did not change the cytokine levels in the overall group.
In persons with ADHD-I, MPH altered cytokine levels, often in the opposite direction than in ADHD-C. In ADHD-I, IL-1β (p = 0.01) and IL-13 (p = 0.006) reached the greatest statistical significance. The differences could be related to comorbid ODD.²²

One study found BDNF in blood serum increased in boys with ADHD (which correlated with poorer IQ test scores) and decreased in girls (which correlated with more omission errors on the Conners’ Continuous Performance Test). Contactin-1 (CNTN1) serum levels were unchanged in ADHD.²³

One study found (unlike for epilepsy and autism spectrum disorders) no increased risk of ADHD due to brain infections, primarily with²⁴

• Enteroviruses
• Streptococcus group B
• Streptococcus pneumoniae
• Herpes simplex

The gut microbiota in ADHD and ASD are quite similar in both alpha and beta diversity and differ significantly from non-affected individuals.
In addition, a subgroup of ADHD and ASD cases had increased levels of lipopolysaccharide-binding protein, which positively correlated with interleukin IL-8, IL-12 and IL-13, compared to non-affected children. This suggests an intestinal barrier disorder and immune system dysregulation in a subgroup of children with ADHD or ASD.²⁵

Adenosine deaminase (ADA) and dipeptidyl peptidase IV (DPP-IV, DPP4) are T cell-related enzymes.
ADA catalyzes the conversion of adenosine to inosine and deoxyadenosine to deoxyinosine. DPP-IV is expressed on the cell membrane of activated T lymphocytes and other cells as CD 26 and plays a role in diabetes.
ADA and DPP-IV serum activity were significantly increased in ADHD. There was no correlation with the Conners’ Teacher Rating Scales (CTRS-R-L) or the Conners’ Parent Rating Scales (CPRS-R-L).²⁶

2.2. Inflammatory markers in the animal model of ADHD¶

In the animal model of ADHD-C, the Spontaneous(ly) hypertensive rat (SHR) found in the brain regions (not in the peripheral blood) of adult male animals:²⁷

• Increased levels of reactive oxygen species (ROS) in the cortex, striatum and hippocampus
• Reduced glutathione peroxidase activity in the PFC and hippocampus
• Reduced TNF-α levels in the PFC, the rest of the cortex, hippocampus and striatum
• Reduced IL-1β levels in the cortex
• Reduced IL-10 levels in the cortex

SHR treated with taurine showed reduced serum levels of C-reactive protein (CRP) and IL-1β.²⁸ While low doses of taurine increased motor activity, high doses of taurine decreased it.

In SHR, treatment with dexmedetomidine was effective:²⁹

• Hyperactivity improved
• Deficits in spatial working memory improved
• Theta EEG rhythms normalized
• Composition of the intestinal microbiota changes
• enriched with beneficial intestinal bacterial genera associated with anti-inflammatory effects in SHR
• pathological values, intestinal permeability, intestinal inflammation values and brain inflammation values significantly improved

Transplantation of the fecal microbiota from DEX-treated SHR to untreated SHR resulted in similar improvements
Dexmedetomidine is an α2-adrenoceptor agonist (like guanfacine) and acts as a short-term sedative.

3. Prenatal stress and the immune system¶

Prenatal stress increases levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1β, particularly in male placentas. Male infants show stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation, which was ameliorated by maternal treatment with nonsterioid anti-inflammatory drugs. The expression of dopamine D1 and D2 receptors was altered by prenatal stress in male offspring.³⁰

4. Neuroinflammation and Parkinson’s disease¶

Like ADHD, Parkinson’s is characterized by a dopamine deficiency. In Parkinson’s, this is caused by the death of dopaminergic neurons, while the cause of the (probably slightly lower) dopamine deficiency in ADHD appears to have more diverse causes.
Neuroinflammation, i.e. inflammation within the CNS, is a relevant cause of Parkinson’s disease.^31323334

Oxidative stress has a considerable influence on dopamine metabolism and at the same time on neuroinflammation and the neurodegeneration underlying Parkinson’s disease.³⁵