Could Immune Responses and Inflammation Be the Cause of ADHD?

There is evidence suggesting that immune system responses may be one (of many) possible causes of ADHD.

Nevertheless, the immune system has a significant impact on behavior.
Its effects are multidirectional.¹²
The immune system can be conditioned. Rats that were conditioned with a combination of a sweetener and an immunosuppressant later exhibited immunosuppression even in response to the sweetener alone.³

The role of neuroinflammation in ADHD is becoming increasingly clear.⁴ ADHD frequently co-occurs with inflammatory and autoimmune disorders. Studies show an association between ADHD and elevated cytokine levels in serum and cerebrospinal fluid. Untreated ADHD is associated with elevated cytokine levels, which decrease with treatment. Studies suggest that the immune system’s response influences the onset of ADHD.⁵ Inflammation appears to be a risk factor for ADHD, particularly in males.⁶

ADHD-C (combined type) and ADHD-HI (predominantly hyperactive/impulsive) are often associated with hyporeactivity of the HPA axis in response to acute stressors, which manifests, among other things, as a blunted cortisol stress response, whereas ADHD-I (predominantly inattentive) very often exhibits hyperreactivity of the HPA axis (stress axis) and the endocrine stress response. The stress systems—and cortisol in particular, as one of the hormones of the third increment of the HPA axis—have a decisive impact on the immune system. While the first increments of the HPA axis, via CRH and ACTH, promote intracellular inflammation control through pro-inflammatory cytokines (defense against viruses and internal disruptive factors), cortisol inhibits this inflammatory response and instead enhances anti-inflammatory cytokines, which reorient the immune system toward combating extracellular foreign substances (bacteria, foreign bodies). This effect of cortisol is called the TH1/TH2 shift. Growth hormone, on the other hand, causes a TH2/TH1 shift.
Bacterial and viral infections during pregnancy and early childhood increase the risk of ADHD.

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

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

• 1. Neuroinflammation in ADHD
• 2. Research on the Immune System and Cytokines in ADHD
  • 2.1. Inflammation Markers in People with ADHD
  • 2.2. Inflammatory Markers in an Animal Model of ADHD
• 3. Prenatal Stress and the Immune System
• 4. Neuroinflammation and Parkinson’s Disease

1. Neuroinflammation in ADHD¶

There is growing evidence that neuroinflammation plays a role in the pathophysiology of ADHD:^7891011
However, a distinction must be made between neuroinflammation and peripheral inflammation. To date, no significant correlation has been found between inflammatory markers in the blood (peripheral) and in the brain (neuroinflammation). The pooled correlation between peripheral and cerebrospinal fluid biomarkers was low at r = 0.21. No significant pooled correlation was found for most cytokines. Exceptions, after excluding outlier studies, were IL-6 with r = 0.26 and TNF-α with r = 0.3. The correlations were highest in older participants (median age over 50 years: r = 0.46) and in patients with autoimmune diseases (r = 0.35).¹²

• ADHD frequently co-occurs with inflammatory and autoimmune diseases:
  • Twins of people with ADHD who do not have the condition themselves have a 19% higher risk of inflammatory diseases.¹³
  • The increased comorbidity of ADHD and asthma has been studied repeatedly.¹¹ Successful treatment of asthma can lead to an improvement in ADHD symptoms.¹⁴ In cases of comorbid asthma and ADHD, IL-6 levels were elevated, but C-reactive protein levels were not.¹⁵
• Studies show an association between ADHD and elevated levels of inflammatory markers¹⁶ and cytokines in serum and cerebrospinal fluid. Elevated cytokine levels were found in untreated ADHD, which decreased in treated ADHD.
• Studies show associations between polymorphisms in genes linked to inflammatory pathways and ADHD
• Early-life stress increases the risk of ADHD through inflammatory mechanisms. Conversely, prenatal exposure to inflammation causes changes in brain development, such as a reduction in cortical volume—which is also observed in ADHD—as well as changes in the neurotransmitter systems involved in ADHD.
• In an animal model, offspring of mothers with immune activation show similarities to ADHD in terms of behavior and neurophysiological changes
• Among 88 adolescents with ADHD, 16 (18.2%) had slightly elevated inflammatory markers (defined as C-reactive protein ≥ 3 mg/l or a BMI ≥ 30 kg/m²). These adolescents showed¹⁷
  • The highest self-reported overall impulsivity
  • The highest self-reported level of inattention
  • The lowest self-reported self-control
  • The highest insulin levels
  • The highest leptin levels
  • Poor cognitive performance on the Go/No-Go task and the WCST

The hypothesis that ADHD is a (non-)allergic hypersensitivity reaction¹⁸ posits that inflammation and/or allergies occur with above-average frequency in ADHD and that hypersensitivity is a central factor in ADHD.

Astrocytes may be an important link between neuroinflammation and ADHD symptoms. Glial cells play a significant role in the immune response. In the three-part synapse, astrocytes are directly involved in maintaining the balance of the neurotransmitters dopamine and norepinephrine, functioning similarly to dopamine transporters by taking up dopamine and norepinephrine at the edge of the synaptic cleft.¹⁹

In our view, the increased susceptibility to inflammation and allergies could also be a consequence of the endocrine stress response—which is often blunted in ADHD-HI and regularly elevated in ADHD-I— which, due to the correspondingly low or high cortisol stress response, leads to an imbalance in the immune system in the form of a TH1 dominance in ADHD-HI and a TH2 dominance in ADHD-I. The increased incidence of inflammation and allergies could therefore be not a causal factor, but rather the immune system’s response to the endocrine imbalance.

A meta-analysis of blood tests for ADHD found that:³⁰

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

Another study found that IL-6, but not CRP, modulates the correlation between sleep problems in early childhood and ADHD at age 10.³¹

2. Research on the Immune System and Cytokines in ADHD¶

2.1. Inflammation Markers in People with ADHD¶

Unfortunately, there are very few studies that have examined cytokines in ADHD.³²
A study compared children with schizophrenia, obsessive-compulsive disorder, and ADHD in terms of IL-2, IFN-gamma, TNF-betaLT, IL-4, IL-5, IL-10, and TNF-alpha levels in their cerebrospinal fluid.
Obsessive-compulsive disorder was highly correlated with TH-1 cytokines. IL-4 was rarely detected, and IL-10 was not detected at all.
Schizophrenia was strongly correlated with TH-2 cytokines. IL-10 and IFN-gamma were rare.
ADHD did not show a clear TH1 or TH2 pattern*.³³ Among children with ADHD, the following was found³²

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

*Unfortunately, we have not yet had access to the full text of the article by Mittleman et al., so we do not know the composition of the ADHD participant group. However, in our view, 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 by hypercortisolism, and cortisol triggers the TH-1/TH-2 shift, which is why ADHD-HI is likely to be TH-1-dominant and ADHD-I TH-2-dominant. However, other studies that differentiated by subtype have also failed to find clear correlations to date. These studies, however, used blood serum, which may be misleading with regard to the neuropsychological effects of cytokines.

In a small study (n = 40), adolescents with ADHD showed elevated blood plasma levels of:³⁴

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

A study found elevated levels of IL-6 and TNF-alpha in the blood serum of obese children with ADHD-HI and high hyperactivity/impulsivity scores.³⁵

In children and adolescents with ADHD, the following were found in plasma:³⁶

• Elevated hs-CRP (high-sensitivity C-reactive protein)
• Elevated IL-6
• TNF-alpha is reduced
• BDNF decreases

A small study involving n = 13 children with ADHD-I and n = 18 children with ADHD-C examined the pro-inflammatory cytokines IL-1β, IL-5, IL-6, and TNF-α, as well as the anti-inflammatory cytokines IL-4, IL-10, and IL-13.
Treatment with MPH did not alter cytokine levels in the overall group.
People with ADHD-I saw changes in cytokine levels with MPH, often in the opposite direction compared to people with ADHD-C. In ADHD-I, IL-1β (p = 0.01) and IL-13 (p = 0.006) showed the greatest statistical significance. The differences may be related to comorbid ODD.³⁷

One study found elevated levels of BDNF in the blood serum of boys with ADHD (which correlated with lower IQ test scores) and reduced levels in girls (which correlated with more omission errors on the Conners’ Continuous Performance Test). Serum levels of Contactin-1 (CNTN1) were unchanged in children with ADHD.³⁸

A study found (unlike in the case of epilepsy and autism spectrum disorders) no increased risk of ADHD due to brain infections, particularly those caused by³⁹

• Enteroviruses
• Group B Streptococcus
• Streptococcus pneumoniae
• Herpes simplex

The gut microbiota in ADHD and ASD are quite similar in terms of both alpha and beta diversity and differ significantly from those of unaffected individuals.
Furthermore, a subgroup of children with ADHD and ASD showed elevated levels of lipopolysaccharide-binding protein compared to people with ADHD, which correlated positively with interleukin IL-8, IL-12, and IL-13. This suggests a disorder of the intestinal barrier and a dysregulation of the immune system in a subgroup of children with ADHD or ASD.⁴⁰

Adenosine deaminase (ADA) and dipeptidyl peptidase IV (DPP-IV, DPP4) are T-cell-associated enzymes.
ADA catalyzes the conversion of adenosine to inosine and deoxyadenosine to deoxyinosine. DPP-IV is expressed, among other places, on the cell membrane of activated T lymphocytes and other cells as CD 26, and plays a role in diabetes.
Serum ADA and DPP-IV activity were significantly elevated in ADHD. No correlation was found with the Conners’ Teacher Rating Scales (CTRS-R-L) or the Conners’ Parent Rating Scales (CPRS-R-L).⁴¹

2.2. Inflammatory Markers in an Animal Model of ADHD¶

In the animal model of ADHD-C, the Spontaneously Hypertensive Rat (SHR), the following were found in adult male animals in the brain regions (but not in peripheral blood):⁴²

• Elevated 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, the hippocampus, and the striatum
• Reduced IL-1β levels in the cortex
• Reduced IL-10 levels in the cortex

SHRs treated with taurine showed reduced serum levels of C-reactive protein (CRP) and IL-1β.⁴³ While low doses of taurine increased motor activity, high doses of taurine decreased it.

In patients with SHR, treatment with dexmedetomidine resulted in:⁴⁴

• Hyperactivity improved
• Improves deficits in spatial working memory
• Normalized theta EEG rhythms
• Changes in the composition of the gut microbiota
• enriched with beneficial gut bacterial genera associated with anti-inflammatory effects in SHR
• Significant improvement in pathological values, intestinal permeability, markers of intestinal inflammation, and markers of brain inflammation

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

3. Prenatal Stress and the Immune System¶

Prenatal stress increases the levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1β, particularly in male placentas. Male children exhibit stress-induced motor hyperactivity, a hallmark of dopaminergic dysregulation, which was improved by treatment of the mother with nonsteroidal anti-inflammatory drugs. The expression of dopamine D1 and D2 receptors was altered by prenatal stress in male offspring.⁴⁵

4. Neuroinflammation and Parkinson’s Disease¶

Like ADHD, Parkinson’s disease is characterized by a dopamine deficiency. In Parkinson’s, this deficiency results from the death of dopaminergic neurons, whereas the (probably somewhat less severe) dopamine deficiency in ADHD appears to have a wider range of causes.
Neuroinflammation—that is, inflammation within the central nervous system—is a significant cause of Parkinson’s disease.^46474849

Oxidative stress has a significant impact on dopamine metabolism, as well as on neuroinflammation and the neurodegeneration underlying Parkinson’s disease.⁵⁰