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Immune responses and inflammation as ADHD causes?


Immune responses and inflammation as ADHD causes?

ADHD-HI (predominantly hyperactive/impulsive) and ADHD-I (predominantly inattentive) represent opposite poles of subtypes that are characteristically distinguished (at the latest in adults) by opposite deviations of HPA axis activity from normal. ADHD-HI is often associated with hyporeactivity of the HPA axis to acute stressors, manifested, among other things, by a flattened cortisol stress response, whereas ADHD-I very often exhibits hyperreactivity of the HPA axis (stress axis) and the endocrine stress response.
The stress systems and especially cortisol as one of the hormones of the 3rd stage of the HPA axis have a decisive effect on the immune system. While the first stages of the HPA axis by means of CRH and ACTH promote intracellular anti-inflammation by proinflammatory cytokines (defense against viruses and internal interfering factors), cortisol causes an inhibition of anti-inflammation and instead enhances anti-inflammatory cytokines, which switch the immune system to fight extracellular foreign bodies (bacteria, foreign bodies). This cortisol effect is called the TH1/TH2 shift. Growth hormone, on the other hand, causes a TH2/TH1 shift.

1. Neuroinflammation in ADHD

There is growing evidence for a role of neuroinflammation in ADHD pathophysiology:12345

  • There is a frequent comorbidity of ADHD with inflammatory and autoimmune disorders
    • Unaffected twins of ADHD sufferers have 19% increased risk of inflammatory diseases6
    • The increased comorbidity of ADHD and asthma has been repeatedly studied5
  • Initial studies show an association of ADHD with elevated cytokine levels in serum and cerebrospinal fluid.
  • Studies show associations between polymorphisms in genes associated with inflammatory pathways and ADHD
  • Early stress increases ADHD risk via inflammatory mechanisms
  • Conversely, prenatal exposure to inflammation causes changes in brain development, e.g., volume reduction in the cortex, which also occurs in ADHD, as well as changes in the neurotransmitter systems involved in ADHD
  • In animal models, offspring of mothers with immune activation show similarities to ADHD in behavior and neurophysiological changes
  • Several studies show elevated cytokine levels in untreated ADHD that decrease in treated ADHD.

The hypothesis that ADHD is a (non)allergic high-sensitivity reaction7 correctly recognizes that inflammation and / or allergy occur with above-average frequency in ADHD and that high sensitivity is a central factor of ADHD. In our view, however, the increased inflammation and allergy is the result of the endocrine stress response, which is often flattened in ADHD-HI and regularly elevated in ADHD-I, leading to a skewed immune system in the form of a TH1 overbalance in ADHD-HI and a TH2 overbalance in ADHD-I due to the corresponding low and high cortisol stress response, respectively. The increased occurrence of inflammations and allergies is therefore not considered as causal, but as a reaction of the immune system to the endocrine imbalance.

Simulation of maternal viral infections causes increased subcortical dopamine function in rat offspring at adult but not at juvenile age89 10 with

  • Deficits in latent inhibition
  • Deficits of prepulse inhibition
  • Increased sensitivity to amphetamine
  • Cognitive impairments
  • Increased dopamine turnover
  • Changes in DA receptor binding

A metastudy of blood tests in ADHD found:11

  • IL-6 tends to be elevated
  • TNF-α reduced
  • unchanged:
    • CRP
    • IL-
    • 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 10 years.12

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 addressed cytokines in ADHD.13
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 represented, 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.14 In the children with ADHD was found13

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

Unfortunately, the full text of the article by Mittleman et al has not been available to us so far, which is why we do not know how the ADHD sample group was composed. However, the fact that ADHD cannot be clearly assigned to one camp is not surprising in our opinion, considering that ADHD-HI is characterized by hypocortisolism and ADHD-I by hypercortisolism, and cortisol induces 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 by subtype also found no clear correlations to date. However, these used blood serum, which may be misleading with respect to the neuropsychological effects of cytokines.

In blood serum, one study found increased IL-6 and TNF-alpha levels in obese children with ADHD-HI and high hyperactivity/impulsivity scores.15

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.16

One study found (unlike for epilepsy and autism spectrum disorders) no increased risk for ADHD from brain infections, primarily with17

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

2.2. Inflammatory markers in animal models of ADHD

In the animal model of ADHD-HI (with hyperactivity), the spontaneous hypertensive rat (SHR) was found in the brain regions (not in the peripheral blood) of adult male animals:18

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

SHR rats treated with taurine showed decreased serum levels of C-reactive protein (CRP) and IL-1β.19 While low levels of taurine increased motor activity, high levels of taurine decreased it.

3. Prenatal stress and immune system

Prenatal stress increases levels of immune response genes, including the pro-inflammatory cytokines IL-6 and IL-1β, particularly in male placentas. Male infants exhibit stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation that was ameliorated by maternal treatment with nonsteroidal anti-inflammatory drugs. Dopamine D1 and D2 receptor expression was altered by prenatal stress in male offspring.20

4. Neuroinflammation and Parkinson’s disease

Like ADHD, Parkinson’s disease is characterized by a dopamine deficiency. In PD, this is caused by the death of dopaminergic neurons, whereas the cause of the (probably somewhat smaller) dopamine deficiency in ADHD seems to have more diverse causes.
Neuroinflammation, i.e. inflammation within the CNS, is a relevant cause of Parkinson’s disease.21222324

Oxidative stress has a significant impact on dopamine metabolism and at the same time on neuroinflammation and neurdodegeneration underlying in Parkinsoon.25

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

  14. Mittleman, Castellanos, Jacobsen, Rapoport, Swedo, Shearer (1997): Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. J Immunol September 15, 1997, 159 (6) 2994-2999

  15. Cortese, Angriman, Comencini, Vincenzi, Maffeis (2019): Association between inflammatory cytokines and ADHD symptoms in children and adolescents with obesity: A pilot study. Psychiatry Res. 2019 May 21;278:7-11. doi: 10.1016/j.psychres.2019.05.030.

  16. Wang, Wu, Lee, Chou, Lee, Chou (2019): Peripheral Brain-Derived Neurotrophic Factor and Contactin-1 Levels in Patients with Attention-Deficit/Hyperactivity Disorder. J Clin Med. 2019 Sep 2;8(9). pii: E1366. doi: 10.3390/jcm8091366.

  17. Lin, Lin, Chou, Lee, Hong (2019): Epilepsy and Neurodevelopmental Outcomes in Children With Etiologically Diagnosed Central Nervous System Infections: A Retrospective Cohort Study. Front Neurol. 2019 May 15;10:528. doi: 10.3389/fneur.2019.00528. eCollection 2019.

  18. Leffa, Bellaver, de Oliveira, de Macedo, de Freitas, Grevet, Caumo, Rohde, Quincozes-Santos, Torres (2017): Increased Oxidative Parameters and Decreased Cytokine Levels in an Animal Model of Attention-Deficit/Hyperactivity Disorder. Neurochem Res. 2017 Nov;42(11):3084-3092. doi: 10.1007/s11064-017-2341-6.

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