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Emergence of ADHD - Introduction

Emergence of ADHD - Introduction

There are several developmental pathways that can alone or simultaneously cause ADHD to develop.

1. Pathways of ADHD development

1.1. Genes as ADHD cause

ADHD can be caused by an interaction of a plurality of random genes without the need for environmental influences. Let us call it “genetically inherited ADHD”.

These gene variants have developed without the influence of stress. If several such gene variants come together in such a way that they have a similar influence on the course of certain processes in the brain, these influences can add up in such a way that the healthy balance of the processes is disturbed. Depending on which processes are affected (e.g., which neurotransmitters are increased or decreased in which brain regions), different disorder patterns develop. In ADHD, several gene variants, all of which act to reduce dopamine and norepinephrine in the brain, can combine to reduce this effect to such an extent that the typical ADHD symptoms develop.
Genetic causation is the most common pathway. The genetic component of ADHD is slightly stronger than that for intelligence, at 76%, with no single gene being the cause. To date, quite a few hundred genes are known or suspected. Candidate Genes in ADHD

1.2. Environment as ADHD cause

Environmental factors can contribute to ADHD development. Let’s call it “acquired ADHD”.

1.2.1. Early or chronic severe stress

Early or chronic severe stress can permanently change the expression of genes, i.e. their activity. This can trigger the ADHD-typical changes in neurotransmitter levels or alter the effect of neurotransmitters. Stress medicine already describes these mechanisms for depression. According to this “vulnerability-stress model,” most mental disorders arise1: Anxiety, Depression, Compulsion, Autism Spectrum Disorders, Borderline and many others
Early severe stressors in terms of child maltreatment sets 45% of the risks of psychiatric disorders that begin in childhood.2 Early severe stressors in terms of child maltreatment may include:3

  • Emotional abuse
  • Physical abuse
  • Sexual abuse
  • Living with a drug addict
  • Living with a mentally ill family member
  • Witness violent treatment of mother
  • Household member in prison
  • Separation or divorce of parents
  • Emotional neglect
  • Physical neglect

Affected individuals who experienced 5 or more of these stressors were at increased risk of psychotropic medication prescriptions:45

  • Anxiolytics: 2.1-fold
  • Antidepressants: 2.9-fold
  • Antipsychotics: 10.3-fold
  • Mood stabilizers: 17.3-fold

Affected individuals who experienced 6 or more of these stressors have a 20-year lower life expectancy.4

Early childhood stress experiences are particularly significant because the stress systems in the brain are just forming in the first years of life. Early childhood stress causes permanent damage to the physiological stress systems (HPA axis, vegetative nervous system, PFC). The second particularly dangerous phase for ADHD is middle adolescence. ADHD sufferers who experienced many severe stressors in adolescence were much more likely to retain their ADHD in adulthood than children with few stressors in adolescence.

Specific to ADHD is that there is a wide range of symptoms that are also typical for acute or chronic stress (where they are functional, i.e. serve to cope with the stressor), whereas in several other mental disorders individual stress symptoms are extremely (and thus dysfunctional) pronounced.
Gene disposition plus early childhood stress as cause of other mental disorders Environmental factors as a cause of ADHD

Acute stress increases levels of the neurotransmitters dopamine,1 norepinephrine and serotonin1 and the hormones CRH, ACTH and cortisol, among others. Chronic stress decreases dopamine and norepinephrine. If stress-induced altered neurotransmitter or hormone levels repeatedly occur acutely or permanently during an (early) infantile phase in which the brain systems that work with these neurotransmitters or hormones are just growing, the altered levels cause the affected brain regions to permanently adapt to them (“calibrate”). This calibration remains for a lifetime. Brain regions that rely on these neurotransmitters or hormones are therefore particularly vulnerable to stress during their growth phases.
If a corresponding genetic disposition is added to this, prolonged stress can cause massive psychological damage in children or lay the foundations for this.
ADHD as a chronicized stress regulation disorder
Stress damage - effects of early childhood and/or prolonged stress

Today, the standard works of stress medicine discuss which areas of the brain develop at which age and deduce from this at which childhood stress loads have occurred because the brain regions that are developing at this time are “maladjusted”. For example, severe maternal anxiety during pregnancy increases the risk of ADHD only in certain weeks of pregnancy.
In contrast, stress outside the years of brain development (i.e., after about age 25) is less dangerous because it causes less irreversible damage-although it is still toxic.

This makes it clear why a parenting license would make sense. Not as an admission requirement for having children, but as a minimum knowledge transfer about the defenseless being entrusted to its parents. It probably won’t help all children. But that is not the point. Seat belts do not protect life in every accident. Every single child whose soul could be saved from injury by them would be worth it.
ADHD - Prevention and screening - What parents can do and⇒ Secure attachment beats genetic disposition in ADHD

1.2.2. Diseases

Diseases can also trigger ADHD.
For example, encephalitis destroys the dopaminergic cells in the brain and can thus trigger a dopamine deficit that causes ADHD-typical symptoms. Since the symptoms are permanent, encephalitis can be considered as a possible causation of ADHD.
Furthermore, thyroid problems can trigger symptoms similar to those of ADHD. Since these symptoms can be remedied by adjusting the thyroid hormones, they are not ADHD. The same applies to vitamin or mineral deficiencies, food intolerances and many other disorders.
Diet and nutrition in ADHD
In order to determine the cause of the symptoms and to exclude other causes of the disorder, an appropriate differential diagnosis should be made during ADHD diagnostics.
Differential diagnostics in ADHD

1.2.3. Immune system

Rather theoretically conceivable are diseases that stimulate the immune system to ADHD-typical behavioral changes. However, there is little evidence for this. It is more likely that diseases contribute to ADHD by activating the stress systems that mediate most ADHD symptoms, just as psychological stress does.
Immune system and behavior

1.2.4. Other environmental factors

A large body of research found a significant amount of environmental factors that can promote ADHD, such as toxins or medications, especially during pregnancy or the first years of life, age and wealth of parents, living environment, and quite a few others.
Environmental factors as a cause of ADHD

1.3. Epigenetics (inherited environmental influences and experiences) as ADHD cause

Acquired ADHD can be passed on to one’s own descendants. In contrast to inherited ADHD of the first variant, only the epigenetic changes in gene activity are passed on here. Animal experiments have demonstrated inheritance of such acquired gene expressions over 2 to 4 generations. Let us call it “epigenetically inherited ADHD.” This ADHD cause is particularly amenable to prevention by caring warm parenting behavior.

The epigenetic changes are easier to trigger if there is a corresponding disposition, and more difficult if there is no disposition. Without genetic disposition, ADHD is only caused (and can then be inherited) by significantly more intense early childhood stress (of traumatizing intensity: physical abuse, psychological abuse, sexual abuse). More about this under the keyword opportunity/risk genes.

1.4. Interaction of multiple pathways in the development of ADHD

A relevant variant of development is that an early childhood stress experience is added to an existing gene disposition. In this case, the genes responsible for ADHD change epigenetically in such a way that ADHD is now manifested (⇒ Genetic and epigenetic causes of ADHD - Introduction). Epigenetics means that (intense) experiences in life can cause changes in gene expression. These acquired changes can in turn be passed on.

2. ADHD: Dopamine and norepinephrine deficiency

ADHD is particularly characterized by decreased dopamine and norepinephrine levels in the brain areas dlPFC and striatum. While acute stress shows increased dopamine and norepinephrine levels in these brain areas, chronic stress, like ADHD, is typically associated with decreased dopamine and norepinephrine levels in these brain regions. Acute as well as chronic stress show almost identical symptoms to ADHD, since the dysfunctions of the brain regions relevant here that trigger the stress/ADHD symptoms occur at any deviation from an average dopamine or noradrenaline level.

Stress has a special significance in ADHD.
Stress is a factor that can trigger the development of ADHD, and ADHD acquired in this way is hereditary as a disposition.
In addition, ADHD symptoms are mediated in large part by the stress systems.
This importance has hardly been considered by the ADHD literature so far. All the more important to us is a comprehensive presentation of the stress systems and their influences.
Stress

3. How significant is which pathway of development of ADHD

3.1. Genetic component: approx. 76

ADHD has a strong genetic component of about 76%. The heritability of ADHD is thus greater than that of intelligence. Among ADHD cases with clinical intensity, up to 90 % are genetically caused.6 However, single genes are not causative, even though certain gene variants are more frequently involved. Hundreds of candidate genes are known. It would not be surprising if there were more than 1000. More than 150 of these we have Candidate genes in ADHD Named. Nevertheless, so far only 5% of the genetic heritability can be attributed to specific gene variants. This is probably also due to the fact that genes (in most mental disorders) only represent a disposition and do not yet say that ADHD exists.

Even in a purely genetic pathway of ADHD, there are alterations in the functioning of the HPA axis (stress axis).
Research topic: ADHD in animal models

Heritability is likely to be measured within 1 generation. Environmental causes may influence the influenced individual, as well as via epigenetics, 2-4 generations of its offspring. Therefore, we assume that the proportion of environmental causes of ADHD is higher than 24%. We estimate it to be about 40%.

Rats as ADHD models

There are several rat breeds that represent ADHD-HI, ADHD-I, and non-affected individuals as animal models.

The Spontaneous(ly) hypertensive rat (SHR) is a genetically distinct strain representing ADHD-HI (with hyperactivity), whereas Wistar-Kyoto rats (WKY) usually represent non-affected individuals as a counterpart model.

That these animals express their disorders solely because of genetic makeup and without the influence of early childhood stress is a strong argument that certain genes alone represent a distinct pathway for the development of mental disorders such as ADHD and that the developmental pathways genes alone and genes + environment coexist.

Interestingly, the findings about SHR do not weaken the theory that ADHD symptoms are mediated by HPA axis dysfunction, but rather strengthen it-because SHR, by virtue of their genetic predisposition alone, already exhibit a dysfunctional HPA axis, the kind of dysfunction that would otherwise only result from early childhood stress.

SHR were originally bred as a model for hypertension. Only later were they found to be a model for ADHD-HI at the same time. If the animals are treated with dexamethasone (a corticosteroid), the hypertension that would otherwise occur in all animals at the age of 15 months does not occur - and the ADHD symptoms also disappear.
Research topic: ADHD in animal models

Unfortunately, this is not a universal solution for the treatment of ADHD, but would only be for those sufferers whose ADHD is mediated by exactly those mechanisms that exist in (genetically distinct) SHR. The causes of ADHD, on the other hand, are more diverse.
However, for certain subsets of ADHD-HI, dexamethasone shock treatment could potentially be helpful. ⇒ Dexamethasone for ADHD. Meanwhile, this method, which we propose, has not yet been tested.

3.2. Influence of the environment time-dependent

Interestingly, the relationship of the influence of genes and environment on an existing ADHD changes over time.7

Measures of hyperactivity/impulsivity and measures of inattention were evaluated in 602 pairs of Chinese twins at 12, 13, and 15 years of age.
On both symptoms were

  • Genetic influences were initially moderate and nonsignificant and became substantial and significant over time
  • The environmental influences were initially substantial and significant and became moderate and nonsignificant over time.

Throughout the youth, the influences resulted from

  • The same genes
  • Other emerging environmental factors

In early adolescence, inattention was kept stable predominantly by genetic influences, hyperactivity/impulsivity increasingly by environmental influences.

The genetic influences of ADHD-HI tended to be smaller, whereas the common environmental influences tended to be larger in China than in Western populations.

At least several of the genes relevant for ADHD are epigenetically activated only by early childhood stress in such a way that they contribute to ADHD. A warm, secure, caring attachment style by parents may reduce the risk of epigenetic activation of genes and thus ADHD risk. ADHD - Prevention and Screening - What Parents Can Do

3.3. Opportunity-risk genes increase environmental influence

Some genes are not only risk genes, but can also become a particularly nurturing and strengthening source if called upon appropriately. (Chance-risk genes, see Parents’ attachment style to the child particularly important for opportunity/risk genes)

Certain gene variants make their carriers particularly sensitive (high sensitivity). This leads to a special receptivity for support (opportunity) but also to the risk of a further increased vulnerability. In these people (approx. 15%), a stress intensity significantly below that of a trauma is already sufficient to activate the gene disposition of ADHD: even an insecure attachment style (cool, distant, purely performance-related, strict, no reliable attachment, etc.) can be sufficient in the case of the genetic disposition present here to manifest ADHD epigenetically.
In contrast, without early childhood stress exposure and appropriate support, highly sensitive people are even more stress-resistant than others.
Irrespective of a genetic disposition, stress generally makes people more sensitive and susceptible.

The (epi-)gene changes (inherited or developed by own traumas) are passed on by the affected persons to their children “dormant” - traumas are inheritable over several generations. In the children of the affected persons, too, only an activation of the “dormant” gene disposition leads to the emergence of AD(HHD).

Since the parents have the genes they pass on with a relevant probability also as a single parent themselves, the parents (or one parent) often suffer from ADHD as well. The ADHD symptoms of (untreated) affected parents then make it highly likely that their children are thereby exposed to an increased stress load and that the inherited gene disposition is thus activated.

Origin


  1. Goldstein, Rasmusson, Bunney, Roth (1994): The NMDA glycine site antagonist (+)-HA-966 selectively regulates conditioned stress-induced metabolic activation of the mesoprefrontal cortical dopamine but not serotonin systems: a behavioral, neuroendocrine, and neurochemical study in the rat. Journal of Neuroscience 1 August 1994, 14 (8) 4937-4950; DOI: https://doi.org/10.1523/JNEUROSCI.14-08-04937.1994

  2. Teicher, Samson (2016): Annual Research Review: Enduring neurobiological effects of childhood abuse and neglect. J Child Psychol Psychiatry. 2016 Mar;57(3):241-66. doi: 10.1111/jcpp.12507. PMID: 26831814; PMCID: PMC4760853.

  3. Felitti, Anda, Nordenberg, Williamson, Spitz, Edwards, Koss, Marks (2019): REPRINT OF: Relationship of Childhood Abuse and Household Dysfunction to Many of the Leading Causes of Death in Adults: The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 2019 Jun;56(6):774-786. doi: 10.1016/j.amepre.2019.04.001. PMID: 31104722.

  4. Brown, Anda, Tiemeier, Felitti, Edwards, Croft, Giles (2009): Adverse childhood experiences and the risk of premature mortality. Am J Prev Med. 2009 Nov;37(5):389-96. doi: 10.1016/j.amepre.2009.06.021. PMID: 19840693.

  5. Teicher (2016): Vortragsfolien

  6. Barkley (2018): Vortrag an der Universität Göteborg, ca. Minute 75

  7. Zheng, Pingault, Unger, Rijsdijk (2019): Genetic and environmental influences on attention-deficit/hyperactivity disorder symptoms in Chinese adolescents: a longitudinal twin study. Eur Child Adolesc Psychiatry. 2019 May 20. doi: 10.1007/s00787-019-01346-0.