Brain development disorder and ADHD

Author: Ulrich Brennecke
Review: Dipl.-Psych. Waldemar Zdero

ADHD is often described as a developmental disorder of the brain in the sense of a developmental delay.
The maturation of the brain is delayed by an average of 3 to 5 years in people with ADHD and the proliferation of neural stem cells is slowed down.

The development of the brain is heavily dependent on various neurotransmitters. In addition to neurotransmitters such as noradrenaline, GABA, glutamate and serotonin and hormones such as oestradiol-17beta, dopamine plays a decisive role in brain development as a neurotrophic factor.
ADHD is caused by a dopamine deficiency. Around 76% of ADHD is genetic. Among the gene mutations and gene polymorphisms associated with ADHD, dopamine is the neurotransmitter most frequently affected, causing lower dopamine levels, lower dopamine efficacy or increased dopamine degradation. Find out more at ⇒ Candidate genes in ADHD In the chapter ⇒ Emergence. Disorders of infant-maternal attachment can cause developmental disorders of the right hemisphere of the brain, which in turn affect the regulation of neurotransmitters such as dopamine and noradrenaline. These right hemisphere abnormalities play a role in ADHD.
The weakening of the dopaminergic system could be a consequence or cause of the impaired brain development described in ADHD, as is the case with ADHD.

Phenylketonuria and Down syndrome are other examples of genetic disorders in which a dopamine deficiency and developmental disorders in the brain occur together. Schizophrenia (which has clear dopaminergic links) is increasingly seen as a brain development disorder in which genetic and early environmental influences also play a role.

Should the brain development delay or disorder described in ADHD (also) prove to be the result of a dopaminergic deficiency (genetic or environmental), this could open up the option of avoiding or mitigating the development of ADHD through dopaminergic treatment during the corresponding time window of brain development. Even if the probability is open in view of the persistence of the genetic cause, which persists throughout life, and even if the suspected connection is confirmed, it could still be decades before it can be used therapeutically, the opportunity it offers at least merits a more in-depth examination of the hypothesis.
Current studies and a recent review support the hypothesis.¹²
In the following, we collect (further) facts to confirm, modify or refute this hypothesis.

Disorders in brain development are to be expected with any deviation from the optimal mean dopamine level, i.e. not only with a lack of dopamine, but also with an excess of dopamine in the developmental phase of the respective brain region.
Early treatment of ADHD with stimulants may reduce the risk of developing addiction later in life, although the extent to which this is related to an impact on brain development is still unknown.

• 1. Delayed brain development in ADHD
  • 1.1. Brain maturation delayed by 3 to 5 years in ADHD
  • 1.2. Attenuated proliferation of neural stem cells in ADHD
  • 1.3. Subsequent brain development even in adulthood
• 2. Brain development and neurotransmitters
  • 2.1. Dopamine and brain development
    • 2.1.1. Developmental course of the dopaminergic system and brain development in rodents
  • 2.2. Phenylketunoria, dopamine deficiency and ADHD
  • 2.3. Down syndrome, neurotransmitter deficiency and ADHD
  • 2.4. Schizophrenia as a brain development disorder
  • 2.5. ADHD treatment initiation with stimulants and addiction
  • 2.6. Succinic semialdehyde dehydrogenase deficiency
• 3. Early attachment disorder impairs self-organization of the right hemisphere of the brain

1. Delayed brain development in ADHD¶

ADHD shows age-constant

• Slightly reduced brain volume of both gray and white matter (- 4 %)
• Significantly reduced volume of the posterior inferior cerebellum (- 15 %)
• Anomalies of the basal ganglia

indicating an early, non-progressive “lesion” involving neurotrophic factors that control overall brain growth and selected dopamine circuits.³

1.1. Brain maturation delayed by 3 to 5 years in ADHD¶

The maturation of the brain is delayed by an average of 3 to 5 years in people with ADHD.⁴
One study found a developmental delay (to reach the first maximum cortex thickness) of 5 years in the mPFC and 2 years in the superior and medial PFC.⁵

1.2. Attenuated proliferation of neural stem cells in ADHD¶

In children and adolescents with ADHD or an increased polygenic risk score, the proliferation of neural stem cells, but not the proliferation of induced pluripotent stem cells, is slowed down.⁴

1.3. Subsequent brain development even in adulthood¶

In the last decade, it has become increasingly clear that neuroplasticity is much stronger into old age than was previously assumed.
In particular, there are indications that the brains of people with ADHD continue to develop to a certain extent into adulthood, which can reduce IQ deficits.⁶
Due to the working memory problems typical of ADHD, IQ in ADHD is impaired in this area.

2. Brain development and neurotransmitters¶

The development of the brain depends, among other things, on the presence of various neurotransmitters. This is primarily being researched in rodents.⁷

2.1. Dopamine and brain development¶

ADHD is associated with a lack of dopamine. This is usually genetic - the heritability of ADHD is around 75% - and is therefore inherited from conception. It is striking that the environmental influences associated with ADHD very often also influence the dopamine balance during pregnancy or in the first years of life.

As a neurotrophic factor, dopamine is essential for brain development. Disorders of the dopaminergic system that persist from conception can impair brain development in terms of cell migration, cell differentiation, neurite outgrowth, spine development and synaptogenesis, among others. Genetic or pharmacological dopamine disorders during development are capable of inducing phenotypes in animal models that correspond to neuropsychiatric disorders such as ADHD, ASD, schizophrenia or addiction.²
Dopaminergic imbalances may have profound influences on the overall rate of neurogenesis during brain development. Gene association studies as well as studies on the importance of dopamine in neurogenesis suggest that an underlying mechanism for the development of disorders may lie in a disrupted link between dopaminergic signaling on the one hand and genes important for neuronal development on the other.⁸
Both dopamine excess and dopamine deficiency during brain development can reduce the density of dendritic spines of medium spiny neurons (MSNs).⁹
Dopamine is one of the many neurotransmitters that can influence the proliferation (rapid growth / multiplication of cells) of progenitor cells (precursor cells of somatic cells that arise from the asymmetric cell division of multipotent stem cells)¹⁰ in the brain,¹¹¹² as well as noradrenaline,¹³ GABA and glutamate,^{1415 16 17} and serotonin.¹⁸ Some hormones also influence brain development, such as fibroblast growth factors (FGF).¹⁹²⁰ Oestradiol-17beta, the most potent female sex hormone, influences not only primary and secondary sexual characteristics, but also embryonic and fetal growth and the development of the brain’s aminergic networks.²¹

• It is possible that dopamine modulates striatal neurotrophin reactivity and thereby influences striatal neuronal development during a defined developmental period of the brain.²²
• D1 receptors appear to regulate the cell cycle during cortex development. They may also have a differential influence on proliferative activity in FGF2-supported versus EGF-supported cerebral cortical progenitor cells.²³
• Increased dopamine levels during pregnancy apparently reduce neurogenesis in some brain regions (in the caudate/putamen, nucleus accumbens, frontal cortex, but not in the globus pallidus) and cause subtle deficits in the number of neurons.²⁴
• Mice in which the dopaminergic cells were largely destroyed using 6-OHDA, which reduced the dopaminergic level to below 10%, showed in the striatum ²⁵²⁶
  • An increase in serotonin and serotonin metabolites (which already occurred when dopamine was reduced by less than 90 %)
  • Unchanged: Enkephalin and preproenkephalin mRNA levels up to 25 days of age
  • Increased expression of enkephalin and preproenkephalin mRNA up to 35 days of age
  • Reduced expression of substance P and preprotachykinin mRNA
  • Unchanged: beta-actin mRNA expression
• Mice that received L-dopa from PD1 to PD5 showed sex-dependent behavioral deviations at 4 weeks of age.²⁷

An early developmental abnormality in the dopamine system could cause a permanent change in striatal neuropeptide systems, which in turn could promote dopamine deficiency states.²⁵

The decisive factor is probably the time of development of the brain at which a (e.g. dopaminergic) imbalance exists. Accordingly, constitutive gene knockouts can trigger other changes than time-limited environmental influences such as pharmacological manipulations, where the timing of the intervention is also relevant.²

Dopamine production and dopamine receptor expression in mammals begins in the fetus.²⁸²⁹
In rats, in which brain development is intensively researched, there is a high growth of dopamine and serotonin transporters in the last week of pregnancy and in the first two weeks after birth, which indicates a particular vulnerability of the dopaminergic and serotonergic systems during this period.³⁰ The brains of rats whose mothers were treated with a dopamine reuptake inhibitor during pregnancy showed a slowed and reduced development of dopamine release in the striatum.³¹

Oxygen deprivation during birth can cause long-term changes in the dopamine system.³² Disorders of the dopamine system can trigger brain development disorders such as those associated with ADHD.

2.1.1. Developmental course of the dopaminergic system and brain development in rodents¶

In humans, the main developmental phase of the striatum, which is strongly affected by the development of the dopaminergic system, is in the second trimester of pregnancy.³³
In rodents, the early postnatal days correspond to human brain development in the third trimester of pregnancy.⁷

Developmental process in rodents:²

(E = embryonic days = after conception; P = postnatal days = after birth)

E12 to E15:

• Start of differentiation of the dopamine neurons in the substantia nigra and ventral tegmentum.
• Subsequently, processes of axonal expansion and synaptic maturation.

E13:

• First dopaminergic cells in the ventral prosencephalon³⁴

E14:

• Neurons from the SN and VTA project via the medial forebrain bundle and reach the nucleus accumbens in the dorsal or ventral striatum³⁴

E15:

• Dopaminergic fibers reach the anlage of the lateral neocortex³⁵

E15, E16:

• The dopaminergic cell groups in SN and VTA as well as their projections rapidly increase in size.³⁴

E17:

• Dopaminergic fibers reach the subplate of the future PFC³⁵ The afferent dopaminergic fibers align with the striatum and form large bundles that are closely connected to the fascicles of the internal capsule.³⁴

E18:

• Projections from SN and VTA reach the medial frontal cortex (mPFC)³⁵³⁴

E15 to E21:

• Steeper increase in D1-type dopamine receptors (D1, D5) in the mPFC than in the striatum
• Steeper increase in D2-type dopamine receptors (D2, D3, D4) in the striatum than in the mPFC
• Dopamine receptors of the D1 type (D1, D5) and the D2 type (D2, D3, D4) are expressed more frequently in the striatum than in the mFC, but show different developmental patterns.³⁶ This indicates that the functional identity of these neurons is already formed embryonically.
• Maturation of dopamine projections in the forebrain follows the pattern of many neuronal pathways: first expansion, then contraction

P1-P60:

• Expansion and maturation of dopaminergic innervation in these regions continues postnatally until P60.³⁵

P1-P14:

• Active maturation period for the striatum³³

P2:

• In parts of the PFC, large numbers of dopaminergic fibers can be seen in the marginal zone (the future layer 1).³⁵

P4:

• Changes in the morphology of the dopaminergic fibers indicate the beginning of the actual DA innervation³⁵

P6:

• The different subareas of the PFC can be recognized by the characteristics of the topographic distribution of the dopaminergic fibres³⁵

P28-P50: late adolescence

• Climax of several molecular determinants of DA signaling
• Intensive postnatal development of forebrain circuits
• Sensitive period for internal and external factors that stimulate or disrupt normal brain development. These factors can influence the risk of neuropsychiatric disorders in humans during the corresponding developmental phase.³⁷

P21:

• Medium-sized spiny projection neurons begin to show defined up (depolarized) and down (hyperpolarized) states characteristic of mature cells, similar to those of adult mice.³⁸

P28:

• The development of synaptic responses and spontaneous activity patterns in medium spiny neurons depends on the arrival and functional maturation of excitatory afferents from the cortex and thalamus. Adult maturation was found at the end of the first postnatal month at the earliest.³⁸²
• In addition to the structural changes, dopamine modulates the maturation of the electrophysiological properties of postsynaptic neurons during brain development. The maturation of the excitability of medium spiny neurons is preceded by an increase in dopaminergic neurotransmission in the striatum, which occurs in the fourth postnatal week.¹² The striatum and cortex express dopamine receptors even before the spread of dopamine afferents.³⁶²⁸
• In mice with developmental dopamine deficits in the striatum, D1 receptor-expressing medium spiny neurons show no maturation and retain their hyperexcitability. There is evidence that this phenotype results from altered phosphatidylinositol 4,5-biphosphate signaling.¹²
• These deficits can be corrected (in mice) by dopamine substitution from birth. Dopamine administration in adulthood no longer corrected the development. This corresponds to the temporal window of dopamine action during brain development described in this article for the physiological maturation of medium spiny neurons (MSNs)¹²

Up to P60: adulthood

• Density of dopaminergic fibers continues to increase.
  No difference in density and topography was observed between postnatal days 60 and 90³⁵

P60-P90:

• Dopaminergic system (including DA biosynthetic enzymes, DA receptors and DAT) reaches maturation³⁷. No change in the density of the dopaminergic fibers can be detected.³⁵

Alterations in the development of dopamine neurons can cause pathological development of neurons and circuits within the dopaminoreceptive regions.¹³⁹

The dopaminergic brain organization of rodents and primates (including humans) shows great similarities and some differences. Only primates show a prominent role of cortical dopamine on pyramidal tract neurons in the primary motor cortex. In rodents, mesocortical dopamine originates predominantly from the ventral tegmentum and addresses many subcortical areas, whereas in primates, mesocortical dopamine also originates from the substantia nigra and addresses only some subcortical regions.⁴⁰ Nevertheless, many studies show that the function and dopaminergic dynamics of the striatum are largely the same in rodents and primates.⁴¹²

2.2. Phenylketunoria, dopamine deficiency and ADHD¶

Phenylketonuria (PKU, a recessive disorder of phenylalanine metabolism due to mutations of the phenylalanine hydroxylase gene) leads to a significant excess of phenylalanine (hyperphenylalaninemia). As phenylalanine and tyrosine pass through the blood-brain barrier via the same transporters, and these transporters have a higher affinity for phenylalanine, too little tyrosine reaches the brain if there is an excess of phenylalanine in the blood. Tyrosine is a precursor for dopamine, from which noradrenaline and adrenaline are further produced. An excess of phenylalanine in the blood therefore leads to a lack of dopamine, noradrenaline and adrenaline in the brain.⁴² Excess phenylalanine also causes changes in cerebral myelin and protein synthesis as well as reduced levels of serotonin in the brain.⁴³ ADHD and phenylketonuria therefore have a dopamine deficiency in common.⁴⁴⁴⁵ People with ADHD often show symptoms of ADHD, although the subtypes with hyperactivity seem to predominate.^46474448

In our view, it is conceivable that the dopamine and noradrenaline deficiency triggered by phenylketonuria could trigger a brain development disorder, which in turn causes the ADHD symptoms, while the dopamine and noradrenaline deficiency in ADHD, which could also affect brain development, is usually determined by a variety of genes or epigenetic factors, but can also be caused by early childhood chronic stress.

2.3. Down syndrome, neurotransmitter deficiency and ADHD¶

Down syndrome is characterized by dysfunctional neuronal brain development in the fetus.
Fetuses with Down syndrome showed in the frontal cortex:⁴⁹

• Reduced levels of the substances required for the acquisition of the morphological characteristics of the brain, neuronal and glial proliferation and synapse formation
  • Neurotransmitters
    • Dopamine
    • Serotonin
    • GABA
  • Amino acid
    • Taurine
• Unchanged mirror of
  • Noradrenaline
  • Arginine
  • Aspartate
  • Glutamine
  • Glutamate
  • Glycine
  • Histidine
  • Serine

The authors consider the reduced levels as an indication of possible mechanisms for the observed dysfunctional neuronal development in the fetal brain of Down syndrome.⁴⁹
In special institutions for children with Down syndrome, more than 50% are said to suffer from ADHD at the same time.⁵⁰

Down syndrome is also associated with an increased ASD prevalence of 39%⁵¹

2.4. Schizophrenia as a brain development disorder¶

Schizophrenia is associated with reduced dopamine in the PFC, which triggers the negative symptoms (e.g. flattening of affect, emotional and social withdrawal, ambivalence (contradictory emotions and thoughts), impoverished thinking) on the one hand and an excess of dopamine in the mesolimbic system on the other, which in turn causes the positive symptoms (e.g. hallucinations, delusions, ego disorders). Schizophrenia can manifest itself as early as adolescence, even if it is not usually diagnosed until early adulthood. Schizophrenia is increasingly seen as a brain development disorder in which strong genetic components and early environmental influences (such as maternal infections) play a role.²

2.5. ADHD treatment initiation with stimulants and addiction¶

Treating ADHD with stimulants as early as possible reduced the risk of developing addiction in adulthood. Each year that stimulant treatment began later increased the risk of developing addiction in adulthood by 1.46 times.⁵² Another study also found that starting ADHD stimulant treatment with MPH later led to a higher risk of developing (non-alcoholic) addiction.⁵³

Whether this is related to the influence of medication on brain development is unknown.

2.6. Succinic semialdehyde dehydrogenase deficiency¶

Succinic semialdehyde dehydrogenase deficiency is a rare neuromatabolic disorder associated with ADHD symptoms.⁵⁴

3. Early attachment disorder impairs self-organization of the right hemisphere of the brain¶

In infancy, the homeostatic structures between the “lower” autonomic and “higher” central brain systems develop in the right hemisphere of the brain,⁵⁵ which serve to generate, regulate and stabilize psychobiological states.
The right hemisphere is much more strongly connected to the limbic system and the mechanisms of autonomic and behavioral arousal than the left hemisphere. The maturation of the right hemisphere is dependent on experience.⁵⁶

Disorders in the bond between infant and mother can therefore cause developmental disorders in the right hemisphere of the brain, affecting the modulation of arousal and the regulation of the neurotransmitters dopamine and noradrenaline. Among other things, dopamine and noradrenaline are responsible for
The brain’s maturation processes are responsible for this.⁵⁷⁵⁸

In ADHD, abnormalities of the right hemisphere of the brain are particularly involved.

Numerous studies confirm that early childhood stress experiences can cause changes in behavior and neurotransmitters. ⇒ Stress damage due to early / prolonged stress