Brain development disorder and ADHD

ADHD is often described as a developmental brain disorder in the sense of a developmental delay.

ADHD shows age constant

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

suggesting an early, non-progressive “lesion” involving neurotrophic factors controlling whole brain growth and selected dopamine circuitry.¹

ADHD is 75% genetically determined. Among the gene mutations and gene polymorphisms associated with ADHD, dopamine is the most commonly affected neurotransmitter, each causing lower dopamine levels, lower dopamine efficacy, or increased dopamine depletion. See more at ⇒ Candidate genes in ADHD In the chapter ⇒ Emergence.

Dopamine is a neurotrophic factor important for brain development.

As a working hypothesis, we consider it conceivable that in the etiology of ADHD there is initially a dopamine deficiency caused genetically or by early environmental influences, which subsequently (co-)causes a disorder of brain development, since dopamine as a neurotrophic substance is important for brain development. In any case, it must be questioned whether the brain developmental delay or disorder described in ADHD could possibly be a (mere?) consequence of a dopamine deficiency (caused genetically or by environmental influences). If proven, this could open the option to prevent or mitigate the development of ADHD by dopaminergic treatment during the appropriate time window of brain development. Even if the likelihood is open in view of the persistence of the genetic cause, which after all persists throughout life, and even in the case of a confirmation of the presumed connection it could still take decades until therapeutic applicability, the opportunity inherent in this deserves at least a more in-depth examination of the hypothesis.
Acute studies and a recent review support the hypothesis.²³
In the following, we collect (further) facts that could confirm, modify or refute the hypothesis.

Disturbances of brain development are to be expected at any deviation from the optimal mean dopamine level, i.e. not only at dopamine deficiency, but also at dopamine excess in the developmental phase of the respective brain region.

• 1. Brain development and neurotransmitters
  • 1.1. Dopamine and brain development
    • 1.1.1. Developmental course of the dopaminergic system and brain development in rodents
  • 1.2. Phenylketunorie, dopamine deficiency and ADHD
  • 1.3. Down syndrome, neurotransmitter deficiency and ADHD
  • 1.4. Schizophrenia as a brain development disorder
  • 1.5. ADHD treatment initiation with stimulants and addiction
  • 1.6. Succinic semialdehyde dehydrogenase deficiency
• 2. Early attachment disorder impairs self-organization of the right cerebral hemisphere

1. Brain development and neurotransmitters¶

The development of the brain depends, among other things, on the presence of various neurotransmitters. This is primarily studied in rodents.⁴

1.1. Dopamine and brain development¶

ADHD is associated with dopamine deficiency. This is mostly genetically determined - the heritability of ADHD is around 75% - and thus inherent from conception. It is striking that the environmental influences associated with ADHD very often also influence the dopamine balance already during pregnancy or the first years of life.

Dopamine, as a neurotrophic factor, is essential for brain development. Disorders of the dopaminergic system that exist 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 disruptions during development are capable of inducing phenotypes in animal models that correspond to neuropsychiatric disorders such as ADHD, ASD, schizophrenia, or addiction.³
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 dysfunction may lie in a disrupted link between dopaminergic signaling on the one hand and genes important for neuronal development on the other.⁵
Both dopamine excess and dopamine deficiency during brain development can reduce the density of dendritic spines of medium spiny neurons (MSNs).⁶
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 resulting from asymmetric cell division of multipotent stem cells)⁷ in the brain,⁸⁹ as well as norepinephrine,¹⁰ GABA and glutamate,^{1112 13 14} and serotonin.¹⁵ Some hormones also influence brain development, such as fibroblast growth factors (FGF).¹⁶¹⁷ Estradiol-17beta, the most potent female sex hormone, influences not only primary and secondary sex characteristics but also embryonic and fetal growth and the development of brain aminergic networks.¹⁸

• It is possible that dopamine modulates striatal neurotrophin reactivity and thereby influences striatal neuronal development during a defined period of brain development.¹⁹
• D1 receptors appear to regulate cell cycle during cortex development. They may also have differential influence on proliferative activity in FGF2-supported versus EGF-supported cerebral cortical progenitor cells.²⁰
• Elevated dopamine levels in pregnancy apparently reduce neurogenesis in some brain regions (in caudate/putamen, nucleus accumbens, frontal cortex, but not globus pallidus) and cause subtle deficits in neuron number.²¹
• Mice in which dopaminergic cells were largely destroyed using 6-OHDA, which reduced dopamine levels to below 10%, showed in the striatum ²²²³
  • An increase in serotonin and serotonin metabolites (which already occurred with a dopamine decrease of less than 90%)
  • Unchanged: Enkephalin and preproenkephalin mRNA levels up to 25 days of age
  • Increased expression of enkephalin and preproenkephalin mRNA until 35 days of age and older
  • Decreased expression of substance P and preprotachykinin mRNA
  • Unchanged: beta-actin mRNA expression
• Mice receiving L-dopa from PD1 to PD5 showed sex-dependent behavioral abnormalities at 4 weeks of age.²⁴

An early developmental abnormality in the dopamine system could cause permanent alteration of striatal neuropeptide systems, which in turn could promote dopamine deficiency states.²²

The developmental timing of the brain at which a (e.g., dopaminergic) imbalance exists is likely to be crucial. Accordingly, constitutive gene knockouts may trigger different changes than time-limited environmental influences such as pharmacological manipulations, for which, moreover, the time of intervention is relevant.³

Dopamine production and dopamine receptor expression in mammals begins in the fetus.²⁵²⁶
In rats, in which brain development is intensively studied, high growth of dopamine and serotonin transporters is shown in the last week of pregnancy and in the first two weeks after birth, suggesting a particular vulnerability of the dopaminergic and serotonergic systems during this period.²⁷ Brains of rats whose mothers were treated with a dopamine reuptake inhibitor during pregnancy showed slowed and reduced development of dopamine release in the striatum.²⁸

Oxygen deprivation during birth can cause long-term changes in the dopamine system.²⁹ Dysfunctions of the dopamine system can trigger brain development disorders such as those associated with ADHD.

1.1.1. 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.³⁰
In rodents, the early postnatal days correspond to human brain development in the third trimester of pregnancy.⁴

Developmental course in rodents:³

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

E12 to E15:

• Onset of dopamine neuron differentiation in substantia nigra and ventral tegmentum.
• Subsequently, processes of axonal expansion and synaptic maturation.

E13:

• First dopaminergic cells in the ventral prosencephalon³¹

E14:

• Neurons from the SN and VTA project across the medial forebrain bundle and reach the nucleus accumbens in the dorsal and ventral striatum, respectively³¹

E15:

• Dopaminergic fibers reach the anlage of the lateral neocortex³²

E15, E16:

• The dopaminergic cell groups in SN and VTA as well as their projections rapidly increase in size.³¹

E17:

• Dopaminergic fibers reach the inferior plate of the future PFC³² Afferent dopaminergic fibers align with the striatum and form large bundles that are tightly connected to the fascicles of the internal capsule.³¹

E18:

• Projections from SN and VTA reach the medial frontal cortex (mPFC)³²³¹

E15 to E21:

• Steeper increase of D1-type dopamine receptors (D1, D5) in the mPFC than in the striatum
• Steeper increase of 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.³³ This indicates that the functional identity of these neurons is already formed embryonically.
• Maturation of dopamine projections in the forebrain follows pattern as in many neuronal pathways: first expansion, then contraction

P1-P60:

• Expansion and maturation of dopaminergic innervation in these regions continues postnatally until P60.³²

P1-P14:

• Active maturation period for the striatum³⁰

P2:

• In parts of the PFC, large numbers of dopaminergic fibers are evident in the peripheral zone (the future layer 1).³²

P4:

• Changes in dopaminergic fiber morphology index onset of DA innervation proper³²

P6:

• The different subareas of the PFC are recognized by the characteristics of the topographic distribution of dopaminergic fibers³²

P28-P50: late adolescence

• Highlight of multiple molecular determinants of DA signaling
• Intensive postnatal development of forebrain circuits
• Sensitive period to internal and external factors that stimulate or disrupt normal brain development. These factors may influence the risk of neuropsychiatric disorders in humans during the appropriate developmental period.³⁴

P21:

• Medium spiny neurons begin to exhibit defined up (depolarized) and down (hyperpolarized) states characteristic of mature cells, similar to those of adult mice.³⁵

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 cortex and thalamus. Adult maturation was evident no earlier than the end of the first postnatal month.³⁵³
• In addition to 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 precedes an increase in dopaminergic neurotransmission in the striatum, which occurs in the fourth postnatal week.²³ Striatum and cortex express dopamine receptors even before the propagation of dopamine afferents.³³²⁵
• In mice with developmental dopamine deficits in the striatum, D1 receptor-expressing medium spiny projection neurons show no maturation and retain their hyperexcitability. Evidence suggests that this phenotype results from altered phosphatidylinositol 4,5-biphosphate signaling.²³
• These deficits can be corrected (in mice) by dopamine substitution from birth. Dopamine administration in adulthood no longer corrected development. This corresponds to the temporal window of dopamine action during brain development for the physiological maturation of medium spiny neurons (MSNs) described in this paper²³

Until P60: Adulthood

• Density of dopaminergic fibers continues to increase.
  No difference in density and topography was observed between postnatal days 60 and 90³²

P60-P90:

• Dopaminergic system (including DA biosynthetic enzymes, DA receptors, and DAT) reaches maturation³⁴. No more change in density of dopaminergic fibers detectable.³²

Alterations in dopamine neuron development can cause pathological development of neurons and circuits within dopaminoceptive regions.²³⁶

The dopaminergic brain organization of rodents and primates (incl. humans) shows great similarities and some differences. Only in primates is there a prominent role of cortical dopamine on pyramidal tract neurons in primary motor cortex. In rodents, mesocortical dopamine originates very 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.³⁷ Nevertheless, many studies show that function and dopaminergic dynamics of the striatum are largely consistent between rodents and primates.³⁸³

1.2. Phenylketunorie, dopamine deficiency and ADHD¶

Phenylketonuria (PKU, a recessive disorder of phenylalanine metabolism due to mutations of the phenylalanine hydroxylase gene) results in a significant excess of phenylalanine (hyperphenylalaninemia). Since phenylalanine and tyrosine pass through the blood-brain barrier by the same transporters, and these transporters have a higher affinity for phenylalanine, when there is excess phenylalanine in the blood, too little tyrosine enters the brain. Tyrosine is a precursor for dopamine, which further gives rise to norepinephrine and epinephrine. Therefore, an excess of phenylalanine in the blood leads to a lack of dopamine, norepinephrine, and epinephrine in the brain.³⁹ In addition, phenylalanine excess causes changes in cerebral myelin and protein synthesis, as well as reduced levels of serotonin in the brain.⁴⁰ ADHD and phenylketonuria thus have the common feature of a dopamine deficiency.⁴¹⁴² Phenylketonuria sufferers often show symptoms of ADHD, although the subtypes with hyperactivity seem to predominate.^43444145

In our view, it would be conceivable that the dopamine and norepinephrine deficiencies triggered by phenylketonuria trigger a brain developmental disorder, which in turn causes the ADHD symptoms, whereas the dopamine and norepinephrine deficiencies in ADHD, which could equally affect brain development, are mostly determined by a variety of genes or epigenetic factors, but can also be caused by early childhood chronic stress.

1.3. Down syndrome, neurotransmitter deficiency and ADHD¶

In Down syndrome, there is dysfunctional neural brain development of the fetus.
Fetuses with Down syndrome showed in frontal cortex:⁴⁶

• Decreased levels of brain chemicals required for the acquisition of brain morphological features, neuronal and glial proliferation, and synapse formation
  • Neurotransmitter
    • Dopamine
    • Serotonin
    • GABA
  • Amino acid
    • Taurine
• Unchanged mirrors from
  • Norepinephrine
  • Arginine
  • Aspartate
  • Glutamine
  • Glutamate
  • Glycine
  • Histidine
  • Serine

The authors consider the reduced levels to indicate possible mechanisms for the observed dysfunctional neuronal development in the fetal brain of Down syndrome.⁴⁶
In special institutions for children with Down syndrome, more than 50% are said to have ADHD at the same time.⁴⁷

1.4. Schizophrenia as a brain development disorder¶

Schizophrenia is associated with decreased dopamine in the PFC, which triggers both the negative symptoms (including flattening of affect, emotional and social withdrawal, ambivalence (conflicting emotions and thoughts), impoverishment of thinking) and excess dopamine in the mesolimbic system, which in turn causes the positive symptoms (including hallucinations, delusions, ego disorders). Although schizophrenia is usually not diagnosed until early adulthood, schizophrenia is increasingly viewed as a brain development disorder in which strong genetic components and early environmental influences (such as those associated with maternal infections) play a role.³

1.5. 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 started later increased the risk of addiction development in adulthood by 1.46 times.⁴⁸ Another study also found that a later onset of ADHD stimulant treatment with MPH resulted in a higher risk of (non-alcoholic) addiction development.⁴⁹

Whether this is related to an effect of medication on brain development is unknown.

1.6. Succinic semialdehyde dehydrogenase deficiency¶

Succinic semialdehyde dehydrogenase deficiency is a rare neuromatabolic disorder associated with ADHD symptoms.⁵⁰

2. Early attachment disorder impairs self-organization of the right cerebral hemisphere¶

In infancy, homeostatic structures develop between the “lower” autonomic and “higher” central brain systems in the right cerebral hemisphere,⁵¹ which serve to generate, regulate, and stabilize psychobiological states.
The right hemisphere is significantly more connected than the left to the limbic system and the mechanisms of autonomic and behavioral arousals. The maturation of the right cerebral hemisphere is experience-dependent.⁵²

Disorders of infant-mother bonding can therefore cause developmental disorders of the right cerebral hemisphere, affecting arousal modulation and regulation of the neurotransmitters dopamine and norepinephrine. Dopamine and norepinephrine are responsible for, among other things
Maturation processes of the brain.⁵³⁵⁴

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

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