Etiology
The etiology of attention deficit hyperactivity disorder (ADHD) is likely multifactorial and composed of both genetic and environmental factors.
Genetic predisposition:
Childhood twin studies report ADHD to be approximately 70% to 80% heritable.[26] Twin studies conducted among adults, however, report much lower heritability rates, ranging from 0.29 to 0.37. It is assumed that this is an experimental error related to inadequate self-reporting and change of symptoms from childhood to adulthood.[27][28][29] Studies that combine data across informants and those that use clinical diagnostic data suggest heritability estimates for adults in the same range (70% to 80%) as for children.[30]
Genetic studies are looking at the difference between those ADHD cases that persist from childhood to adulthood and those which do not. It is suggested that persistence is related to enduring subcortical dysfunction, whereas remission is dependant on maturational changes in executive control.[31]
The D2 dopamine receptor gene, the dopamine beta-hydroxylase gene, the D5 dopamine receptor gene, the D4 dopamine receptor gene, the dopamine transporter gene (DAT1), the SNAP-25 (synaptosome-associated protein) gene, the ANKK1 (ankyrin repeat and kinase domain containing) gene, the low-density lipoprotein receptor-related protein genes LRP5 and LRP6, the ADGRL3 (adhesion G protein-coupled receptor) gene, the BAIAP2 (BAR/IMD domain containing adaptor protein) gene, the serotonin transporter gene (5-HTT), and the dopamine beta-hydroxylase gene (DBH) have all been implicated in the etiology of ADHD.[32]
Research on copy number variants (CNVs) has identified an increased number of large CNVs in children with ADHD, along with other neurodevelopmental and mental health disorders, suggesting possible overlap with other disorders and a strong genetic linkage.[33]
A genome-wide study from the United States, Europe, Scandinavia, China, and Australia confirmed a polygenic cause for most ADHD with many genetic risk variants, each having a small effect, combining to increase risk for the disorder.[34]
There is some evidence that a proportion of genes do not affect ADHD symptoms until later in life, while others have an effect on ADHD throughout life.
Gene-by-environment interactions have been suggested; the interplay between genes and the environment in the development of ADHD, as well as epigenetic factors, are subjects of ongoing research.[35][36]
Environmental factors:
A number of environmental factors are associated with ADHD, although due to the complexity of the likely interplay between genetic and environmental factors, it is difficult to establish causality.
Low birth weight has the strongest evidence for association with ADHD, with family studies suggesting a causal role, i.e., this association is not simply the result of genetic confounding.[37][38]
Childhood adversity is strongly associated with ADHD symptoms, as are nonshared environmental factors, especially sibling interaction, parental treatment, and peer group characteristics.[39]
The England-Romanian adoptive studies have demonstrated that, for those Romanian orphans within care for more than 6 months, the rate of ADHD is double that in the general population.[40] This association is dose dependent and is believed to be causal, although the effect of lesser (and more commonplace) levels of deprivation is less clear.[41]
Other pregnancy and delivery complications have been associated with the development of ADHD.
While maternal smoking was linked with the onset of ADHD, it is now believed to reflect genetic effects rather than direct toxic effects of nicotine.[42][43]
There is the suggestion of an association between maternal alcohol and prescription and nonprescription drug use, although the evidence overall is inconclusive.[44]
Prenatal antidepressant use in mothers is associated with an increased risk of ADHD in offspring, but the risk also appears to be elevated in children whose mothers used antidepressants before conception and in those with psychiatric illness who did not use antidepressants, suggesting that the association may be at least partly explained by the preexisting maternal psychiatric condition.[45][46]
In a large Danish study prenatal use of the anticonvulsant drug valproate was associated with a 50% increased risk of ADHD, there was no link with other anticonvulsant drugs.[47]
Pathophysiology
Understanding of the pathophysiology of ADHD is rapidly evolving and there is currently no single unifying theory to explain it.
Neuropsychology:
ADHD causes difficulties across a number of cognitive domains, including global and more specific deficits. A number of executive functional impairments may occur in adults with ADHD, similar to findings in children with the disorder. These include differences in vigilance, motor inhibition, organization, problem-solving, verbal learning, nonverbal memory, and motivation. It is important to note that specific patterns of cognitive dysfunction vary considerably between individuals, emphasizing the complex and heterogeneous nature of ADHD.[48] An emerging area of interest is the fact that cognitive difficulties in ADHD may be dynamic in nature, varying between settings and dependent on the nature of the task involved.[49] For example, individuals may make more errors during tasks that are more slowly or quickly paced, but not those of intermediate pace.[50] In daily life, ADHD symptoms may be more severe during lengthy tasks and those that are experienced as less interesting.[51] There is evidence that some people with ADHD respond differently to controls to positive and negative reinforcement.[52] According to the maturational lag model, children with ADHD have neurodevelopmental profiles representative of typically developing children at younger ages, possibly as a result of delay in cortical development (by as much as 2-3 years) depending on the specific cortical region.[53][54][55]
Brain neurochemistry:
Up to 85% of patients with ADHD respond to stimulants, so the mechanism of action of methylphenidate and amphetamine provides an important clue. Stimulants increase the free brain levels of norepinephrine and dopamine by blocking presynaptic neuronal reuptake and triggering release of these neurotransmitters, suggesting that ADHD may result from dysfunction (downregulation) of norepinephrine and dopamine.[56]
The immediate response of people with ADHD to stimulants would appear to be via activation of dopamine pathways within the corpus striatum and catecholamine/dopamine activation within the frontal lobes. ADHD brain chemistry has also been linked to dysfunctions in the serotonergic system.[57]
Brain structure:
Structural differences are seen in adults and children with ADHD compared to typically developing controls:
Decreased volumes in specific areas, for example, the frontal cortical (especially right), subcortical, caudate, corpus callosum, cerebellar structures, and corpus striatum (including nucleus accumbens).[26][58]
These structural differences are subtle and only significant when comparing groups of patients with ADHD with unaffected controls, so it is not possible to use neuroimaging to diagnose ADHD in individual patients.
Subcortical brain changes in children with ADHD may dissipate as they reach adulthood.[58]
There is some evidence of a normalisation of structural abnormalities in ADHD in response to stimulant therapy.[59]
Differences in several large neural networks have been identified, including the default mode network (DMN), dorsal and ventral attentional networks, salience networks, and frontostriatal and mesocorticolimbic circuits, suggesting that structural differences in ADHD are not just localized to specific brain regions, but instead involve large scale interconnections between brain networks.[60][61]
Functional imaging:
Functional imaging studies including single photon emission-CT (SPECT), functional magnetic resonance imaging (fMRI), PET scan, and proton magnetic resonance spectroscopy (pMRS) have identified differences in adults and children with ADHD:
Reduced glucose metabolism in the prefrontal and premotor cortex and the superior prefrontal cortex, and inhibited activation of the anterior cingulate in adults with ADHD.[26][62]
Hypoperfusion and hypofunction in the prefrontal and striatal regions of children and adults with ADHD.[63][64]
The corpus striatum is physiologically responsible for movement moderation, and also for filtration of perceived stimuli and linking this with a response from the frontal lobes via the frontostriatal pathway. The corpus striatum also seems to have an effect on the willingness to work in order to achieve a reward. It is the main center of dopamine activity within the brain. It is likely that reduction in its function, associated with the findings of reduced volume, are related to an atypical response to stimuli resulting in distractibility, emotional response to stimuli, and motivation.
Other brain regions such as the parietal cortex, inferior parietal lobe, superior temporal sulcus, and reticular activating system have been implicated in the executive function and attentional impairments characteristic of ADHD.[26]
Frontostriatal and frontocortical tracts may remain abnormal in people with ADHD throughout life despite treatment.
Of note, certain functional brain changes have been demonstrated to differ between children with persistent ADHD versus those who have experienced remission of symptoms, hinting at a causal link between brain functional changes and ADHD.[65]
However a key limitation of the current neuroimaging literature overall is that it has not yet been possible to distinguish potential underlying neurologic causes of ADHD from potential neurologic adaptations to ADHD; further longitudinal data is therefore needed.[44]
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