What is the neurological basis of ADHD?

Evidence exists for the association between attention-deficit hyperactivity disorder (ADHD), or hyperkinetic disorder (HKD), and possible structural,1-12 functional13-20 and neurotransmitter21-27 alterations in various regions of the brain in children, adolescents and adults with ADHD.

Childhood/adolescent ADHD and the brain by Dr Mitul Mehta

Adult ADHD and the brain by Dr Mitul Mehta and Professor Philip Asherson


Structural alterations in ADHD

Structural abnormalities that have been observed in children, adolescents and adults with ADHD versus individuals without ADHD include: lower grey matter density1-3; white matter abnormalities4,5; reduced total brain volume and volume of some brain structures1,6-8,28; delayed cortical maturation in children and adolescents9-11; and reduced cortical thickness in adults.1,12

The results of some studies that have investigated the structural alterations in ADHD are presented below:

  • A prospective follow-up magnetic resonance imaging (MRI) study found that adults with ADHD (n=59) had significantly lower mean surface-wide cortical thickness and regional grey matter density (p<0.001) compared with adults without ADHD (n=80).1 The bilateral dorsal network was affected by these structural changes (found in the parietal, temporal and posterior frontal regions), which supported previous evidence of the involvement of this region in attention functioning.1
  • Another study correlated total brain volume with self-reported ADHD symptoms in adults (aged 18–35 years; n=652). A significant association between the number of self-reported ADHD symptoms and total brain volume was found, such that adults who reported ≥6 symptoms had a lower brain volume than those who reported ≤3 symptoms of ADHD. The authors hypothesised that these results suggested that self-reported ADHD symptoms in adults may have neurobiological underpinnings.8
  • The ENIGMA-ADHD working group found decreased subcortical volumes in individuals with ADHD (age range 4–63 years), including the nucleus accumbens (Cohen’s d = −0.15), amygdala (d = −0.19), caudate nucleus (d = −0.11), hippocampus (d = −0.11), putamen (d = −0.14), and intracranial volume (d = −0.10) compared with individuals without ADHD. Furthermore, decreases in the surface area of frontal, cingulate and temporal regions were also found in individuals with ADHD versus unaffected individuals.28
  • In a prospective MRI study, children and adolescents with ADHD (n=223) exhibited delays in cortical maturation versus those without ADHD (n=223). Delays were most prominent in prefrontal regions, which are important for control of cognitive processes, including attention and motor planning.10

Functional alterations in ADHD

Regions of the brain that have been implicated in ADHD correspond to certain brain networks that involve frontal regions or support executive function and attention (Figure 1).13

Figure 1: Functional abnormalities in the ADHD brain. Reproduced with permission from Purper-Ouakil D et al. Pediatr Res 2011; 69: 69R-79R.13

Functional abnormalities in the ADHD brain

Functional neuroimaging studies have identified under- or over-activation of some brain networks in adults with ADHD compared with adults without ADHD, in particular:

  • Over-activation (reduced suppression) of the default mode network during task performance.19,20
  • Under-activation of fronto-striatal and fronto-parietal circuits, and other frontal brain regions.14-18
  • Under-activation of systems involved in executive function and attention.12,14

Different models have suggested how these alterations may lead to symptoms of ADHD, for example:

  • Impairments in prefrontal-striatal networks may contribute to the inattention observed in ADHD.13
  • Impairments in frontal-limbic networks may be linked to symptoms of hyperactivity.13

Neurotransmitter alterations in ADHD

There are alterations in activity and communication between different regions and networks of the ADHD brain.29-32 Evidence has suggested that disruptions in the relay of messages between neurons by the chemicals dopamine and noradrenaline (in animal studies) also contribute to the neurobiology of ADHD.21,22,33 Additionally:

  • Maturation of certain dopaminergic neural pathways appears to be delayed in children and adolescents with ADHD.34
  • Levels of available dopamine receptor and transporter molecules are typically lower in some parts of the brain in adults with ADHD than in adults without ADHD.22,35,36
  • In rats, interference with the noradrenaline system impacts on impulsivity, attentional accuracy and response control.21,23
  • Established pharmacological treatments for ADHD are known to interact with the dopamine and noradrenaline systems.24

There is also evidence for the roles of other signalling systems in ADHD. Polymorphisms in the serotonin transporter gene have been associated with differential response to ADHD treatment37 and the presence of comorbid conduct disorder in children and adolescents with HKD.25 In adults with ADHD, there is evidence that deficiencies in glutamate signalling may play a role in modulating neurotransmitter release in some brain regions.26,27 One study found that a glutamate gene set was associated with hyperactivity/impulsivity symptom severity (p=0.009) suggesting that genes involved in glutamate neurotransmission may play a role in the manifestation of ADHD symptoms.38

What is the heritability of ADHD?

ADHD is acknowledged to have an underlying genetic component,39,40 with a high estimated heritability rate,39-41 and the involvement of specific candidate genes reported.42 Using data from the Swedish Twin Registry (n=37,714 adult twins), researchers estimated that the genetic contribution to ADHD was 72% in adult twins.39 Furthermore, in a second Swedish study, 52% of the correlation between inattentive and hyperactive-impulsive symptoms was accounted for by genetic influences, and 48% by non-shared environmental influences (n=15,198 adult twin pairs).40

Pooled data from twin studies have estimated the mean heritability of ADHD to be 76%.41

One study investigated children and adolescents with ADHD (n=25) adopted within the first year of life and reported that rates of ADHD were significantly higher between biological relatives (parent–child or sibling) compared with adoptive relatives.43

  • In the adopted ADHD group, 6% of adoptive parents and 8% of adoptive siblings had symptoms of ADHD.43
  • In a control group of 101 children and adolescents with ADHD who had not been adopted and lived with their biological families, 18% of parents and 31% of siblings had symptoms of ADHD.43

The molecular genetics of ADHD

The molecular genetics of ADHD is an evolving field; nevertheless, studies have reported many candidate genes to be associated with the disorder. Potentially useful biomarkers include42:

  • Variants in DAT1 and DRD4 genes due to their associations with neuropsychological tasks, activation in specific brain areas, methylphenidate response and gene expression levels.
  • The noradrenergic system (norepinephrine transporter, norepinephrine, 3-methoxy-4-hydroxyphenylglycol, monoamine oxidase, neuropeptide Y) due to the altered peripheral levels, the association with neuropsychological tasks, symptomatology drug effect and brain function.
  • Dopamine beta hydroxylase and catechol-O-methyltransferase.

Data from a systematic review has suggested that some genetic mechanisms of ADHD differ between children and adults and so useful biomarkers may vary with the age of presentation. Associations were found with genes belonging to dopaminergic, neurodevelopmental systems and an opioid receptor for children with ADHD. While for adults with ADHD, associations were found with genes involved in circadian rhythms and a more generic neurodevelopmental or neurite outgrowth network.44

Are there environmental risk factors for ADHD?

Several environmental risk factors have been associated with the potential development of ADHD,45-49 and combinations of specific polymorphisms and environmental risk factors may increase the likelihood of some ADHD symptoms.50-58

Pregnancy or early childhood risk factors for ADHD

Data from the Quebec Longitudinal Study of Child Development identified pregnancy or early childhood risk factors associated with symptoms of ADHD in a total of 2057 children from the age of 5 months until the age of 8 years. The study reported several early risk factors for later development of ADHD symptoms, including premature birth (adjusted odds ratio [aOR] 1.93), low birth weight (aOR 2.11) and prenatal tobacco exposure (aOR 1.41).45 A longitudinal Finnish study of 828 newborn infants found those who were small for gestational age at birth were 3.6-times more likely to have ADHD symptom scores above the clinical cut-off at age 56 months than children of normal birth weight (95% confidence interval [CI] 1.63–7.95; p=0.002).59

Results from a US survey of 2588 children (aged 8–15 years) suggested that maternal cigarette use during pregnancy was significantly associated with childhood ADHD (aOR 2.4, 95% CI 1.5–3.7; p=0.001).47 Similarly, a study of 356 British children (aged 6–16 years) with ADHD identified maternal smoking during pregnancy as a risk factor for greater hyperactive-impulsive symptom severity.46 Parental history of antisocial personality disorder (specifically, paternal anxiety-mood disorder) has also been shown to be related to persistence of ADHD into adulthood.60

Socioeconomic risk factors for ADHD

A number of international studies have identified socioeconomic factors associated with the development of ADHD symptoms. These include:

  • Non-intact family* (adjusted odds ratio [aOR] 1.85; 95% confidence interval [CI] 1.26–2.70)45
  • Single-parent household (aOR 1.45; 95% CI 1.38–1.52)48
  • Paternal history of antisocial behaviour (aOR 1.78; 95% CI 1.28–2.47)45
  • Maternal depression (aOR 1.35; 95% CI 1.18–1.54)45
  • Lower maternal education (aOR 2.20; 95% CI 2.04–2.38)48
  • Lower social class (r2=0.02; p=0.0346 and OR 6.2; 95% CI 3.4–11.349)
  • Households of social welfare recipients (aOR 2.06; 95% CI 1.92–2.21)48
  • Young maternal age at birth of the target child (aOR 1.78; 95% CI 1.17–2.69).45

*Child not living with both biological parents

Environmental contaminant risk factors for ADHD

Environmental exposure to lead has been identified as a risk factor for ADHD in several studies:

  • In the US National Health and Nutrition Examination Survey, high blood lead concentrations in children (aged 8–15 years; n=2588) were significantly associated with ADHD (aOR 2.3; 95% CI 1.5–3.8; p=0.001).47
  • Data from the New England Children’s Amalgam Trial suggested that children (aged 6–10 years) with blood lead levels of 5–10 μg/dL had lower scores in tests of IQ, achievement, attention and working memory than children with levels of 1–2 μg/dL (p=0.03).61
  • Low-level lead exposure was associated with higher ADHD scores in a study of 246 African American inner-city children at age 7.5 years.62

Do gene–environment interactions underlie the aetiology of ADHD?

ADHD aetiology may result from complex interactions between genetic and environmental influences50-58 and may explain individual differences observed in response to environmental risk factors (Figure 2).

Figure 2: Combinations of specific polymorphisms and environmental risk factors that may increase the likelihood of ADHD symptoms. Figure developed from multiple sources.50-58

a) Children and adolescents

Combinations of polymorphisms and environmental risk factors that may increase the likelihood of ADHD symptoms in children and adolescents

b) Adults

Combinations of polymorphisms and environmental risk factors that may increase the likelihood of ADHD symptoms in adults

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