Evidence exists for the association between attention-deficit hyperactivity disorder (ADHD) and possible structural,1-12 functional11,13-20 and neurotransmitter21-30 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 Prof Philip Asherson
Imaging studies suggest that ADHD is typically associated with some structural abnormalities in the brain.
The following structural abnormalities have been observed in children/adolescents and adults with ADHD versus healthy controls:
- Lower grey matter density1-3
- White matter abnormalities4,12
- Reduced total brain volume and volume of some brain structures1,5-7
- Cortical differences
- Delayed cortical maturation in children/adolescents8-10
- Reduced cortical thickness in adults.1,11
In a prospective magnetic resonance imaging (MRI) study, children and adolescents with ADHD (n=223) exhibited delays in cortical maturation versus typically developing controls (n=223).9 Delays were most prominent in prefrontal regions (Figures).
Cortical maturation in patients with and without ADHD. Reproduced with kind permission.9
Rate of cortical maturation in patients with and without ADHD. Reproduced with kind permission.9
A prospective follow-up study, which compared MRI brain scans of adults with ADHD and adults without ADHD (n=59 and n=80, respectively), found that adults with ADHD had significantly lower mean surface-wide cortical thickness and regional grey matter density (p<0.001) compared with adults without ADHD.1
The bilateral dorsal network was affected by these structural changes (found in the parietal, temporal and posterior frontal regions), and the researchers concluded that this supported previous evidence of the involvement of this region in attention functioning (Figure).1
These findings support the work of the first study of cortical thickness in adults with ADHD, which compared MRI scans of adults with ADHD with scans of adults without ADHD (n=24 and n=18, respectively) and found that adults with ADHD had significant thinning in the cortical neural network associated with attention, which primarily involved the right frontal and parietal lobes, compared with adults without ADHD (p=0.034).11
Grey matter density and cortical thickness in patients with ADHD. Reproduced with kind permission.1
Regions of the brain that have been implicated in ADHD correspond to brain networks (e.g. involving frontal regions, or supporting executive function and attention) (Figure).13
Figure: Functional abnormalities in the ADHD brain. Reproduced with kind permission.13
Neurobiological correlates of adult ADHD
Functional neuroimaging studies have identified under- or over-activation of some brain networks in adults with ADHD compared with healthy controls.14-16
One meta-analysis of 16 functional MRI studies of adults with and without ADHD demonstrated that the patterns of under- and over-activation differed significantly between these groups of patients. Networks under-activated in ADHD were almost exclusively located in the frontoparietal network, whereas over-activated regions were found in the visual, dorsal attention and default mode networks.14
Furthermore, the overall distribution of under- and over-activation differed significantly between networks, indicating that the pathology of ADHD may be based upon the interrelationships between networks.14
Meta-analysis of 16 functional MRI studies: patterns of activation differ significantly between networks (p<0.0001). Reproduced with kind permission.14
Techniques such as functional MRI and diffusion tensor imaging are providing insights into the possible dysfunction of these neural networks in ADHD.
Different models have been proposed to describe how dysfunction of particular networks may lead to symptoms of ADHD:
- Impairments in prefrontal-striatal networks may contribute to the inattention observed in ADHD13
- Impairments in frontal-limbic networks may be linked to symptoms of hyperactivity.13
Functional neuroimaging studies have identified under- or over-activation of some brain networks in ADHD versus control subjects, in particular:
- Over-activation (reduced suppression) of the default mode network during task performance19,20
- Under-activation of fronto-striatal and fronto-parietal circuits, and other frontal brain regions14-18
- Under-activation of systems involved in executive function and attention.11,14
Catecholamine signalling systems may be disrupted in the ADHD brain.21-24
Maturation of certain dopaminergic neural pathways appears to be delayed in children and adolescents with ADHD.24
Levels of available dopamine receptor and transporter molecules are typically lower in some parts of the brain in adults with ADHD than in healthy controls.21-23
In rats, interference with the noradrenaline system impacts on:28,29
- Attentional accuracy
- Response control.
Established ADHD treatments are known to interact with the dopamine and noradrenaline systems.14,21,31-66
Emerging evidence suggests possible roles for other signalling systems
Polymorphisms in the serotonin transporter gene have been associated with differential response to ADHD treatment27 and the presence of comorbid conduct disorder in children and adolescents with hyperkinetic disorder.30
In adults with ADHD, deficiencies in glutamate signalling may play a role in modulating neurotransmitter release in some brain regions.25,26
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