Etiology

The etiology of attention deficit hyperactivity disorder (ADHD) is likely multifactorial and composed of genetic and environmental factors.

Genetic predisposition

There is substantial evidence for a strong genetic contribution to ADHD, with the mean heritability for ADHD shown to be 76% based on twin studies.[30] Some propose that several genes interact to cause the ADHD phenotype, while others see ADHD as the final common pathway for variant alleles.[3]

Several genetic approaches have yielded interesting data.

Linkage analysis examines the linkage between the disorder and evenly spaced DNA markers throughout the entire genome.[31] Linkage data suggest that ADHD is associated with markers at chromosomes 4, 5, 6, 8, 11, 16, and 17.[32]

Association analysis examines specific candidate genes based on known ADHD pathophysiology. A statistically significant association with ADHD has been demonstrated in the genes coding for dopamine 4 and 5 receptors, the dopamine transporter, the enzyme dopamine beta-hydroxylase, the serotonin transporter gene, the serotonin 1B receptor, and the synaptosomal-associated protein 25 gene.[30]

The development of powerful new tools for genetic analysis has allowed genome-wide association studies, which have already identified a number of significant risk loci and may provide more focused data in the coming years.[33][34] Adolescent Brain Cognitive Development Opens in new window UK Biobank Opens in new window In particular, the interplay between genes and the environment in the development of ADHD, as well as epigenetic factors, requires further exploration.[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. Environmental factors account for 12% to 40% of the variance in twin ADHD scores.[37] Low birth weight has the strongest evidence for association with ADHD, with family studies suggesting a causal role, that is, this association is not simply the result of genetic confounding.[38][39][40]​​​​ Other risk factors include maternal smoking, obstetric complications during pregnancy and labor, gestational exposure to stress, poverty, lead exposure, iron deficiency, and psychosocial adversity.[10][41][42]​​​[43][44][45]​ Many of these risk factors are considered likely be at least partly attributable to genetic confounding.[46]​ Severe early deprivation (such as institutional rearing or child maltreatment) has been shown to contribute to ADHD.[47][48]

Evidence on any association between maternal alcohol and prescription and non-prescription drug use is currently suggestive overall.[49]

Pathophysiology

Understanding of the pathophysiology of ADHD is rapidly evolving and there is not yet a unifying theory.

Brain neurochemistry: up to 85% of ADHD patients respond to stimulants, so the mechanism of action of methylphenidate and amphetamine provides an important clue.[50] 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 a dysfunction of norepinephrine and dopamine.[51] One proposed theory is that abnormal dopamine transporter density contributes to the disorder.[52] Another is that the norepinephrine transporter, and/or glutamate receptor, and/or monoamine oxidase A transporter is involved.[53][54][55] ADHD brain chemistry has also been linked to dysfunctions in the serotonergic system.[55][56]

Neuropsychology: executive dysfunction is common in ADHD and this has led to theories about dysfunction in frontal-subcortical circuits, which mediate response inhibition, vigilance, and working memory.[57]​ However, specific patterns of executive dysfunction vary considerably between individuals with ADHD, emphasizing its complex and heterogenous nature.[58]​ 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.[59]​ For example, individuals may make more errors during tasks that are more slowly or quickly paced, but not those of intermediate pace.[60]

Brain structure: neuroimaging studies have demonstrated that children with ADHD have reduced brain volume in certain areas, including the cerebellum, the splenium of the corpus callosum, the total cerebrum, the right cerebrum, the right caudate, sensorimotor brain regions, various frontal regions, and the nucleus accumbens (within the limbic system).[61][62][63]​​ These structural differences are 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. There is some evidence that stimulant therapy may be associated with normalization of structural abnormalities in ADHD.[64][65]

Brain function: functional neuroimaging including single photon emission-CT (SPECT), functional magnetic resonance imaging (fMRI), PET scan, and proton magnetic resonance spectroscopy (pMRS) studies have demonstrated differences in children with ADHD, including reduced activation in the basal ganglia and anterior frontal lobe, and altered cortico-striatal-thalamic connectivity.[66][67]​​​ Differences have been identified in several other large neural networks, including the default mode network (DMN), dorsal and ventral attentional networks, salience networks, and frontostriatal and mesocorticolimbic circuits.[68][69]​ Another study showed that children with ADHD had higher connectivity in the ventral striatum and orbitofrontal cortex, and lower connectivity in the superior parietal cortex and precuneus networks.[70] The neuroimaging literature on ADHD is growing rapidly.[63][71]​​[72]​​ However, a key limitation of the current neuroimaging literature is that it has not yet been possible to distinguish potential underlying neurologic causes of ADHD from potential neurologic adaptations to ADHD.[49]​​

Classification

Diagnostic and Statistical Manual of Mental Disorders, 5th edition, Text Revision (DSM-5-TR) classification of ADHD[1]

ADHD may be classified as one of the following subtypes:

  • Combined presentation: if both inattention criterion and hyperactivity-impulsivity criterion are met for the past 6 months.

  • Predominantly inattentive presentation: if inattention criterion is met but hyperactivity-impulsivity criterion is not met for the past 6 months.

  • Predominantly hyperactive/impulsive presentation: if hyperactivity-impulsivity criterion is met and inattention criterion is not met for the past 6 months.

Patients may be classified as being “in partial remission” if full criteria were previously met, fewer than the full criteria have been met for the past 6 months, and the symptoms still result in impairment in social, academic, or occupational functioning.

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