In most cases ADHD can be considered a multifactorial disorder, where multiple biological and environmental risk factors, cumulatively increase the likelihood of developing the disorder. ADHD is highly heritable. Disruption to dopamine and noradrenaline, particularly lowered synaptic levels, is thought to be a key to the pathophysiology of ADHD (Arnsten & Pliszka, 2011; Levy, 1991; Pliszka, McCracken, & Maas, 1996).
Meta-analysis of brain imaging data has revealed that individuals with ADHD show less activation in regions of the brain that are associated with executive functions such as inhibitory control (Hart, Radua, Nakao, Mataix-Cols, & Rubia, 2013). Several environmental factors contributing risk towards the development of ADHD have emerged. As with genetic risk factors, these environmental exposures are not specific to ADHD, but may contribute to the general risk of developmental pathology across clinical syndromes. In most children with ADHD, no environmental risk factors are identified.
ADHD is highly heritable in both children and in adults, with heritability estimated at 70–80% (Faraone et al., 2021; Faraone & Larsson, 2019; Larsson, Chang, D’Onofrio, & Lichtenstein, 2014; Levy, Hay, McStephen, Wood, & Waldman, 1997). It has been considered as both a continuous trait that varies in the general population and as a discrete diagnostic category. A recent genome-wide association meta-analysis identified 12 independent genomic loci that increase susceptibility to ADHD (Demontis et al., 2019).
Notably, significant genetic correlations were observed between ADHD and 43 other phenotypes, including educational outcomes, major depressive disorder, smoking, obesity-related phenotypes and mortality (Demontis et al., 2019). These findings explain the well-recognised clinical phenomenon whereby individuals with a similar genetic risk burden (for example, full biological siblings) may present with different developmental or mental health disorders such as ADHD, intellectual disability, autism spectrum disorder, or mood disorders; a concept in developmental psychopathology known as multifinality. The molecular pathways by which genes confer risk for ADHD and related disorders are not yet known.
The clinical effectiveness of psychostimulants in treating ADHD has led to the hypothesis that disruption to dopamine and noradrenaline – particularly lowered synaptic levels – is a key to the pathophysiology of ADHD (Arnsten & Pliszka, 2011; Levy, 1991; Pliszka et al., 1996). For instance, methylphenidate, which is used to treat ADHD, raises extracellular levels of dopamine and noradrenaline (Gamo, Wang, & Arnsten, 2010). Amphetamine (another stimulant treatment) also raises levels of dopamine and noradrenaline, but also interacts with other neurochemicals including acetylcholine, serotonin, opioids and glutamate (Cortese, 2020). The non-stimulant medications atomoxetine also raises levels of both noradrenaline and dopamine in the prefrontal cortex (Gamo et al., 2010), whereas other non-stimulants such as clonidine or guanfacine act more specifically to affect noradrenaline levels (Cortese, 2020).
Support for disruption to monoamine signalling (noradrenaline and dopamine are monoamines) has also arisen from the neurochemistry of animal models of ADHD (Gainetdinov et al., 1999; Giros, Jaber, Jones, Wightman, & Caron, 1996; Rahi & Kumar, 2021; Russell, Allie, & Wiggins, 2000). Although molecular imaging studies focusing on transporter and receptor densities of the dopamine system in individuals with ADHD showed initial promise, subsequent studies have proven equivocal (Fusar-Poli, Rubia, Rossi, Sartori, & Balottin, 2012).
Neuropsychological studies show that ADHD is associated with difficulties with executive functions such as working memory, planning, sustained attention and inhibitory control, and maintaining consistent performance over time (Faraone et al., 2021). People with ADHD may also show a preference for smaller immediate rewards over larger delayed rewards and may display impulsive decision making. There is marked heterogeneity among people with ADHD in terms of neuropsychological performance; some people with ADHD may experience few difficulties across these domains whereas others may experience many more (Nigg, Willcutt, Doyle, & Sonuga-Barke, 2005). This neuropsychological heterogeneity likely reflects multiple pathways in the brain that are relevant to the aetiology of ADHD. Neuropsychological difficulties may impact people with ADHD across a broad range of settings, including educational and occupational settings, and may impact their ability to engage with treatment.
Large-scale brain imaging consortia, such as ENIGMA (http://enigma.ini.usc.edu), have significantly enhanced our understanding of the structural brain correlates of ADHD. Hoogman et al. (2017) performed a cross-sectional mega-analysis of subcortical structural brain differences between individuals with and without ADHD across ages. They reported smaller volumes of the nucleus accumbens, amygdala, caudate, hippocampus and putamen, and overall intracranial volumes, with effect sizes generally higher in children than adults (Hoogman et al., 2017). A subsequent analysis by the same group examined the structure of cortical areas and found lower surface area values for frontal, cingulate and temporal regions in children but not in adolescents or adults (Hoogman et al., 2019) (see also Faraone et al., 2021 for review). Further, using computational neuroanatomic techniques, Shaw et al. (2007) found a delay in cortical maturation, particularly in the prefrontal regions that play a critical role in the control of cognitive processes such as attention.
Studies of functional brain imaging are typically performed at rest or under cognitive challenge. Meta-analysis has revealed that individuals with ADHD show less activation in regions of the brain that are associated with inhibitory control, such as the inferior frontal cortex, supplementary motor areas and basal ganglia, as well as dorsolateral prefrontal, parietal and cerebellar areas important for attention, compared to those without ADHD (Hart et al., 2013).
In resting-state functional MRI the subject is not required to perform a task, but rather is asked to lie quietly in the MRI scanner, thus permitting ease of scanning across a wide-age range. Typically, investigators are interested in patterns of correlated activity across the brain. Such analyses have identified several distinct networks across the brain. One such network, known as the default mode network, is active during wakeful rest. It has been proposed that individuals with ADHD are less able to suppress default-mode activity that may break through to intrude during task-active scenarios, and may contribute to fluctuating performance and inattention (Kelly, Uddin, Biswal, Castellanos, & Milham, 2008), although recent studies have provided conflicting evidence of this (Cortese, Aoki, Itahashi, Castellanos, & Eickhoff, 2021; Sutcubasi et al., 2020). Although brain imaging offers the potential to reveal novel biological insights, the reliability of findings on ADHD is compromised by heterogeneity within and between studies and the effects of age and medication history.
Environmental risk factors
Several environmental factors that may contribute towards the risk of developing ADHD have emerged. These were recently comprehensively reviewed in the World Federation of ADHD International Consensus Statement (Faraone et al., 2021) and include exposure to toxicants such as lead, phthalate, organophosphate pesticides, long-term maternal use of paracetamol during pregnancy, and prenatal exposure to the anti-epileptic drug valproate. Prenatal exposure to maternal smoking has also been linked to an increased incidence of ADHD, but this effect is significantly diminished when adjusting for family history of ADHD, suggesting a link to an underlying genetic predisposition rather than a pure environmental risk per se (Faraone et al., 2021).
Research has focused on prenatal and birth complication events as potential risk factors for ADHD. Marked preterm birth (gestational age less than 32 weeks) and very low birth weight (birth weight less than 1.5 kg) have emerged as risk factors for ADHD from meta-analyses of large datasets. Maternal obesity, hypertension, preeclampsia, and hypothyroidism during pregnancy have also been associated with an increased risk of ADHD in offspring (Faraone et al., 2021).
A number of large-scale studies and meta-analyses of cohort studies have linked the risk for ADHD to nutrient deficiencies (Faraone et al., 2021). These include lower overall blood levels of ferritin, and omega-3 polyunsaturated fatty acids in individuals with ADHD, compared with non-ADHD controls and the association of lower maternal vitamin D levels with increased risk of ADHD in offspring (Faraone et al., 2021).
There is also a range of situational/environmental factors that can substantially increase the risk for the development of ADHD. These factors include intrauterine exposure to maternal stress (for example, death of a close relative during pregnancy), trauma (for example, sexual abuse), physical neglect (particularly for ADHD inattentive type), and psychosocial adversity (lowered family income, out-of-home care, paternal criminality, or maternal mental disorder) (Faraone et al., 2021). As with genetic risk factors, these environmental exposures are not specific to ADHD. Rather they may contribute to the general risk of developmental pathology across clinical syndromes.
Gene-environment interactions are also important to consider. Relevant parental characteristics such as smoking and parenting style are likely influenced by genetic factors (Rutter, 2005). Furthermore, these risks may be epigenetically transmitted across generations (Nigg, 2018). Cross-disciplinary research integrating genetic, neurobiological, environmental, and social data is needed to further advance our understanding of the aetiological pathways leading to ADHD.