Biological Factors
Heritability. ADHD appears to have a strong genetic component, as seen through many conducted twin studies. These twin studies have provided a mean heritability estimate of 76% in children and adolescents (Faraone et al., 2005). The results of recent meta-analyses conducted on twin and adoption studies have also found that genetic factors accounted for 71% to 73% of the variance in the symptoms of inattention and hyperactivity, respectively (Purper-Ouakil et al., 2011).
Candidate genes. Candidate gene association studies select genes of interest based on the knowledge of the disorder and function of the gene (Purper-Ouakil et al., 2011). Pharmacological treatments for ADHD have suggested the role of dopamine (DA) and norepinephrine (NA) neurotransmitters. Thus, the candidate genes of interest are those that focus on such catecholinergic systems. The most consistent genes found to be biomarkers for the ADHD phenotype, have been the genes encoding for DA receptor D4 (DRD4), DA receptor D5 (DRD5), DA transporter (SLC6A3/DAT1), serotonin receptor 1B (HTR1B), serotonin transporter (SLC6A4/5HTT), and synaptosomal-associated protein 25 (SNAP-25) genes (Faraone et al., 2005). 13 ADHD Genome-Wide Association Studies have also identified cadherin13(CDH13) to play a role in ADHD. CDH13 has been reported to act negatively on regular nerve growth (Rivero et al., 2015). The involvement of this gene in ADHD is consistent with the imaging findings that suggest ADHD brains are slightly smaller than healthy counterparts (Hawi et al., 2015). DRD4 has also attracted a great deal of interest as a candidate gene. Studies have suggested an association between this gene and the behavior of novelty seeking that is seen in individuals with ADHD (Kirley et al., 2002). Moreover, an increased rate of copy number variants (CNV) has also been reported in the candidate genes of individuals with ADHD (Williams et al., 2010). The most widely confirmed copy number variant has been DRD4*7; the 7-repeat allele of the D4 dopamine receptor gene. This defective gene that causes deficiencies in the translation of the dopaminergic signal to the 2nd messenger system, has been found in 50%-60% of those with ADHD (Spencer et al., 2002), and mediates a dampened response to dopamine (Kirley et al., 2002). However, a recent meta-analysis concluded that this gene-phenotype relationship is moderated by race and varies greatly among ethnicities (Nikolaidis & Gray, 2010).
Neurogenetic disorders. ADHD-like characteristics are also common in neurological disorders caused by genetic abnormalities. These include patients with Tuberous Sclerosis, Neurofibromatosis I, Turner Syndrome, Williams syndrome, Velocardiofacial syndrome, Prader-Willy syndrome, and Fragile X syndrome. Although each may arise from multiple molecular bases, they give rise to common symptoms downstream as well as in the neural circuits (Curatolo et al., 2010). These disorders are distinct from ADHD, but studying the neurobiology and molecular bases, are likely to assist in defining ADHD etiology.
Disruption of Catecholamines. Evidence from the behaviour and biochemistry in animal models of ADHD, neuropharmacological studies, as well as neuroimaging studies of ADHD adults, have shown the dysregulation of catecholamine neurotransmission to play a primary role in the etiology of ADHD (Kirley et al., 2002).
Dopamine. Problems with dopamine uptake and metabolism has been predicted, as dopamine plays a key role in attentional, psychomotor, and rewarding behaviours that are abnormal in those with ADHD (Russell, Sagvolden, & Johansen, 2005). Dopamine has also been a neurotransmitter of particular interest as the dopamine transporter is the principal target for methylphenidate and other stimulants used to treat ADHD. Dopamine (DA) neurons play an important modulatory role in the brain as they make up much of the reward circuits. The neurons fire in response to unexpected reward, and decrease when a predicted reward is absent, thus acting to reinforce behaviour. It has been suggested that deficient reinforcement of appropriate behaviour or extinction of previously reinforced behaviour, may be responsible for the symptoms of ADHD such as delay aversion, impulsivity, inability to sustain attention, and hyperactivity in a familiar environment (Russell et al., 2005). In addition, dopamine transporter (DAT) knockout studies in animal models have shown results of hyperactivity and impaired attention, suggesting that the symptoms are caused by a deficit in the transporter. The knockout of the transporter increased levels of extracellular dopamine, yet the electrically stimulated release of dopamine was decreased, suggesting that the phasic release of dopamine is reduced and the dopaminergic system to be hypofunctional (Russell et al., 2005).
In a study conducted by Russell, V.A (2002) on Spontaneously Hypertensive Rats (SHR), the main animal models for the disorder, researchers found abnormalities in DA function. These anomalies included a reduced release of the neurotransmitter in the prefrontal cortex, nucleus accumbens and striatum, decreased DA turnover in the subthalamic nuclei, vental tegmental area and frontal cortex, and reduced DA vesicular storage (Russell, 2002). The decrease of dopamine modulation in the prefrontal cortical circuits may be associated with attention response deficiencies and impaired executive functioning (Russell et al., 2005). Studies conducted on adults with ADHD have also shown results of abnormally low dopamine accumulation in the PFC (Russell, 2002). In a subsequent study conducted on SHR rats, Leo et al. (2003) found that the DA transporter gene expression as well as the reuptake of DA, are significantly reduced in the SHR midbrain during the first month of postnatal development, causing increased extracellular levels of dopamine. This suggests that the development of ADHD symptoms could be the result of the inappropriately increased levels of dopamine in early development, as they cause compensatory changes that give rise to hypofunctional dopamine neurons and impaired reinforcement mechanisms (Russell et al., 2005).
Norepinephrine. In addition to the dopaminergic hypothesis, noradrenergic (NA) neurons have also been predicted to be poorly regulated in the prefrontal regions of those with ADHD. NA neurons assist in attentiveness by increasing responses to relevant stimuli, while reducing responses to irrelevant stimuli (Pilszka, 2005). Norepinephrine works to enhance this signal-to-noise ratio. These functions are disturbed in ADHD as norepinephrine concentrations are altered in several areas of the brain including the substantia nigra, PFC, and locus coeruleus. The locus coeruleus (LC) plays an important role in attention, arousal and vigilance. The NA neurons that project from the LC to the prefrontal cortex, release norepinephrine and modulate the neural circuits that are responsible for selective and sustained attention. Both low and high activity in the LC correlates with impaired vigiliance (Russell et al., 2005).
Studies conducted on SHR rats have shown that autoreceptor-mediated feedback inhibition of norepinephrine release was deficient and less effective in SHR. When stimulated for NE release, norepinephrine concentrations were higher in the LC of SHR rats than in the wildtype. This increased release could give rise to a high extracellular concentration of NE in the LC, explaining the compensatory increase in reuptake of NE and down regulation of β-adrenoreceptors seen in the frontal cortex of SHR mice. The activation of β-adrenoreceptors by NE works to alter the strength of neural circuits to reinforce or eliminate behaviour; thus, the resulting decreased activation in ADHD can account for the deficit in adaptive changes (Russell et al., 2005). Likewise, the increased basal activity of the NA neurons in the locus coeruleus may decrease the response in the prefrontal cortex. Treatments that reduce LC activity have been predicted to improve attentional and cognitive processes (Bymaster et al., 2002).
Current pharmacological treatments such as the antagonist for NE transporter (NET1), atomoxetine, has proven to be an effective method of treating ADHD by increasing the synaptic availability of norepinephrine (Bymaster et al., 2002). This further emphasizes the role of the NA system in ADHD.
Neuropsychological endophenotypes. Endophenotypes for ADHD are heritable traits in patients that are likely linked to the genetic etiology of the disorder. Cognitive deficits have consistently been identified as a potential marker for the neural dysfunctions in the disorder. Executive functioning deficits such executive control (i.e. response inhibition, working memory), variable response speed, delayed aversion, and variability in motor timing, have all been implicated in patients with ADHD (Purper-Ouakil et al., 2011). Twin studies have shown unaffected co-twins to display similar deficits even after controlling for subclinical cases, suggesting that these variables meet the criteria for neuropsychological endophenotypes (Bidwell et al., 2007).
Sustained attention. Sustained attention refers to the ability to endogenously maintain an alert state in the absence of any exogenous cues, and is one of the most commonly observed symptoms in those with ADHD. The ability requires multiple executive functions including response inhibition, in order to prioritize sensory inputs for further processing (Bellgrove et al., 2006). Functional imaging studies as well as studies in right frontal lesion patients, have shown a right frontal focus in sustained attention processes. Activity in this network is strongly mediated by NA (Bellgrove et al., 2006). Sustained attention has been studied in patients via the administration of the Sustained Attention Response Task (SART), as performance on the SART correlates highly with everyday lapses in attention seen in those with ADHD. Results found that ADHD patients as well as their unaffected siblings were both impaired on this sustained attention test, providing evidence for a genetic basis and sustained attention as a neuropsychological endophenotype (Bellgrove et al., 2006). Bellgrove and colleagues (2006) further tested for this genetic basis by looking at the gene for Dopamine Beta Hydroxylase (DBH), the enzyme responsible for converting dopamine to noradrenaline. They compared the performance on the SART depending on whether ADHD children carried risk mutations in the DBH gene or not. Results showed increased deficits in sustained attention when carrying two high-risk DBH mutations compared to the wild-type. This suggests the role of DBH in ADHD patients (Bellgrove et al., 2006).
Spatial selective attention. Spatial selective attention allows individuals to enhance the processing of sensory events at certain locations in space. There have long been observations that children with ADHD are also impaired in directing their attention to left space. Studies have shown that those who did poorly on sustained attention tasks (i.e. SART), also showed left-sided inattention, suggesting that the orienting bias in the right hemisphere is impaired. The attenuated leftward bias has also been seen in unaffected family members of those with ADHD, suggesting a genetic link (Bellgrove et al., 2009). It has been argued that ADHD may act as the neurodevelopmental form of neglect syndrome. The role of dopamine has been suggested as a causal link, because deficits in spatial orienting seen in patients with Parkinson’s disease are associated with dopamine loss in the right striatum, and the right sided bias seen in ADHD children was resolved with dopamine agonists and stimulants such as MPH (Bellgrove et al., 2009). To further study this neurobiological and genetic link, Bellgrove et al. (2009) investigated the hypothesis that the observed unilateral spatial neglect in ADHD, might be influenced by the role of the dopamine transporter (DAT1) genotype. The results found that ADHD children carrying risk variants of the DAT1 gene, displayed atypical allocation of attention to the right and a pronounced reorienting deficit for targets in left space (Bellgrove et al., 2009).
Interaction of spatial and non-spatial attention. Non-spatial processes such as sustained attention and attentional load, appear to influence spatial selective attention. Patients with right hemisphere lesions that experience consequent neglect syndrome, also showed impairments in sustained attention. In a study conducted by Bellgrove and colleagues (2013), they found attentional load to affect spatial attention in both those with right hemisphere lesions as well as children with ADHD. Both groups were slower to respond to left targets under high attentional load. This, along with numerous structural, functional and molecular imaging studies, suggest abnormalities in fronto-parietal and fronto-striatal circuits of the right hemisphere in those with ADHD (Bellgrove et al., 2013). In further studies, it was seen that treatment with stimulants such as MPH, served to eliminate this load-related spatial symmetry (Silk et al., 2014).
Environmental Factors
Prenatal factors. Prenatal alcohol exposure has been associated with ADHD diagnosis. It has been known to induce brain structure anomalies, especially seen in the cerebellum. These children are likely to become hyperactive, impulsive, and disruptive (Coffin et al., 2005). Maternal smoking has also been related to the disorder. Its effect on nicotinic receptors modulates dopaminergic activity, resulting in the pathophysiology of ADHD (Kotimaa et al., 2003).
Perinatal factors. Poor attention and hyperactivity are well-defined behavioural correlates of prematurity and low birth weight (Van Mil et al., 2015). It has been found that low birth weight increases the risk of developing the disorder by 2-3 fold, and mediates the severity of ADHD symptoms (Curatolo et al., 2010)
Postnatal factors. Postnatal factors include malnutrition and dietary deficiencies. A link between the imbalance of fatty acids and ADHD has been suggested, but further evidence is needed. Similarly, the role of iron deficiency has been proposed (Curatolo et al., 2010). Other postnatal environmental influences related to ADHD include neonatal anoxia and brain injury. Additionally, psychosocial adversity such as familial issues (i.e. inconsistent parenting) and early social deprivation have also been linked to the disorder (Purper-Ouakil et al., 2011).
Brain Phenotypes in ADHD
Neuroimaging. Brain imaging studies have predicted a dysfunction in the frontostriatal pathways in ADHD; the areas of the neural circuits that underlie motor control, executive functions, and inhibition of behaviours.
Through 21 structural imaging studies (MRI), researchers have found that those with ADHD show reductions in volume in the PFC, basal ganglia, dorsal anterior cingulate cortex, corpus callosum, and cerebellum (Emond et al., 2009). Interestingly, the extent of normalization or progressive deterioration of volume, mediates the severity of ADHD symptoms (Giedd & Rapoport, 2010). Longitudinal studies have also shown developmental delays in brain maturation; cortical thickness was hindered especially in regions of the middle prefrontal cortex (Giedd & Rapoport, 2010), along with a 3-year delay in grey matter peaks seen in ADHD patients when compared to healthy controls (Shaw et al., 2006). The delays in the PFC are consistent with the deficits seen in cognitive processes such as inattention and lack of motor planning. White matter volumes are also implicated in this disorder. Silk et al. (2008) studied 15 young males with ADHD and found WM abnormalities in the regions underlying the inferior parietal, occipito-parietal, inferior frontal, and inferior temporal cortex; the regions that form a part of the WM pathways connecting the prefrontal and parieto-occipital areas with the striatum and cerebellum, further emphasizing the role of frontostriatal circuits in the disorder (Silk et al., 2008).
Studies of functional MRI in children and adolescents with ADHD have also shown decreased connectivity in a fronto-striato-parieto-cerebrellar circuit. The circuits that control attention in the PFC, such as working memory, alerting, and response inhibition, are much less active in individuals with ADHD than controls. These frontosubcortical systems are also rich in catecholamines, which provides further evidence for the noradrenergic and dopaminergic hypotheses of ADHD (Spencer et al., 2002). Bush and colleagues (2005) conducted a study measuring blood flow in the brain during response inhibition tasks, in individuals with ADHD. To measure response inhibition, they administered the Counting Stroop test. They found that ADHD patients took increased time to complete the tasks, and showed decreased activity in the dorsal anterior cingulate cortex when compared to controls. Instead of activating the cognitive division of the anterior cingulate cortex like their healthy counterparts, ADHD adults activated the fronto-striato-insula-thalamic network. This increased activation in diffuse brain regions provides evidence for a compensatory mechanism in those with ADHD (Bush et al., 2005). This is also seen in studies with children with ADHD. Functional imaging shows decreased activation in the IFG, caudate nucleus, and basal ganglia providing evidence for a developmental delay in frontostriatal circuity; but also increased activity in the right inferior parietal area and posterior cingulate gyrus implying that ADHD children need to recruit a more diffuse network of brain areas in order to perform a task (Tong, Hawi, & Bellgrove, 2017).
Neurocognitive models of ADHD. The dual pathway model of ADHD, suggests that inattention and deficits in executive functioning are directly associated with impairments in the prefrontal-striatal circuits, while hyperactivity is linked with the dysfunction of reward systems in the frontal-limbic systems. The model recognizes that single disorders can have multiple causal pathways, each mediated by different psycho-patho-physiological processes. Dopamine is a key regulator in both pathways of the model, however each circuit is influenced by different branches of the dopamine system. The executive circuit is modulated by meso-cortical and nigro-striatal branches, while the reward circuit is primary modulated by the meso-limbic branch of the dopamine system, which projects from the VTA to nucleus accumbens (Sonuga-Barke, 2003).
Another model of ADHD suggests that symptoms arise due to poor adjustment of behaviour to environmental cues. These impairments arise from bottom-up processes such as the deficient signaling of the PFC by subcortical and posterior systems. Individuals with ADHD are unable to detect discrepancies between current and expected contexts leading to inappropriate behaviours (Purper-Ouakil et al., 2011).
Treatments
Pharmacological treatments and neurobiology. Pharmacological treatments of ADHD all share a common focus on the regulation of catecholamines in the prefrontal cortex, as anomalies in these levels influence behaviours such as poor attention, impulsivity, and hyperactivity. Simulant medications such as methylphenidate (MPH), appear to be the pharmacological treatment of choice. In general, they act on dopamine (DAT) and norepinephrine (NET) transporters. Treatment with MPH causes an increase in DA signalling via multiple methods; inhibiting the reuptake of dopamine by blocking the dopamine transporter, inhibiting the dopamine D2 receptor, and amplifying the DA tone. MPH can also work to inhibit the reuptake of norepinephrine (Curatolo et al., 2010). Specifically, MPH targets the striatum where DAT density is high, and binds to neuronal DAT to increase the DA concentration in the synaptic cleft. MPH also effects the vesicular monoamine transporter 2 (VMAT-2). VMAT-2 in the CNS uptakes cytoplasmic DA into synaptic vesicles to avoid oxidative deamination. MPH acts on the VMAT-2 by redistributing it into the cytoplasm which promotes the uptake of DA into the vesicles and increases the content available to vesicular release (Loureiro-Vieira et al., 2017). Amphetamine is also another stimulant used to treat ADHD. It binds to DAT, NET, and 5-HTT causing an increase in the neurotransmitters in the synaptic cleft. Although it acts on all three transporters, its main mechanism for action is on DAT. In contrast to MPH, AMPH acts as a substrate on DAT and results in a major increase of dopamine from the presynaptic terminal. AMPH also has an affinity for VMAT-2, which promotes DA and 5-HT release from the storage vesicles, making them readily available for reverse transport into the synaptic cleft (Loureiro-Vieira et al., 2017).
Non-stimulants such as atomoxetine (ATX) are also commonly used to treat ADHD. ATX is a selective NET inhibitor, serving to increase NE levels in the synaptic cleft (Bymaster et al., 2002). α2 agonists can also be used as treatment for ADHD. NE has a high affinity for this receptor, and it has been hypothesized that this adrenergic receptor is defective in the PFC of those with ADHD. Thus, treating patients with α2 agonists such as clonidine and guanfacine can mimic NE actions on the receptor and control deviant behaviours (Arnsten, 2010).
Limitations and need for new treatments. While pharmacological and behavioural treatments have both been shown to greatly benefit ADHD patients, the effects are transient and do not appear to be long-lasting. Even extended-release medications only serve to alleviate symptoms and benefit the individual for 8-to-12 hours. Additional strategies must be implemented to be beneficial for longer periods. Although pharmacological treatments appear to prepare the brain for learning, further research should be done on treatments that can facilitate compensatory changes in the brain (Curatolo et al., 2010). In addition, there is considerable inter-individual variability on the efficacy of the various pharmacological treatments (Loureiro-Vieira et al., 2017). As stimulants and non-stimulants have distinct neural effects, it is reasonable that children may respond preferentially to one, yet the moderator of these differences is not well-defined. An interesting study conducted by Bellgrove et al. (2008), hypothesized that the existence of left spatial inattention in ADHD, predicted stimulant response. It was found that attentional asymmetry predicted an enhanced therapeutic response to MPH. Those that experienced spatial selective attention prior to any ADHD treatment, found their symptoms to be more normalized with MPH after 6 weeks than those without this inattention. This is consistent with the assumption that dopaminergic neurons play an important role in spatial selective attention (Bellgrove, 2008).
Limitations in research
Although there have been significant advances in the understanding of ADHD, the exact cause and neurological bases of the disorder are not still not precise and there are many limitations and assumptions made in the research conducted. The main symptoms of ADHD are described to be hyperactivity, distractibility, and impulsivity. However, this can be observed in virtually all children in certain parts of their lives, as there are likely to be many environmental contexts that contribute to these characteristics. How can we define ADHD precisely if the diagnosis is based on three global types of behaviour? As a result, the definition and diagnosis of ADHD is still highly unstable and subjective on the decisions of psychological professionals.
This has also resulted in apparent differences in prevalence between world regions. Likewise, European countries are more likely to use the ICD-10 criteria, while North American countries use the DSM-5. Using the DSM-5 as the diagnostic criteria increases the diagnosis of ADHD by 3 to 4 fold (Singh, 2008). Additionally, much of the research conducted have largely overlooked the female sex. There are many discrepancies in the way ADHD symptoms manifest in girls; the externalized symptoms seen in boys such as running and impulsivity, vary from the internalized symptoms such as inattention and mind-wandering that are seen in girls with the disorder. There also appear to be neurological differences between the sexes as there are apparent inconsistencies in MPH metabolism (Loureiro-Vieira et al., 2017). Thus, it would seem logical that conducting research directed at both sexes is imperative, as this lack of investigation can often lead to the disorder being over diagnosed in males, and left untreated among females.
Moreover, much of the research done on the implicated neural circuits is retrospective. For example, many studies have looked at the results of pharmacological treatments, and then worked retrospectively to formulate the hypothesis that deficient dopamine neurotransmission or certain brain regions are involved in ADHD. Although these studies are not suggesting a direct causal link, this limitation should be considered. Generating a post-hoc hypothesis can often lead to false positives.
Conclusion
ADHD is a prevalent and chronically impairing condition, hence understanding the neurobiology behind the disorder is imperative to optimize treatment outcome. Many novel studies have suggested biological bases such as the dysregulation of catecholamines, as well as structural and functional neural anomalies such as delays in cortical maturation and impaired fronto-subcortical pathways. Additionally, neuropsychological endophenotypes such as sustained attention and unilateral spatial neglect have suggested the roles of candidate genes such as DBH and DAT1 to be linked to the etiology of the disorder. If left untreated, individuals with ADHD are likely to participate in at-risk behaviours such as substance abuse, as well as social maladjustment, immaturity, lower educational and occupational achievement, and high rates of separation and divorce (Spencer et al., 2007). Thus, it is essential that the diagnosis of disorder is well defined and that the management plans account for inter-individual variances in treatment response. Currently, pharmacological treatments with stimulants such and methylphenidate and non-stimulants such as atomoxetine are used widely used and effective as treatments for ADHD symptoms and target the dysregulated neurotransmitters. However, these are not long lasting solutions and further investigation on improved treatments must be continued.