Review article
The neurobiology and genetics of Attention-Deficit/Hyperactivity Disorder (ADHD): What every clinician should know

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Abstract

This review, addressed mainly to clinicians, considers commonly asked questions related to the neuroimaging, neurophysiology, neurochemistry and genetics of Attention-Deficit/Hyperactivity Disorder (ADHD). It provides answers based on the most recent meta-analyses and systematic reviews, as well as additional relevant original studies. Empirical findings from neurobiological research into ADHD reflect a shift in the conceptualisation of this disorder from simple theoretical views of a few isolated dysfunctions to more complex models integrating the heterogeneity of the clinical manifestations of ADHD. Thus, findings from structural and functional neuroimaging suggest the involvement of developmentally abnormal brain networks related to cognition, attention, emotion and sensorimotor functions. Brain functioning alterations are confirmed by neurophysiological findings, showing that individuals with ADHD have elevated theta/beta power ratios, and less pronounced responses and longer latencies of event-related potentials, compared with controls. At a molecular level, alterations in any single neurotransmitter system are unlikely to explain the complexity of ADHD; rather, the disorder has been linked to dysfunctions in several systems, including the dopaminergic, adrenergic, serotoninergic and cholinergic pathways. Genetic studies showing a heritability of ∼60–75% suggest that a plethora of genes, each one with a small but significant effect, interact with environmental factors to increase the susceptibility to ADHD. Currently, findings from neurobiological research do not have a direct application in daily clinical practice, but it is hoped that in the near future they will complement the diagnostic process and contribute to the long-term effective treatment of this impairing condition.

Introduction

Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent childhood-onset neuropsychiatric condition, with an estimated worldwide-pooled prevalence of ∼5% in school-age children.1 According to the current criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text-revision (DSM-IV-TR), ADHD is defined by a persistent and age-inappropriate pattern of inattention, hyperactivity-impulsivity or both.2 The tenth edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10)3 includes the category of “Hyperkinetic disorder”, which requires both symptoms of inattention and hyperactivity/impulsivity and, therefore, is roughly equivalent to “ADHD combined type” defined by the DSM-IV (TR). ADHD is frequently comorbid with other neuropsychiatric and neurodevelopmental disorders, including oppositional defiant disorder, conduct disorder, anxiety and depressive disorders, developmental coordination disorder, sleep disorders, learning difficulties and substance abuse disorder.4, 5

Despite ADHD possibly being the most studied condition in child psychiatry worldwide,6 the exact causes and the mechanisms underlying this disorder are not yet completely understood. Excessive overactivity, restlessness, distractibility and short attention span were first included in the category “Hyperkinetic reaction of childhood (or adolescence)” of the DSM-II7 (published in 1968), thus suggesting that this behavioural disturbance was a reaction to the child’s environment. However, the accumulating evidence from twin and adoption studies in the past 20 years supports a genetic contribution to ADHD, and shows that environmental factors interact with a genetic vulnerability, leading to manifest neurobiological correlates.8

This paper, addressed mainly to clinicians, considers commonly asked questions relating to the underlying neurobiology of ADHD, and provides evidence-based answers with reference to the most recent meta-analyses and systematic reviews. The question-and-answer format of this paper is intended to be a useful guide to the clinician and an updated complement to available reviews on the neurobiology of ADHD, which have been mainly scholarly and descriptive.9, 10, 11 Although the present article is not intended as a systematic review, in order to identify all pertinent published meta-analyses and systematic reviews, a comprehensive search of the following databases was conducted: MEDLINE®/PubMed®, Ovid (including PsycINFO®), Web of Science®, Embase and Embase Classic, CINAHL® and ERIC. The last search was performed on November 10th, 2011. Narrative reviews and original articles are also cited, where appropriate, in order to expand upon and update the findings of the meta-analyses and systematic reviews.

Four major research areas in the neurobiology of ADHD are considered: neuroimaging, neurophysiology, neurochemistry and genetics. The paper will focus mainly on findings in childhood. The key points of the present review are summarised in Table 1.

Section snippets

Neuroimaging

Several imaging techniques have been used to explore brain structure and function in individuals with ADHD. Given the ethical issues posed by the use of computed tomography (CT) or positron emission tomography (PET)/single photon emission CT (SPECT) in children, magnetic resonance imaging (MRI) has rapidly gained a prominent place in ADHD neuroimaging research. Accordingly, although several CT and PET/SPECT studies in individuals with ADHD have been published, particularly before the advent of

What are the underlying electroencephalography abnormalities in ADHD?

Several studies have performed power spectral analysis, i.e. measurement of the ‘power’ (wave amplitude squared) produced by brain waves alternating between 3.5 and 28.0 Hz, in children with ADHD. A meta-analysis of these studies has shown a predominance of power at 3.5–8.0 Hz (theta) in children with ADHD, compared with 13.0–30.0 Hz (beta) in healthy controls.54 Other systematic reviews (cited in Monastra55) indicate that ∼90% of patients diagnosed with ADHD exhibit elevated theta/beta power

What do we know about neurochemistry changes and how they relate to current ADHD pharmacotherapy?

Animal models suggest that the dopaminergic and adrenergic systems are involved in the pathophysiology of ADHD. For the adrenergic system, it has been found that the alpha 2-adrenergic receptors in the dorsolateral prefrontal cortex are involved in inhibitory control of locomotor activity, which is a prominent finding in ADHD.57 Regarding the dopaminergic system, although no animal model resembles the clinical situation of ADHD perfectly, the phenotypes of neonatal 6-hydroxy-dopamine (DA)

What do we currently know about the genetics of ADHD?

Early familial studies have shown that the risk of ADHD among parents and siblings of children who had ADHD is increased by between two- and eight-fold.64 However, familial studies cannot distinguish between the contribution of genetics and environmental effects in the aetiology of a disorder. Adoption and twin studies can help to separate, although not completely, genetic from environmental factors observed in family studies.65 Adoption studies have unequivocally found that biological

Do findings from different areas of research converge?

Table 2 provide a summary of the Anatomical, functional, neurophysiological, neurochemical and genetic correlates of ADHD. The reader may view this plethora of data from different areas and methods of research (neuroimaging, neurophysiology, genetics, neurochemistry, etc.) as mixed and somewhat inconsistent. In part, it is, mostly due to methodological issues and to the complexity and heterogeneity of the disorder, which is not captured by simple and linear aetiopathophysiological models, but

Acknowledgements

Dr Samuele Cortese M.D., Ph.D., takes full responsibility for the content of this review. Editorial assistance was provided by Jackie Bannister and James Reed of Fishawack Communications Ltd. and by Alyson Bexfield of Caudex Medical, funded by Shire.

Dr Cortese has received financial support to attend medical meetings from Eli Lilly and Company (2007–9) and Shire Pharmaceuticals (2009–10), and has been a co-investigator in studies sponsored by GlaxoSmithKline (2006), Eli Lilly and Company

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