Review articleThe neurobiology and genetics of Attention-Deficit/Hyperactivity Disorder (ADHD): What every clinician should know
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
References (96)
- et al.
Patterns and predictors of attention-deficit/hyperactivity disorder persistence into adulthood: results from the national comorbidity survey replication
Biol Psychiatry
(2005) - et al.
The neurobiology of attention deficit/hyperactivity disorder
Eur J Paediatr Neurol
(2009) - et al.
Neurobiology of ADHD
Neuropharmacology
(2009) - et al.
Structural MRI of pediatric brain development: what have we learned and where are we going?
Neuron
(2010) - et al.
Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder
Biol Psychiatry
(2007) - et al.
Behavioral performance predicts grey matter reductions in the right inferior frontal gyrus in young adults with combined type ADHD
Psychiatry Res
(2010) - et al.
Magnetic resonance imaging of boys with attention-deficit/hyperactivity disorder and their unaffected siblings
J Am Acad Child Adolesc Psychiatry
(2004) - et al.
Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder
Lancet
(2003) - et al.
Widespread cortical thinning is a robust anatomical marker for attention-deficit/hyperactivity disorder
J Am Acad Child Adolesc Psychiatry
(2009) - et al.
Attention-deficit/hyperactivity disorder: a preliminary diffusion tensor imaging study
Biol Psychiatry
(2005)
The macrostructural and microstructural abnormalities of corpus callosum in children with attention deficit/hyperactivity disorder: a combined morphometric and diffusion tensor MRI study
Brain Res
Structural and functional imaging approaches in attention deficit/hyperactivity disorder: does the temporal lobe play a key role?
Psychiatry Res
Diffusion tensor imaging study of white matter fiber tracts in pediatric bipolar disorder and attention-deficit/hyperactivity disorder
Biol Psychiatry
Differential fractional anisotropy abnormalities in adolescents with ADHD or schizophrenia
Psychiatry Res
Causal models of attention-deficit/hyperactivity disorder: from common simple deficits to multiple developmental pathways
Biol Psychiatry
Spontaneous attentional fluctuations in impaired states and pathological conditions: a neurobiological hypothesis
Neurosci Biobehav Rev
Reduced activation and inter-regional functional connectivity of fronto-striatal networks in adults with childhood attention-deficit hyperactivity disorder (ADHD) and persisting symptoms during tasks of motor inhibition and cognitive switching
J Psychiatr Res
Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naive children with ADHD during a rewarded continuous performance task
Neuropharmacology
Cingulate-precuneus interactions: a new locus of dysfunction in adult attention-deficit/hyperactivity disorder
Biol Psychiatry
Atypical default network connectivity in youth with attention-deficit/hyperactivity disorder
Biol Psychiatry
Methylphenidate normalizes frontocingulate underactivation during error processing in attention-deficit/hyperactivity disorder
Biol Psychiatry
Atomoxetine modulates right inferior frontal activation during inhibitory control: a pharmacological functional magnetic resonance imaging study
Biol Psychiatry
Locomotor hyperactivity induced by blockade of prefrontal cortical alpha2-adrenoceptors in monkeys
Biol Psychiatry
Animal models concerning the role of dopamine in attention-deficit hyperactivity disorder
Neurosci Biobehav Rev
Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder
J Am Acad Child Adolesc Psychiatry
Molecular genetics of attention-deficit/hyperactivity disorder
Biol Psychiatry
Twin studies and their implications for molecular genetic studies: endophenotypes integrate quantitative and molecular genetics in ADHD research
J Am Acad Child Adolesc Psychiatry
Molecular genetics of attention deficit hyperactivity disorder
Psychiatr Clin North Am
Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder
J Am Acad Child Adolesc Psychiatry
Measured gene-by-environment interaction in relation to attention-deficit/hyperactivity disorder
J Am Acad Child Adolesc Psychiatry
Neuroimaging of attention deficit hyperactivity disorder: can new imaging findings be integrated in clinical practice?
Child Adolesc Psychiatr Clin N Am
Comparison of a standard psychiatric evaluation to rating scales and EEG in the differential diagnosis of attention-deficit/hyperactivity disorder
Psychiatry Res
A post hoc subgroup analysis of an 18-day randomized controlled trial comparing the tolerability and efficacy of mixed amphetamine salts extended release and atomoxetine in school-age girls with attention-deficit/hyperactivity disorder
Clin Ther
The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety
Neuropharmacology
Dopamine transporter gene variation modulates activation of striatum in youth with ADHD
Neuroimage
The worldwide prevalence of ADHD: a systematic review and metaregression analysis
Am J Psychiatry
Diagnostic and statistical manual of mental disorders
The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines
Attention deficit disorder with developmental coordination disorders
Arch Dis Child
Attention deficit hyperactivity disorder: the most studied and yet the most controversial diagnosis
Ment Retard Dev Disabil Res Rev
Diagnostic and statistical manual of mental disorders
Molecular genetics of attention-deficit/hyperactivity disorder: an overview
Eur Child Adolesc Psychiatry
Neurobiology of attention deficit/hyperactivity disorder
Pediatr Res
Neuroimaging in attention-deficit hyperactivity disorder: beyond the frontostriatal circuitry
Can J Psychiatry
Structural brain change in attention deficit hyperactivity disorder identified by meta-analysis
BMC Psychiatry
Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication
Am J Psychiatry
New insights into attention-deficit/hyperactivity disorder using structural neuroimaging
Curr Psychiatry Rep
Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attention-deficit/hyperactivity disorder
Arch Gen Psychiatry
Cited by (212)
Enhancement of visual dominance effects at the response level in children with attention-deficit/hyperactivity disorder
2024, Journal of Experimental Child PsychologyUsing caffeine as a chemical means to induce flow states
2024, Neuroscience and Biobehavioral ReviewsLongitudinal Trajectories of White Matter Development in Attention-Deficit/Hyperactivity Disorder
2023, Biological Psychiatry: Cognitive Neuroscience and NeuroimagingBetter characterization of attention and hyperactivity/impulsivity in children with ADHD: The key to understanding the underlying white matter microstructure
2022, Psychiatry Research - NeuroimagingThe effects of neurofeedback training for children with cerebral palsy and co-occurring attention deficits: A pilot study
2024, Child: Care, Health and Development