Neurobiology of ADHD

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a prevalent and debilitating disorder diagnosed on the basis of persistent and developmentally-inappropriate levels of overactivity, inattention and impulsivity. The etiology and pathophysiology of ADHD is incompletely understood. There is evidence of a genetic basis for ADHD but it is likely to involve many genes of small individual effect. Differences in the dimensions of the frontal lobes, caudate nucleus, and cerebellar vermis have been demonstrated. Neuropsychological testing has revealed a number of well documented differences between children with and without ADHD. These occur in two main domains: executive function and motivation although neither of these is specific to ADHD. In view of the recent advances in the neurobiology of reinforcement, we concentrate in this review on altered reinforcement mechanisms. Among the motivational differences, many pieces of evidence indicate that an altered response to reinforcement may play a central role in the symptoms of ADHD. In particular, sensitivity to delay of reinforcement appears to be a reliable finding. We review neurobiological mechanisms of reinforcement and discuss how these may be altered in ADHD, with particular focus on the neurotransmitter dopamine and its actions at the cellular and systems level. We describe how dopamine cell firing activity is normally associated with reinforcing events, and transfers to earlier time-points in the behavioural sequence as reinforcement becomes more predictable. We discuss how a failure of this transfer may give rise to many symptoms of ADHD, and propose that methylphenidate might act to compensate for the proposed dopamine transfer deficit.

Introduction

Attention-deficit hyperactivity disorder (ADHD) is a prevalent and debilitating disorder diagnosed on the basis of persistent and developmentally-inappropriate levels of overactivity, inattention and impulsivity (American Psychiatric Association, 1994). At present there is no biomedical laboratory test for ADHD and the diagnosis is based on observation of certain behavioural symptoms. Lack of a demonstrable physical cause or causes for ADHD has led to some controversy in popular press, with media reports raising concerns about treating children with stimulant medications. However the effectiveness of drug treatment and the familial nature of the disorder have led many researchers to suspect an underlying neurobiological etiology.

The diagnostic criteria for ADHD given by DSM IV include descriptions of 9 symptoms in each of two domains (inattention and hyperactivity/impulsivity). Different subtypes are defined (Predominantly Inattentive, Predominantly Hyperactive Impulsive, Combined). Not all symptoms have to be present for the diagnosis to be made: it is sufficient to have 6 of 9 in either domain, or both domains in the case of combined-type. Enumerating the number of ways an individual can meet criteria illustrates the potential heterogeneity of the diagnosis: the number different combinations of 6 drawn from 9 is 504.

The heterogeneous nature of ADHD as a diagnostic category has several possible implications. These criteria are used clinically and provide the grouping criteria for studies. Lack of homogeneity in study populations has led some to conclude that a single unitary cause is unlikely. The diagnosis may encompass multiple disorders each with a different etiology, in which case more homogeneous subcategories may provide refined phenotypes. Alternatively, there may be a common underlying cause that is capable of manifesting in different forms.

Our aim in this review is to address how symptoms of ADHD might arise from putative pathophysiological mechanisms. A number of reviews that have tackled the neurobiology of ADHD have focused on imaging and genetics. Relatively little attention has been given to the neurotransmitter systems involved at the cellular pathophysiology and neural systems level. In this review we focus on this middle ground, intervening between the gene and symptom level. We acknowledge that the present state of knowledge is far from complete and does not permit a complete account. Nevertheless, we outline a theoretical framework based on the basic neurobiology of dopaminergic actions in the frontostriatal system, which may help to integrate across these different levels of organization. We extend a previous theoretical paper, in which we proposed that altered dopamine signalling underlies a number of ADHD symptoms. We here consider how genetic alterations associated with ADHD might underlie such altered dopamine signalling, with a particular focus on dopamine receptors and transporters, and review recent evidence from combined imaging and genetic studies that address the hypothesis. We conclude by using this framework to explain some of the symptoms of ADHD and to suggest possible mechanisms for the therapeutic actions of methylphenidate.