A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment

Abstract

Through the combined use of 18F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case–control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder.

Non-diagnostic based approaches to helping children who could be labelled ADHD and their families

“…As ADHD is not a medical diagnosis it is not surprising that there has been a failure to find any specific and/or characteristic biological abnormality such as characteristic neuroanatomical, genetic or neurotransmitter abnormalities (Campo et al, 2013; Timimi & Timimi, 2015; Whitely, 2015). …”

The use of methylphenidate as a cognitive enhancer by health sciences students at a South African university: - a pilot study

“…Symptoms decline with age, but may persist into adulthood with a global prevalence of approximately 4% [3], necessitating extended pharmacological management with psychoactive agents [4]. Traditional psychoactive substances consist of central nervous system (CNS) stimulants (amphetamine derivatives and methylphenidate) and non-stimulant agents (atomoxetine).…”

Establishing a novel cognitive task in rats of relevance to schizophrenia

“…From the literature on human studies, it was predicted that response to amphetamine would be dependent on individual baseline accuracy (Mattay et al, 2000;Allman et al, 2010;del Campo et al, 2013). Therefore, analysis of performance sub-groups was conducted by median split into either low or high performing groups (n=20/group) based on signal trial performance (average accuracy on 0.12, 0.5, 1s) on the saline treatment day.…”

“…Few studies have correlated changes in drug response in individual animals with baseline performance despite the use of this measurement in human studies (del Campo et al, 2013;Cherkasova et al, 2014). This was highlighted by a recent study that reanalysed a series of studies for individual baseline dependency of drug effects (Bickel et al, 2016).…”

“…The growing interest in cognitive enhancing agents has led to controversial debates about the ethical use of psychostimulants in healthy individuals (Sahakian and Morein-Zamir, 2007;Greely et al, 2008;Ilieva et al, 2013;Allen and Strand, 2015). However in healthy control groups, the evidence suggests enhancement from stimulants may be dependent on baseline performance (Mattay et al, 2000;Allman et al, 2010;del Campo et al, 2013). Therefore, investigating the response to psychostimulants as a function of individual baseline performance should be incorporated into rodent studies, as a similar relationship should be expected (Levin et al, 2011).…”