Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naïve children with ADHD during a rewarded continuous performance task
Introduction
Attention Deficit Hyperactivity Disorder (ADHD) develops in childhood and is characterized by behavioral features of age-inappropriate inattention, impulsiveness and hyperactivity (DSM-IV). ADHD has consistently been associated with neuropsychological deficits in tasks of vigilance and sustained attention, in particular in the Continuous Performance task (CPT) (Rubia et al., 2001, Rubia et al., 2007, Willcutt et al., 2005) as well of motivation and reward (Luman et al., 2005). Surprisingly, however, relatively few fMRI studies have investigated the neural correlates of vigilance or reward in children with ADHD. The few published studies found abnormalities in bilateral inferior prefrontal cortex and cerebellum during a CPT (Rubia et al., 2009c) and under-functioning in the posterior cingulate and in ventral striatum in the context of reward (Rubia et al., 2009c, Scheres et al., 2007). Also, despite evidence for reduced fronto-striatal and fronto-parietal functional connectivity in children with ADHD during the resting state (Kelly et al., 2007), and in adult ADHD during a cognitive task (Wolf et al., 2009), no studies have tested for functional connectivity deficits during cognitive task performance in children with ADHD.
The psychostimulant Methylphenidate (MPH) is the most effective, first choice treatment for ADHD that ameliorates the behavioural symptoms in 70% of children with ADHD (Arnsten, 2006, Wilens, 2008). However, little is known on its mechanisms of action. MPH is a catecholamine reuptake inhibitor with stronger dopamine agonist effects in the basal ganglia, and both dopamine and noradrenalin agonist effects in cortical brain regions (Arnsten, 2006). The behavioural and cognitive features of ADHD are thought to be mediated at least in part by a dopamine dysfunction; there is consistent evidence in adults with ADHD for elevated dopamine transporter levels and reduced DA availability in striatal regions (Krause, 2008, Wilens, 2008). Poor performance in the CPT such as enhanced omission and commission errors has been shown to be improved with an acute dose of MPH in children with ADHD (Konrad et al., 2004, Riccio et al., 2001, Solanto et al., 1997, Sykes et al., 1972), although some studies have found improvements in omission or commission errors only (Riccio et al., 2001, Rosa-Neto et al., 2005, Johnson et al., 2008).
Relatively few fMRI studies have investigated the effects of MPH on neuro-cognitive performance in children with ADHD. These studies were conducted in ADHD children with a medication history and showed that MPH enhances the activation of the caudate (Shafritz et al., 2004, Vaidya et al., 1998) and frontal lobes (Vaidya et al., 1998) during tasks of cognitive control. Given evidence for long-term effects of chronic MPH treatment on brain structure and function (Konrad et al., 2006, Shaw et al., 2009), however, it is crucial to investigate the acute effects of MPH on brain function in medication-naïve children with ADHD.
No fMRI studies, furthermore, have investigated the effects of MPH on the CPT, one of the most compromised cognitive tests in ADHD, or on the effects of monetary incentives upon this function. MPH is known to enhance the salience of stimuli and to have motivational effects on cognitive performance (Volkow et al., 2004). Furthermore, a positron emission tomography study showed that in patients with ADHD, baseline scores of task performance on the CPT (omission, commission, reaction times and variability) correlated with MPH evoked change in D2 and D3 receptor availability, suggesting that performance on the CPT is mediated by DA and that MPH effects are most pronounced in the more inattentive and impulsive subjects. Similarly, motivational states such as those induced by reward are known to enhance arousal and to potentiate selective attention processes (Lang et al., 1990, Rothermund et al., 2001). fMRI studies show that this is because reward upregulates brain regions that mediate selective attention such as ventrolateral prefrontal, parietal and posterior cingulate cortices (Mohanty et al., 2008, Small et al., 2005). Recent developmental theorists have proposed the distinction between “cool” cognitive executive functions such as attention and inhibition that are known to be mediated by lateral fronto-striatal and fronto-parietal networks and “hot” executive functions that involve incentives and motivation and are mediated by the orbitofrontal cortex and limbic brain structures (Zelazo and Muller, 2002). We therefore thought it important to investigate the effects of MPH not only on the neural substrates of “cool” cognitive functions that are impaired in children with ADHD, but also on “hot” limbic reward systems that mediate motivation and feed back into attention systems (Lang et al., 1990, Mohanty et al., 2008). Furthermore, despite evidence for dopamine agonists to modulate fronto-striatal inter-connectivity (Honey et al., 2004), to our knowledge, no study has investigated the effects of Methylphenidate on functional inter-connectivity in children or adults with ADHD.
We used fMRI to investigate the effects of MPH in 13 medication-naïve children with ADHD on brain activation and on task-relevant functional inter-connectivity in a double-blind, randomised, placebo-controlled study while they performed a CPT with and without reward. The rewarded CPT modification should therefore investigate the effects of MPH on “cool” cognitive/attention and “hot” motivation networks in ADHD children. Furthermore, to test for potential normalisation effects of MPH on expected deficits in children with ADHD in both brain activation and inter-regional connectivity when compared to healthy controls, we compared brain activation in ADHD children under either treatment conditions with that of healthy age-matched comparison children.
We hypothesised that under placebo, we would replicate our previous findings of inferior frontal underactivation in ADHD children & adolescents during CPT task performance (Rubia et al., 2009c) and of posterior cingulate and limbic abnormalities in response to reward (Rubia et al., 2009c, Scheres et al., 2007). We furthermore hypothesised that children with ADHD compared to controls would show reduced functional inter-connectivity between inferior frontal, striatal and parietal brain regions during the vigilant attention condition. For the MPH effects, we hypothesised that during the attention condition, MPH within children with ADHD would increase activation and functional inter-connectivity in fronto-striato-parietal attention areas and therefore ameliorate/normalise activation and functional connectivity differences between controls and children with ADHD in these brain regions. For the reward condition, we hypothesised that MPH would normalise/ameliorate dysfunctions in limbic or paralimbic brain regions that mediate motivation.
Section snippets
Subjects
Thirteen male right-handed adolescent boys in the age range of 10–15 years (mean age (in years (yrs), months (ms)) = 12 yrs, 6 ms, SD = 1 year, 4 ms) who met clinical diagnostic criteria for the combined, inattentive-hyperactive subtype ADHD (DSM-IV), were recruited through clinics. Clinical diagnosis of combined subtype of ADHD was established through interviews with an experienced child psychiatrist (A-M.M.) using the standardized Maudsley diagnostic interview (Goldberg and Murray, 2002) which
Effects of reward
ANOVA showed that there was no effect of reward on omission errors within each group (ADHD under placebo, under MPH and controls) or reward by group interactions (p > 0.05). Reward therefore did not affect performance in either patient group. Consequently, all subsequent analyses were conducted on omission errors to all trials.
Effects of MPH within children with ADHD
Within children with ADHD, repeated measures ANOVA showed no significant effects of MPH compared to placebo on omission (F (df = 1,12) = .8, p > 0.4) or commission errors (F (df
Discussion
MPH significantly normalised the performance deficits in omission errors that were observed in children with ADHD under placebo, compared to controls. The trend for higher commission errors in children with ADHD compared to controls remained after MPH, suggesting that the beneficial effects were more pronounced for inattention problems (reflected by omission errors) than impulsivity errors (reflected by commission errors).
During the vigilant attention condition, children with ADHD under placebo
Acknowledgements
This research was funded by grants from the Welcome Trust ((053272/Z/98/Z/JRS/JP/JAT) and the Medical Research Council (G9900839), UK. A.C. was supported by a fellowship from the Alicia Koplowitz foundation. None of the authors has any conflict of interest to declare.
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