Influence of methylphenidate on spatial attention asymmetry in adolescents with attention deficit hyperactivity disorder (ADHD): preliminary findings
Introduction
Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood neurodevelopmental conditions, affecting 7% of school-aged children (Graetz et al., 2001). Features include extreme levels of hyperactivity, impulsivity or inattention that are developmentally inappropriate. Although the search for an objective “attention deficit” in ADHD has been long and often fruitless (Huang-Pollock, Nigg, & Carr, 2005), accumulating evidence suggests lateralised impairments in the control of visuospatial attention may be a reliable attentional phenotype (Bellgrove et al., 2013, Bellgrove et al., 2009, Geeraerts et al., 2007, Ter Huurne et al., 2013, Waldie and Hausmann, 2010). Thus children with ADHD are slower and less accurate at detecting targets presented in the left, as compared to right, hemi-field and are slower and less accurate in responding to invalidly cued left, compared to right, targets (Bellgrove et al., 2013, Bellgrove et al., 2009, Ter Huurne et al., 2013). Although some preliminary evidence suggests that the indirect catecholamine agonist methylphenidate (MPH) may modulate spatial attention in ADHD (Bellgrove et al., 2008, Nigg et al., 1997, Sheppard et al., 1999), further placebo-controlled studies are needed. Here we used placebo-controlled, randomised trial methodology to ask whether 20 mg MPH could remediate left spatial inattention in adolescents with ADHD.
Multiple lines of evidence suggest that MPH may have utility in remediating lateralised attention deficits associated with ADHD. First, the pathological bias of spatial attention that arises from acquired damage to the right cerebral hemisphere (‘neglect syndrome’) can be reduced by treatment with both dopamine and noradrenaline agonists (Fleet et al., 1987, Gorgoraptis et al., 2012, Malhotra et al., 2006). The α-2-adrenoreceptor agonist clonidine, which at low doses acts presynaptically to decrease noradrenergic cell firing and noradrenaline release, asymmetrically modulates both response speed and brain activity in right superior parietal cortex during spatial reorienting (Coull, Nobre, & Frith, 2001). Second, experimental lesioning of the nigral dopamine projections in rodents induces “neglect” for the contralesional side of space (Iversen, 1984). Even in the intact rodent brain individual differences in orienting preferences are intimately linked to inter-hemispheric differences in striatal dopamine levels. For example, it is well established that rodents preferentially orient away from (or contralateral to) the hemisphere with elevated dopaminergic activity (Glick and Shapiro, 1985, Glick et al., 1986). Third, common DNA variation in the dopamine transporter gene (DAT1), encoding the principal molecular target for MPH, is associated with asymmetries of spatial attention in children with and without ADHD and in non-clinical adults (Bellgrove et al., 2008, Bellgrove et al., 2007, Bellgrove et al., 2005, Bellgrove et al., 2009, Newman et al., 2012). Fourth, MPH acts on areas of the brain that are important for directed attention, including the striatum and frontal and parietal cortices (Mehta et al., 2000, Rubia et al., 2009, Tomasi et al., 2011, Volkow et al., 1998). Although spatial asymmetries in children with ADHD have been shown to differ when “on” and “off” MPH (Sheppard et al., 1999), to our knowledge there is only one published placebo-controlled study (Nigg et al., 1997). That study employed a spatial cuing paradigm and reported a reaction time asymmetry under placebo conditions with responses to un-cued targets on the left slower than on the right. Treatment with MPH normalised this reaction time asymmetry.
It is now well established that right hemisphere dominant spatial attention systems can be modulated by a range of non-spatial factors including arousal, sustained attention and attentional capacity (Bellgrove et al., 2013, Malhotra et al., 2009, Robertson et al., 1997, Shapiro et al., 2002). Bellgrove et al. (2013) employed a task in which participants were required to detect peripheral targets while concurrently monitoring for targets presented at fixation within a rapid serial visual presentation (RSVP) stream. Attentional load at fixation was manipulated by requiring participants to either ignore the central RSVP stream (no-load), identify a pop-out target (low-load) or a target defined by a conjunction of features (high-load), across trial blocks. In non-clinical adults and children, attentional load at fixation led to a symmetric slowing of response times to peripheral targets, indicating the influence of non-spatial processing load on spatial target detection. In children with ADHD and in adult patients with acquired right-hemisphere damage, the imposition of load led to an asymmetric deterioration in response times, such that responses to left targets slowed more with load than responses to right targets. Similar data in patients with right-hemisphere lesions has been reported elsewhere (Bonato, Priftis, Marenzi, Umilta, & Zorzi, 2010).
The current study had two main objectives. First, we sought a conceptual replication of the findings of Bellgrove et al. (2013) by examining the effect of non-spatial processing load on peripheral target detection. To manipulate non-spatial load we used a variant of the task described by Schwartz et al. (2005) in which participants attended to coloured T-shapes presented within an RSVP stream at fixation, while also monitoring lateral locations for the occurrence of a target. In the low-load task, participants were required to detect any red shape whereas in the high load task targets were defined by a conjunction of colour and form (yellow upright T and green inverted T). ADHD adolescents participated as part of a placebo-controlled, randomised controlled trial of 20 mg MPH, and performed the task post-consumption of a gelatine capsule containing either MPH or lactose. Control participants performed the task on a single occasion post consumption of a gelatine capsule containing lactose. We compared the performance of the ADHD adolescents under placebo conditions to that of Controls. We hypothesised that increased load at fixation would lead to an asymmetric deterioration in response times in the ADHD adolescents but not Controls. Performance of the ADHD adolescents under MPH and placebo was compared in a within-subjects design. We hypothesised that the load-related asymmetry in response times to peripheral targets would be present under placebo but absent under MPH.
Section snippets
Participants
Seventeen male adolescents aged 12–18 years (mean=13.7±1.9 years) with ADHD-Combined Type (ADHD-CT), were identified in a specialised clinic based at the Royal Children׳s Hospital, Melbourne. ADHD (DSM-IV criteria) was defined through the following: (1) a semi-structured clinical interview with the child׳s parent(s). The Anxiety Disorders Interview Schedule for Children (A-DISC) is a semi-structured diagnostic interview schedule based on DSM-IV criteria for childhood anxiety disorders and a
Central task performance
A load (low versus high)×group (ADHD under placebo versus Control) analysis of central task accuracy (% correct) showed accuracy was reduced under high load [F(1, 23)=102.7, p<.001] across groups (see Table 2). Controls had significantly higher accuracy than the ADHD group [F(1, 23)=8.35, p=.008], and there was no load by group interaction (p=.19).
A drug (MPH versus placebo)×load (low versus high) ANOVA assessing the effect of MPH on the central task performance (% correct) of adolescents with
Discussion
This study sought to investigate the influence of non-spatial attentional load at fixation on lateralised target detection in adolescents with ADHD compared to Controls. Further, we examined the influence of an acute dose of MPH, compared to placebo, on load-dependent peripheral target detection in children with ADHD. Increasing attentional load at fixation disproportionately impacted target detection in the left, but not right, hemi-field in children with ADHD but not in Controls. This
Acknowledgements
This work was supported by a Project Grant to MAB from the National Health and Medical Research Council of Australia (No. 569533), by the Victorian Government׳s Operational Infrastructure Support Program and by the Royal Children׳s Hospital staff and patients. TS was supported by a NHMRC Career Development Award.
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