Pattern Classification of Working Memory Networks Reveals Differential Effects of Methylphenidate, Atomoxetine, and Placebo in Healthy Volunteers

Neuropsychopharmacology (2011) 36, 1237–1247 & 2011 American College of Neuropsychopharmacology. All rights reserved 0893-133X/11 $32.00 www.neuropsychopharmacology.org Pattern Classification of Working Memory Networks Reveals Differential Effects of Methylphenidate, Atomoxetine, and Placebo in Healthy Volunteers Andre F Marquand*,1, Sara De Simoni1, Owen G O’Daly1, Steven CR Williams1, Janaina Mourão-Miranda1,2 and Mitul A Mehta1 1 Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, King’s College London, London, UK; 2Department of Computer Science, Centre for Computational Statistics and Machine Learning, University College London, London, UK Stimulant and non-stimulant drugs can reduce symptoms of attention deficit/hyperactivity disorder (ADHD). The stimulant drug methylphenidate (MPH) and the non-stimulant drug atomoxetine (ATX) are both widely used for ADHD treatment, but their differential effects on human brain function remain unclear. We combined event-related fMRI with multivariate pattern recognition to characterize the effects of MPH and ATX in healthy volunteers performing a rewarded working memory (WM) task. The effects of MPH and ATX on WM were strongly dependent on their behavioral context. During non-rewarded trials, only MPH could be discriminated from placebo (PLC), with MPH producing a similar activation pattern to reward. During rewarded trials both drugs produced the opposite effect to reward, that is, attenuating WM networks and enhancing task-related deactivations (TRDs) in regions consistent with the default mode network (DMN). The drugs could be directly discriminated during the delay component of rewarded trials: MPH produced greater activity in WM networks and ATX produced greater activity in the DMN. Our data provide evidence that: (1) MPH and ATX have prominent effects during rewarded WM in task-activated and -deactivated networks; (2) during the delay component of rewarded trials, MPH and ATX have opposing effects on activated and deactivated networks: MPH enhances TRDs more than ATX, whereas ATX attenuates WM networks more than MPH; and (3) MPH mimics reward during encoding. Thus, interactions between drug effects and motivational state are crucial in defining the effects of MPH and ATX. Neuropsychopharmacology (2011) 36, 1237–1247; doi:10.1038/npp.2011.9; published online 23 February 2011 Keywords: methylphenidate; atomoxetine; working memory; reward; pattern recognition INTRODUCTION Stimulant and non-stimulant medications that influence dopamine (DA) and noradrenaline (NA) neurotransmission can reduce symptoms of attention deficit/hyperactivity disorder (ADHD). The stimulant drug methylphenidate (MPH) has been shown to have consistently greater clinical efficacy than atomoxetine (ATX), a non-stimulant drug recently approved for the treatment of ADHD in the USA and Europe (Spencer et al, 1998; Michelson et al, 2001; Faraone et al, 2005; Kemner et al, 2005; Starr and Kemner, 2005; Newcorn et al, 2008). ATX nonetheless offers several potential advantages over MPH, including reduced abuse liability, reduced risk of motor side effects and as an alternative treatment for patients non-responsive to stimu*Correspondence: A Marquand, Department of Neuroimaging, Centre for Neuroimaging Sciences, Box P089, King’s College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK, Tel: + 44 203 228 3066, Fax: + 44 203 228 2116, E-mail: Received 14 October 2010; revised 6 January 2011; accepted 6 January 2011 lants (Newcorn et al, 2008). However, the mechanisms underlying their differences on human brain function are unclear. There is converging evidence that weakened prefrontal cortex (PFC) function underlies several of the hallmark deficits in ADHD (Arnsten, 2006). In particular, working memory (WM)Fthe ability to hold and manipulate information for future actionFis impaired in ADHD (Martinussen et al, 2005; Willcutt et al, 2005) and has been strongly linked to the activity of the catecholamines (DA and NA) within the PFC (Brozoski et al, 1979; Arnsten and Goldman-Rakic, 1985). WM performance is also known to be improved with MPH (Elliott et al, 1997; Bedard et al, 2004; Mehta et al, 2004), currently understood as resulting from an increased efficiency of frontoparietal WM regions shown using PET neuroimaging studies (Mehta et al, 2000; Schweitzer et al, 2004). Studies in experimental animals suggest that ATX has a similar ability to improve WM function (Gamo et al, 2010), via effects on prefrontal cortical activity, although there are no comparative human neuroimaging studies of the effects of MPH and ATX on WM networks. fMRI patterns for methylphenidate and atomoxetine AF Marquand et al 1238 Previous studies in experimental animals have indicated that: (1) MPH inhibits both DA and NA transporters (DAT and NAT, respectively; Seeman and Madras, 1998; Han and Gu, 2006); (2) ATX is a selective inhibitor of NAT (Wong et al, 1982; Bolden-Watson and Richelson, 1993); and (3) both drugs increase concentrations of DA and NA in the PFC, but only MPH increases DA in the striatum (Bymaster et al, 2002). However, the neural consequences of these differential actions in human beings and their implications for functional brain networks are currently unknown. Theoretically, systemically administered MPH and ATX may differentially influence distributed brain regions due to localized effects at DAT and NAT sites (Ciliax et al, 1999; Schou et al, 2005) and consequent effects on connected brain areas, in addition to the differential effects on striatal catecholamine neurotransmission shown in rodents (Bymaster et al, 2002). Thus, differential effects of MPH and ATX may be distributed across multiple brain regions. Multivariate pattern recognition (PR) methods are sensitive to such spatially distributed information by making use of the correlation between brain voxels and afford substantially greater sensitivity than conventional mass-univariate analysis methods (Haynes and Rees, 2006; Kriegeskorte et al, 2006; Norman et al, 2006). Therefore, we combined event-related fMRI with a novel whole-brain PR analytic approach to characterize and discriminate acute effects of MPH and ATX in healthy volunteers performing a WM task. Although we expected reductions in PFC activity after MPH, this study represents the first attempt to: (1) examine the effects of ATX on WM networks and (2) test potential differences between prefrontal cortical and striatal activation following administration of MPH and ATX in humans. Finally, recent literature suggests an important contribution of reward to the regulation of WM-related brain activity (Ichihara-Takeda et al, 2010). This accords with evidence that both reward and MPH have similar effects on sustained attention task performance in ADHD (Trommer et al, 1991; Andreou et al, 2007). Therefore, we also explored the role of reward on WM function, with a focus on determining its im (...truncated)