Dissociable effects of methylphenidate, atomoxetine and placebo on regional cerebral blood flow in healthy volunteers at rest: A multi-class pattern recognition approach

Andre F Marquand,David C Alsop,Owen G O'Daly,Fernando O Zelaya,Steven C.R Williams,R Paul Maguire,Mitul A Mehta,Sara De Simoni

doi:10.1016/j.neuroimage.2012.01.058

Abstract

The stimulant drug methylphenidate (MPH) and the non-stimulant drug atomoxetine (ATX) are both widely used for the treatment of attention deficit/hyperactivity disorder (ADHD), but their differential effects on human brain function are poorly understood. PET and blood oxygen level dependent (BOLD) fMRI have been used to study the effects of MPH and BOLD fMRI is beginning to be used to delineate the effects of MPH and ATX in the context of cognitive tasks. The BOLD signal is a proxy for neuronal activity and is dependent on three physiological parameters: regional cerebral blood flow (rCBF), cerebral metabolic rate of oxygen and cerebral blood volume. To identify areas sensitive to MPH and ATX and assist interpretation of BOLD studies in healthy volunteers and ADHD patients, it is therefore of interest to characterize the effects of these drugs on rCBF. In this study, we used arterial spin labeling (ASL) MRI to measure rCBF non-invasively in healthy volunteers after administration of MPH, ATX or placebo. We employed multi-class pattern recognition (PR) to discriminate the neuronal effects of the drugs, which accurately discriminated all drug conditions from one another and provided activity patterns that precisely localized discriminating brain regions. We showed common and differential effects in cortical and subcortical brain regions. The clearest differential effects were observed in four regions: (i) in the caudate body where MPH but not ATX increased rCBF, (ii) in the midbrain/substantia nigra and (iii) thalamus where MPH increased and ATX decreased rCBF plus (iv) a large region of cerebellar cortex where ATX increased rCBF relative to MPH. Our results demonstrate that combining ASL and PR yields a sensitive method for detecting the effects of these drugs and provides insights into the regional distribution of brain networks potentially modulated by these compounds.

Highlights

Pharmacological agents that increase the extracellular concentration of the catecholamines noradrenaline (NA) and dopamine (DA) are commonly prescribed to relieve the symptoms of attentiondeficit hyperactivity disorder (ADHD)
The multiclass Sparse multinomial logistic regression (SMLR) classifier trained to discriminate between all drug conditions correctly classified 100.00% of MPH scans, 93.33% of ATX scans and 60.00% of PLC scans, leading to an overall accuracy of 84.44%, exceeding the 33.33% accuracy that would be predicted by chance (χ2 = 39.40, p = 2.78 × 10− 9)
We presented discriminative activity patterns for each drug relative to PLC and a pattern that directly discriminated between MPH and ATX, which collectively identified their differential effects across widespread brain regions

Summary

Introduction

Pharmacological agents that increase the extracellular concentration of the catecholamines noradrenaline (NA) and dopamine (DA) are commonly prescribed to relieve the symptoms of attentiondeficit hyperactivity disorder (ADHD). Methylphenidate (MPH) is a stimulant drug that is the treatment of choice in most cases the non-stimulant drug atomoxetine (ATX) is increasingly being used for ADHD treatment. MPH has a greater clinical efficacy than ATX (Faraone et al, 2005; Kemner et al, 2005; Michelson et al, 2001; Newcorn et al, 2008; Spencer et al, 1998; Starr and Kemner, 2005), but ATX offers several advantages over MPH. ATX provides an alternative treatment for patients who do not. ⁎ Corresponding author at: Department of Neuroimaging, Centre for Neuroimaging Sciences, Box P089, Institute of Psychiatry.

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