Pattern classification of working memory networks reveals differential effects of methylphenidate, atomoxetine, and placebo in healthy volunteers

Neuropsychopharmacology. 2011 May;36(6):1237-47. doi: 10.1038/npp.2011.9. Epub 2011 Feb 23.


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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Adult
  • Atomoxetine Hydrochloride
  • Central Nervous System Stimulants / pharmacology
  • Humans
  • Magnetic Resonance Imaging / methods
  • Male
  • Memory, Short-Term / classification
  • Memory, Short-Term / drug effects*
  • Memory, Short-Term / physiology
  • Methylphenidate / pharmacology*
  • Neuropsychological Tests / standards
  • Placebo Effect
  • Propylamines / pharmacology*
  • Reward
  • Task Performance and Analysis
  • Young Adult


  • Adrenergic Uptake Inhibitors
  • Central Nervous System Stimulants
  • Propylamines
  • Methylphenidate
  • Atomoxetine Hydrochloride