title: Neurofunctional effects of methylphenidate and atomoxetine in boys with attention-deficit/hyperactivity disorder during time discrimination.
abstract: BACKGROUND
  The catecholamine agonists methylphenidate and atomoxetine effectively treat attention-deficit/hyperactivity disorder (ADHD). Furthermore, dopamine agonists have shown to improve time estimation in ADHD, a core cognitive deficit. However, few have compared the effects of methylphenidate and atomoxetine on brain function in ADHD, and none during time estimation. Using single dose challenges, we investigated shared and drug-specific effects in ADHD adolescents on the neural substrates of time discrimination (TD).
  
  
  METHODS
  Twenty ADHD adolescent male subjects were compared in a randomized double-blind cross-over design after single doses of methylphenidate, atomoxetine, and placebo in functional magnetic resonance imaging during TD. Normalization effects were assessed by comparing brain activation under each drug condition with that of 20 healthy age-matched control subjects.
  
  
  RESULTS
  Relative to control subjects, patients under placebo showed TD deficits and reduced activation of ventrolateral prefrontal cortex (VLPFC)/insula, inferior frontal cortex, and supplementary motor area. Performance differences were normalized only by methylphenidate, relative to both atomoxetine and placebo. Both medications, however, significantly upregulated right VLPFC/insula activation within patients and normalized its underactivation in ADHD boys under placebo relative to control subjects. The supplementary motor area and inferior frontal cortex activation differences that were observed under placebo were reduced by methylphenidate and atomoxetine, respectively, but neither survived rigorous testing for normalization.
  
  
  CONCLUSIONS
  While only methylphenidate had a drug-specific effect of improving TD performance deficits, both drugs significantly upregulated and normalized right VLPFC underactivation in ADHD boys under placebo relative to control subjects, suggesting shared effects of stimulants and nonstimulants on a key prefrontal dysfunction during timing.
authors.affiliation: Department of Child Psychiatry, Institute of Psychiatry, King's College London, United Kingdom. Electronic address: anna.smith@kcl.ac.uk.
authors.forename: Anna
authors.initials: A
authors.lastname: Smith
authors.forename: Ana
authors.initials: A
authors.lastname: Cubillo
authors.forename: Nadia
authors.initials: N
authors.lastname: Barrett
authors.forename: Vincent
authors.initials: V
authors.lastname: Giampietro
authors.forename: Andrew
authors.initials: A
authors.lastname: Simmons
authors.forename: Mick
authors.initials: M
authors.lastname: Brammer
authors.forename: Katya
authors.initials: K
authors.lastname: Rubia
mesh_terms: D000293:Adolescent; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000503:physiopathology*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D001931:Brain Mapping; D018592:Cross-Over Studies; D004192:Discrimination, Psychological; D004311:Double-Blind Method; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D011437:Propylamines / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D011437:Propylamines; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride
keywords: Attention-deficit/hyperactivity disorder; atomoxetine; functional magnetic resonance imaging; methylphenidate; supplementary motor area; time discrimination