title: Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis.
abstract: BACKGROUND
  Psychostimulant medication, most commonly the catecholamine agonist methylphenidate, is the most effective treatment for attention-deficit/hyperactivity disorder (ADHD). However, relatively little is known on the mechanisms of action. Acute effects on brain function can elucidate underlying neurocognitive effects. We tested methylphenidate effects relative to placebo in functional magnetic resonance imaging (fMRI) during three disorder-relevant tasks in medication-naïve ADHD adolescents. In addition, we conducted a systematic review and meta-analysis of the fMRI findings of acute stimulant effects on ADHD brain function.
  
  
  METHODS
  The fMRI study compared 20 adolescents with ADHD under either placebo or methylphenidate in a randomized controlled trial while performing stop, working memory, and time discrimination tasks. The meta-analysis was conducted searching PubMed, ScienceDirect, Web of Knowledge, Google Scholar, and Scopus databases. Peak coordinates of clusters of significant effects of stimulant medication relative to placebo or off medication were extracted for each study.
  
  
  RESULTS
  The fMRI analysis showed that methylphenidate significantly enhanced activation in bilateral inferior frontal cortex (IFC)/insula during inhibition and time discrimination but had no effect on working memory networks. The meta-analysis, including 14 fMRI datasets and 212 children with ADHD, showed that stimulants most consistently enhanced right IFC/insula activation, which also remained for a subgroup analysis of methylphenidate effects alone. A more lenient threshold also revealed increased putamen activation.
  
  
  CONCLUSIONS
  Psychostimulants most consistently increase right IFC/insula activation, which are key areas of cognitive control and also the most replicated neurocognitive dysfunction in ADHD. These neurocognitive effects may underlie their positive clinical effects.
authors: Departments of Child and Adolescent Psychiatry (KR, AAA, AIC, AS) and Neuroimaging (MJB), Institute of Psychiatry, King's College London, United Kingdom. Electronic address: katya.rubia@kcl.ac.uk.
authors: Katya
authors: K
authors: Rubia
authors: Departments of Child and Adolescent Psychiatry (KR, AAA, AIC, AS) and Neuroimaging (MJB), Institute of Psychiatry, King's College London, United Kingdom.
authors: Analucia A
authors: AA
authors: Alegria
authors: Departments of Child and Adolescent Psychiatry (KR, AAA, AIC, AS) and Neuroimaging (MJB), Institute of Psychiatry, King's College London, United Kingdom.
authors: Ana I
authors: AI
authors: Cubillo
authors: Departments of Child and Adolescent Psychiatry (KR, AAA, AIC, AS) and Neuroimaging (MJB), Institute of Psychiatry, King's College London, United Kingdom.
authors: Anna B
authors: AB
authors: Smith
authors: Departments of Neuroimaging, Institute of Psychiatry, King's College London, United Kingdom.
authors: Michael J
authors: MJ
authors: Brammer
authors: Fundació per a la Investigació i la Docència Maria Angustias Giménez Research Unit, Germanes Hospitalaries and Centro de Investigación Biomédica en Red de Salud Mental (JR), Barcelona, Spain.
authors: Joaquim
authors: J
authors: Radua
mesh_terms: D000293:Adolescent; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D001289:Attention Deficit Disorder with Hyperactivity / Q000628:therapy; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D046690:Deep Brain Stimulation / Q000379:methods; D007091:Image Processing, Computer-Assisted; D007266:Inhibition, Psychological; D008279:Magnetic Resonance Imaging; D008774:Methylphenidate / Q000627:therapeutic use; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D016032:Randomized Controlled Trials as Topic
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D010100:Oxygen
keywords: ADHD; fMRI; meta-analysis; methylphenidate; review; stimulants