title: Cortical responses to amphetamine exposure studied by pCASL MRI and pharmacokinetic/pharmacodynamic dose modeling.
abstract: BACKGROUND
  Perfusion measurement by arterial spin labeling (ASL) techniques is well suited for pharmaceutical magnetic resonance imaging (phMRI) studies to investigate how drugs change the cerebral perfusion status and further, neuronal activity.
  
  
  METHODS
  Twelve healthy normal male volunteers participated in the study which was based on a double blinded design. Six subjects were randomly selected to receive a single oral dose of 20mg d-amphetamine and six were given placebo. Perfusion measurements by pseudo-continuous ASL (pCASL) technique were repeatedly performed at 10 different time points with a 3T clinical MRI scanner during a 10 hour period after dose together with physiologic data and blood sample collections. The dynamic changes in cerebral perfusion in response to the plasma concentration variations of d-amphetamine were analyzed at voxel-level and for regions of interest.
  
  
  RESULTS
  Compared to the placebo group a 20% reduction in cerebral blood flow (CBF) was observed in gray matter for the subjects that received d-amphetamine. The most significant reduction of regional CBF (rCBF) was detected in the basal ganglia, frontal region and insular cortex using voxel based analysis. A relation between d-amphetamine exposure and CBF response was found using PK/PD modeling, which predicted on average a 15% decrease of the CBF in gray matter at a plasma concentration of 30 ng/ml.
  
  
  CONCLUSIONS
  In this study we have demonstrated that repeated perfusion measurements by pCASL technique was sufficiently robust to differentiate the neurological response between the groups that received d-amphetamine and placebo. Quantitative and repetitive CBF measurements can be used for PK/PD modeling of CNS drug responses in humans.
authors.affiliation: Department of Diagnostic Medical Physics, Karolinska University Hospital Huddinge, Stockholm, Sweden. love.engstrom-nordin@karolinska.se
authors.forename: Love Engström
authors.initials: LE
authors.lastname: Nordin
authors.forename: Tie-Qiang
authors.initials: TQ
authors.lastname: Li
authors.forename: Jacob
authors.initials: J
authors.lastname: Brogren
authors.forename: Patrik
authors.initials: P
authors.lastname: Johansson
authors.forename: Niclas
authors.initials: N
authors.lastname: Sjögren
authors.forename: Kristin
authors.initials: K
authors.lastname: Hannesdottir
authors.forename: Charlotta
authors.initials: C
authors.lastname: Björk
authors.forename: Märta
authors.initials: M
authors.lastname: Segerdahl
authors.forename: Danny J J
authors.initials: DJ
authors.lastname: Wang
authors.forename: Per
authors.initials: P
authors.lastname: Julin
mesh_terms: D000328:Adult; D000661:Amphetamine / Q000493:pharmacokinetics*; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics*; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004311:Double-Blind Method; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D013113:Spin Labels; D055815:Young Adult
chemical_list: D000697:Central Nervous System Stimulants; D013113:Spin Labels; D000661:Amphetamine