Plasma level-dependent effects of methylphenidate on task-related functional magnetic resonance imaging signal changes.
BACKGROUND
Methylphenidate (MPH) is a dopamine and noradrenaline enhancing drug used to treat attentional deficits. Understanding of its cognition-enhancing effects and the neurobiological mechanisms involved, especially in elderly people, is currently incomplete.


OBJECTIVE
The aim of this study was to investigate the relationship between MPH plasma levels and brain activation during visuospatial attention and movement preparation.


METHODS
Twelve healthy elderly volunteers were scanned twice using functional magnetic resonance imaging (fMRI) after oral administration of MPH 20 mg or placebo in a within-subject design. The cognitive paradigm was a four-choice reaction time task presented at two levels of difficulty (with and without spatial cue). Plasma MPH levels were measured at six time points between 30 and 205 min after dosing. FMRI data were analysed using a linear model to estimate physiological response to the task and nonparametric permutation tests for inference.


RESULTS
Lateral premotor and medial posterior parietal cortical activation was increased by MPH, on average, over both levels of task difficulty. There was considerable intersubject variability in the pharmacokinetics of MPH. Greater area under the plasma concentration-time curve was positively correlated with strength of activation in motor and premotor cortex, temporoparietal cortex and caudate nucleus during the difficult version of the task.


CONCLUSIONS
This is the first pharmacokinetic/pharmacodynamic study to find an association between plasma levels of MPH and its modulatory effects on brain activation measured using fMRI. The results suggest that catecholaminergic mechanisms may be important in brain adaptivity to task difficulty and in task-specific recruitment of spatial attention systems.
Müller
Ulrich
U
MRC Behavioural and Clinical Neuroscience Centre, University of Cambridge, Cambridge, UK. um207@cam.ac.uk
Suckling
J
J
Zelaya
F
F
Honey
G
G
Faessel
H
H
Williams
S C R
SC
Routledge
C
C
Brown
J
J
Robbins
T W
TW
Bullmore
E T
ET
D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001288:Attention / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D001931:Brain Mapping; D000697:Central Nervous System Stimulants / Q000097:blood / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003071:Cognition / Q000187:drug effects*; D003463:Cues; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008774:Methylphenidate / Q000097:blood / Q000494:pharmacology*; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D016037:Single-Blind Method; D013028:Space Perception / Q000187:drug effects; D013223:Statistics as Topic; D013997:Time Factors
D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D010100:Oxygen