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Plasma level-dependent effects of methylphenidate on task-related functional magnetic resonance imaging signal changes

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Abstract

Rationale

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.

Objectives

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.

Conclusion

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.

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Acknowledgements

This work was supported by GlaxoSmithKline and the Wellcome Trust, by a research fellowship of the Alexander von Humboldt Foundation (UM) and was completed within the MRC Behavioural and Clinical Neuroscience Centre (BCNC). We gratefully thank the volunteers who participated in this study for their cooperation, and colleagues at the MRI Unit, Maudsley Hospital, London, UK, for technical assistance with fMRI data acquisition.

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Authors and Affiliations

  1. Department of Psychiatry, University of Cambridge, Cambridge, UK

    Ulrich Müller, J. Suckling, G. Honey & E. T. Bullmore

  2. Department of Experimental Psychology, University of Cambridge, Cambridge, UK

    Ulrich Müller & T. W. Robbins

  3. Institute of Psychiatry, King’s College London, London, UK

    J. Suckling, F. Zelaya, G. Honey, S. C. R. Williams & E. T. Bullmore

  4. GlaxoSmithKline, Clinical Research Unit, Addenbrooke’s Centre for Clinical Investigation, Cambridge, UK

    H. Faessel, C. Routledge & J. Brown

  5. MRC Centre for Behavioural and Clinical Neuroscience, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK

    Ulrich Müller

  6. Brain Mapping Unit, Department of Psychiatry, Addenbrooke’s Hospital, University of Cambridge, Cambridge, CB2 2QQ, UK

    E. T. Bullmore

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  1. Ulrich Müller
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  2. J. Suckling
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  3. F. Zelaya
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  4. G. Honey
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  5. H. Faessel
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  6. S. C. R. Williams
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  7. C. Routledge
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  10. E. T. Bullmore
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Correspondence to Ulrich Müller or E. T. Bullmore.

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Müller, U., Suckling, J., Zelaya, F. et al. Plasma level-dependent effects of methylphenidate on task-related functional magnetic resonance imaging signal changes. Psychopharmacology 180, 624–633 (2005). https://doi.org/10.1007/s00213-005-2264-9

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  • DOI: https://doi.org/10.1007/s00213-005-2264-9

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