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Processing efficiency of a verbal working memory system is modulated by amphetamine: an fMRI investigation

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Abstract

Rationale

Working memory performance may be improved or decreased by amphetamine, depending on baseline working memory capacity and amphetamine dosage. This variable effect suggests an optimal range of monaminergic activity for working memory, either below or above which it is compromised. We directly tested this possibility with human participants by varying amphetamine dosage and measuring the efficiency of cortical processing in brain regions associated with working memory.

Objectives

The modulation of cortical processing in a verbal working memory network by dextroamphetamine (d-amph) was examined using BOLD functional magnetic resonance imaging (fMRI) with healthy participants. The goal of the study was to test the hypothesis of an inverted U-shaped relationship between d-amph dose and processing efficiency of a verbal working memory system.

Methods

d-amph dosage was increased cumulatively every 2 h across four scanning sessions collected in a single day. The primary measure used for analyses in this study was the extent of activation in brain regions empirically defined as a working memory network.

Results

An inverted U-shaped relationship was observed between the amount of d-amph administered and working memory processing efficiency. This relationship was specific to brain areas functionally defined as working memory regions and to the encoding/maintenance phase (as opposed to the response phase) of the task.

Conclusion

The results are consistent with the hypothesis that the neurochemical effects of amphetamine modulate the efficiency of a verbal working memory system. The effect of amphetamine on working memory in healthy individuals may provide insight regarding the working memory deficits seen in schizophrenia, given the overlap between neurochemical systems affected by amphetamine, and those disordered in schizophrenia.

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Notes

  1. We based these hypotheses both on previous research showing that a low dose of amphetamine can improve working memory performance, as well as on pilot work from our own lab that showed a 20-mg dose of amphetamine greatly hindered working memory performance and exacerbated cortical processing efficiency on a similar task. We want to emphasize that these predictions were specific to the particular task employed in this experiment and acknowledge that a given dose of amphetamine will have differential effects depending on the individual and the specific task employed.

  2. For example, Uftring et al. (2001) found that a 20-mg dose of amphetamine increased the extent of activation in task-related cortical regions, but did not have any effect on reaction time or accuracy. To achieve the same level of behavioural performance, more cortex was recruited during the task—a reduction in cortical processing efficiency.

  3. We would like to clarify that the use of the terms “low dose”, “medium dose”, and “high dose” is relative to the dosage levels used in the present study. A 12.5-mg dose of d-amph is not in fact a particularly high dose (25 mg would typically be considered a high dose), but it was the highest dose employed here.

  4. We must note that these data are an average of both men and women. As one reviewer pointed out, men and women may differ in their response to amphetamine. To ensure that no such differences were present in this study, we conducted an ANOVA for the amphetamine group with sex as a between-subjects factor, and dose and load as within-subjects factors, using the voxel counts obtained from the a-priori mask as the dependent measure. There were no significant main or interaction effects of sex (all ps>0.05), indicating that in the present study, amphetamine affected brain activity in a similar manner for both men and women.

  5. A similar data pattern was obtained for the peak response amplitude estimates for these focal regions of interest. That is, a U-shaped relationship between BOLD response amplitude and amphetamine dose was present only for the encoding/maintenance phase of the task, and only in the dorsolateral prefrontal cortex. The quadratic trend for the response amplitude data, however, did not quite reach significance, t (11)=1.44, p=0.08. Where as voxel counts and response amplitude estimates are certainly not independent, this result highlights the fact that the two measures are dissociable. Given that the present research question centers on cortical efficiency, we felt activation extent rather than peak amplitude was the appropriate measure.

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Acknowledgements

The authors would like to thank the Michael Smith Foundation for Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Dr. Norma Calder Schizophrenia Foundation for their support of this research.

All participants in this experiment provided informed consent prior to their participation in the study. This research was conducted with the approval of the University of British Columbia Clinical Research Ethics Board and in accordance with the current laws of Canada.

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Authors and Affiliations

  1. Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC, Canada, V6T 1Z4

    Christine M. Tipper

  2. Department of Psychiatry, University of British Columbia, Vancouver, Canada

    Tara A. Cairo, Anthony G. Phillips & Elton T. C. Ngan

  3. Division of Psychiatry, Queens Medical Centre, Nottingham, UK

    Peter F. Liddle

  4. Department of Research, Riverview Hospital, Coquitlam, Canada

    Todd S. Woodward

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  1. Christine M. Tipper
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  2. Tara A. Cairo
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  3. Todd S. Woodward
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  4. Anthony G. Phillips
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  6. Elton T. C. Ngan
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Correspondence to Christine M. Tipper.

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Tipper, C.M., Cairo, T.A., Woodward, T.S. et al. Processing efficiency of a verbal working memory system is modulated by amphetamine: an fMRI investigation. Psychopharmacology 180, 634–643 (2005). https://doi.org/10.1007/s00213-005-0025-4

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  • DOI: https://doi.org/10.1007/s00213-005-0025-4

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