Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype (original) (raw)

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Acknowledgements

We thank D. Sarpal, P. Koch and A. Bonner-Jackson for research assistance, M. Akil and V. Mattay for helpful discussion of this manuscript vis à vis their own results, A. Grace for helpful comments on the interpretation of the data, T. Goldberg for neuropsychological testing and R. Carson for expertise in PET kinetic modeling.

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Authors and Affiliations

  1. Department of Health and Human Services, Section on Integrative Neuroimaging, Genes, Cognition and Psychosis Program, National Institute for Mental Health, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892-1365, Maryland, USA
    Andreas Meyer-Lindenberg, Philip D Kohn, Shane Kippenhan & Karen Faith Berman
  2. Department of Health and Human Services, Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute for Mental Health, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892-1365, Maryland, USA
    Andreas Meyer-Lindenberg, Philip D Kohn, Bhaskar Kolachana, Shane Kippenhan, Daniel R Weinberger & Karen Faith Berman
  3. Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, DHHS, 49 Convent Drive, Bethesda, 20892-4472, Maryland, USA
    Aideen McInerney-Leo & Robert Nussbaum

Authors

  1. Andreas Meyer-Lindenberg
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  2. Philip D Kohn
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  3. Bhaskar Kolachana
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  4. Shane Kippenhan
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  5. Aideen McInerney-Leo
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  6. Robert Nussbaum
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  7. Daniel R Weinberger
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  8. Karen Faith Berman
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Corresponding author

Correspondence toAndreas Meyer-Lindenberg.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Relationship between dopaminergic stimulation and prefrontal cortex activity, drawn schematically after Goldman-Rakic et al. and Mattay et al. In the latter study, the differential effect of an acute increase in dopaminergic tone induced by amphetamine was used to probe the position on the u-shaped curve in the setting of acute pharmacological modulation, which led to improved function and prefrontal efficiency in val-allele carriers, but deteriorating function in met-homozygotes. (JPG 48 kb)

Supplementary Fig. 2

Task-related activations and deactivations. Effect of task - significant activations (red) and deactivations (blue), comparing the working memory (2-back) condition with its sensorimotor control (0-back). Highlighted voxels are significant at the_P_⩽0.05 corrected level (see Supplementary Tables 1 and 2). (JPG 99 kb)

Supplementary Fig. 3

Hypothetical fit of data to “inverted-u” response curve. “Inverted-u” shaped relationship between observed left DLPFC 0-back rCBF and dopamine synthesis rate, hypothetically assuming that a given rate of midbrain dopamine neuronal activity and dopamine synthesis (Ki) will result in twice as much prefrontal dopamine in met-homozygotes (see discussion in Chen et al. 2004); to reflect this, Kis were doubled for met-homozygotes. Second-order polynomial fit curve shown. Datapoints for val-carriers shown as filled circles, met-homozygotes as empty circles. (JPG 33 kb)

Supplementary Table 1

Further subject information and ROI measurements, by genotype. (PDF 48 kb)

Supplementary Table 2

Working-memory task related activations. (PDF 42 kb)

Supplementary Table 3

Working-memory task related deactivations. (PDF 42 kb)

Supplementary Table 4

Correlations of PFC rCBF with midbrain F-DOPA Ki. (PDF 45 kb)

Supplementary Methods (PDF 56 kb)

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Meyer-Lindenberg, A., Kohn, P., Kolachana, B. et al. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype.Nat Neurosci 8, 594–596 (2005). https://doi.org/10.1038/nn1438

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