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The Journal of Neuroscience, December 5, 2007, 27(49):13393-13401; doi:10.1523/JNEUROSCI.4041-07.2007

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Behavioral/Systems/Cognitive
Catechol-O-Methyltransferase Val158Met Modulation of Prefrontal–Parietal–Striatal Brain Systems during Arithmetic and Temporal Transformations in Working Memory

Hao-Yang Tan,¹ Qiang Chen,¹ Terry E. Goldberg,² Venkata S. Mattay,¹ Andreas Meyer-Lindenberg,¹ Daniel R. Weinberger,¹ and Joseph H. Callicott¹

¹Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, and ²Psychiatry Research Division, The Zucker Hillside Hospital, Glen Oaks, New York 11004

Correspondence should be addressed to either Dr. Hao-Yang Tan or Dr. Joseph H. Callicott, Unit for Dynamic Imaging Genetics, Clinical Brain Disorders Branch, National Institute of Mental Health, 10 Center Drive, Room 4C-216, Bethesda, Maryland 20892. Email: tanh{at}mail.nih.gov or Email: callicottj{at}mail.nih.gov

Working memory (WM) is critically mediated by dopaminergic tuning of signal-to-noise in cortical neural assemblies. However, little is known about the distributed neuronal networks impacted by dopaminergic modulation in the component processes of WM. Here, we used the genotype of the Val158Met polymorphism in catechol-O-methyltransferase (COMT) as an index of relative cortical dopamine bioavailability and tuning efficiency, to examine the spatial and subprocess specificity by which dopaminergic modulation occurs within the prefrontal-parietal-striatal network during WM, thus empirically showing that dopamine plays key roles in updating and stabilizing new information at the neural systems level. In an event-related fMRI task dissociating component numerical WM subprocesses, baseline numerical size comparison engaged ventrolateral prefrontal cortical activation that correlated with COMT Val-allele load (COMT Val>Met), while performing arithmetic transformations further engaged this genotype effect in dorsolateral prefrontal cortex (DLPFC), as well as in parietal and striatal regions. Critically, additional temporal integration of information in WM disproportionately engaged greater COMT Val>Met effects only at DLPFC. COMT Val>Met effects were also observed in DLPFC during encoding of new information into WM, but not at its subsequent retrieval. Thus, temporal updating operations, but less so the retrieval of already encoded representations, engaged relatively specific dopaminergic tuning at the DLPFC. Manipulating and rapidly updating representations were sensitive to dopaminergic modulation of neural signaling in a larger prefrontal-parietal-striatal network. These findings add to the integration of dopaminergic signaling in basic cortical assemblies with their roles in specific human brain networks during the orchestration of information processing in WM.

Key words: cerebral cortex; executive cognition; dopamine; fMRI; dopamine; genetics

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Received June 1, 2007; revised Oct. 9, 2007; accepted Oct. 12, 2007.

Correspondence should be addressed to either Dr. Hao-Yang Tan or Dr. Joseph H. Callicott, Unit for Dynamic Imaging Genetics, Clinical Brain Disorders Branch, National Institute of Mental Health, 10 Center Drive, Room 4C-216, Bethesda, Maryland 20892. Email: tanh{at}mail.nih.gov or Email: callicottj{at}mail.nih.gov

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