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The Journal of Neuroscience, May 18, 2005, 25(20):5038-5045; doi:10.1523/JNEUROSCI.0476-05.2005

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Behavioral/Systems/Cognitive
Effect of Catechol-O-Methyltransferase val¹⁵⁸met Genotype on Attentional Control

Giuseppe Blasi,^1,2 * Venkata S. Mattay,^1 * Alessandro Bertolino,^1,2,3 Brita Elvevåg,¹ Joseph H. Callicott,¹ Saumitra Das,¹ Bhaskar S. Kolachana,¹ Michael F. Egan,¹ Terry E. Goldberg,¹ and Daniel R. Weinberger¹

¹Genes, Cognition, and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1379, ²Neuroscience Psychiatric Group, Department of Neurological and Psychiatric Sciences, University of Bari, 70124 Bari, Italy, and ³Department of Neuroradiology, Istituto di Ricovero e Cura a Carattere Scientifico "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo, Italy

The cingulate cortex is richly innervated by dopaminergic projections and plays a critical role in attentional control (AC). Evidence indicates that dopamine enhances the neurophysiological signal-to-noise ratio and that dopaminergic tone in the frontal cortex is critically dependent on catechol-O-methyltransferase (COMT). A functional polymorphism (val¹⁵⁸met) in the COMT gene accounts for some of the individual variability in executive function mediated by the dorsolateral prefrontal cortex. We explored the effect of this genetic polymorphism on cingulate engagement during a novel AC task. We found that the COMT val¹⁵⁸met polymorphism also affects the function of the cingulate during AC. Individuals homozygous for the high-activity valine ("val") allele show greater activity and poorer performance than val/methionine ("met") heterozygotes, who in turn show greater activity and poorer performance than individuals homozygous for the low-activity met allele, and these effects are most evident at the highest demand for AC. These results indicate that met allele load and presumably enhanced dopaminergic tone improve the "efficiency" of local circuit processing within the cingulate cortex and thereby its function during AC.

Key words: attention; cognitive control; catechol-O-methyltransferase; genetics; dopamine; dorsal cingulate; fMRI; variable attentional control task

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Received Feb 4, 2005; revised April 12, 2005; accepted April 13, 2005.

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