Influence of COMT Gene Polymorphism on fMRI-assessed Sustained and Transient Activity during a Working Memory Task

Abstract

The catechol O-methyltransferase (COMT) gene--encoding an enzyme that is essential for the degradation of dopamine (DA) in prefrontal cortex (PFC)--contains a single nucleotide polymorphism (val/met) important for cognition. According to the tonic-phasic hypothesis, individuals carrying the low-enzyme-activity allele (met) are characterized by enhanced tonic DA activity in PFC, promoting sustained cognitive representations in working memory. Val carriers have reduced tonic but enhanced phasic dopaminergic activity in subcortical regions, enhancing cognitive flexibility. We tested the tonic-phasic DA hypothesis by dissociating sustained and transient brain activity during performance on a 2-back working memory test using mixed blocked/event-related functional magnetic resonance imaging. Participants were men recruited from a random sample of the population (the Betula study) and consisted of 11 met/met and 11 val/val carriers aged 50 to 65 years, matched on age, education, and cognitive performance. There were no differences in 2-back performance between genotype groups. Met carriers displayed a greater transient medial temporal lobe response in the updating phase of working memory, whereas val carriers showed a greater sustained PFC activation in the maintenance phase. These results support the tonic-phasic theory of DA function in elucidating the specific phenotypic influence of the COMT val(158)met polymorphism on different components of working memory.

Age-related and Genetic Modulation of Frontal Cortex Efficiency

“…The present results converge with findings of previous studies (e.g., de Frias et al, 2009) in suggesting that to achieve the same level of performance as younger adults and COMT Met carriers, older adults and COMT Val carriers need to recruit the DLPFC to a high degree already during WM maintenance. Lowered dopamine for older adults and COMT Val carriers could impair sustained DLPFC processing via D1 receptors during the delay phase (Cohen, Braver, & Brown, 2002), which cascades into stronger DLPFC engagement during maintenance.…”

Effects of two dopamine-modulating genes (DAT1 9/10 and COMT Val/Met) on n-back working memory performance in healthy volunteers

“…From previous studies that investigated the effect of COMT effect on n-back performance (Egan et al 2001 ;Stefanis et al 2004 ;Bruder et al 2005 ;Bertolino et al 2006 ;Caldu et al 2007 ;de Frias et al 2010), only one found a significant effect, with Met/Met homozygotes performing better than the rest (Goldberg et al 2003). However, the n-back task used in their study required individuals to respond to each stimulus whereas our study did not (Goldberg et al 2003).…”

Modulating effect of COMT genotype on the brain regions underlying proactive control process during inhibition

“…Obviously, we cannot rule out the possibility that the phasic dopamine effect is very tenuous [see for example (Rosa, et al, 2010)], that other genes than COMT are related to the phasic component of dopamine regulation [see for example (Bilder, et al, 2004)] or that our procedure was not perfectly designed to evidence the distinction between tonic/phasic dopaminergic regulation [for a clearer distinction between these two regulation systems see (de Frias, et al, 2010)]. …”