Catechol-O-methyltransferase (COMT) influences the connectivity of the prefrontal cortex at rest

Elizabeth M Tunbridge,Clare E Mackay,Paul J Harrison,Sarah M Farrell

doi:10.1016/j.neuroimage.2012.11.059

Elizabeth M Tunbridge, Clare E Mackay + Show 2 more

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https://doi.org/10.1016/j.neuroimage.2012.11.059

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Abstract

Catechol-O-methyltransferase (COMT) modulates dopamine in the prefrontal cortex (PFC) and influences PFC dopamine-dependent cognitive task performance. A human COMT polymorphism (Val158Met) alters enzyme activity and is associated with both the activation and functional connectivity of the PFC during task performance, particularly working memory. Here, we used functional magnetic resonance imaging and a data-driven, independent components analysis (ICA) approach to compare resting state functional connectivity within the executive control network (ECN) between young, male COMT Val158 (n = 27) and Met158 (n = 28) homozygotes. COMT genotype effects on grey matter were assessed using voxel-based morphometry. COMT genotype significantly modulated functional connectivity within the ECN, which included the head of the caudate, and anterior cingulate and frontal cortical regions. Val158 homozygotes showed greater functional connectivity between a cluster within the left ventrolateral PFC and the rest of the ECN (using a threshold of Z > 2.3 and a family-wise error cluster significance level of p < 0.05). This difference occurred in the absence of any alterations in grey matter. Our data show that COMT Val158Met affects the functional connectivity of the PFC at rest, complementing its prominent role in the activation and functional connectivity of this region during cognitive task performance. The results suggest that genotype-related differences in prefrontal dopaminergic tone result in neuroadaptive changes in basal functional connectivity, potentially including subtle COMT genotype-dependent differences in the relative coupling of task-positive and task-negative regions, which could in turn contribute to its effects on brain activation, connectivity, and behaviour.

Highlights

Catechol-O-methyltransferase (COMT) modulates dopaminergic transmission in the prefrontal cortex (PFC) (Tunbridge et al, 2004)
We focused on the executive control network (ECN) given the key role of COMT in prefrontal function, and investigated whether grey matter volume contributed to any differences in resting connectivity
COMT genotype alters the functional connectivity of the executive control network Voxel-wise comparisons of Val158 and Met158 homozygotes showed a significant effect of COMT genotype on the functional connectivity of the ECN

Summary

Introduction

Catechol-O-methyltransferase (COMT) modulates dopaminergic transmission in the prefrontal cortex (PFC) (Tunbridge et al, 2004). The human COMT gene contains a well-studied functional polymorphism (Val158Met) in its sequence: the Val158 allele encodes a more active isoform than the Met158 allele (Chen et al, 2004). Consistent with prefrontal dopamine's key role in cognition (Cools and D'Esposito, 2011; Goldman-Rakic et al, 2000), the Val158Met polymorphism has been associated with human executive function, working memory (Egan et al, 2001; Farrell et al, 2012). Pharmacological COMT inhibition is beneficial to cognitive function, albeit in a COMT genotype-dependent manner; COMT inhibition has received attention as a therapeutic target for cognitive dysfunction (Apud et al, 2007; Farrell et al, 2012; Giakoumaki et al, 2008). Rodent studies have consistently shown that low COMT activity is beneficial in terms of cognitive performance

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