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

Abstract

Catechol-O-methyltransferase (COMT) modulates dopamine in the prefrontal cortex (PFC) and influences PFC dopamine-dependent cognitive task performance. A human COMT polymorphism (Val(158)Met) 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 Val(158) (n=27) and Met(158) (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. Val(158) 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 Val(158)Met 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.

Fig. 1

The ECN spatial map, shown thresholded at Z > 3, in the three most informative orthogonal planes and superimposed on the MNI152 standard space template image.

Fig. 2

The effect of COMT Val¹⁵⁸Met genotype on ECN functional connectivity. Results are shown thresholded using Z > 2.3 and a family-wise error cluster significance level of p < 0.05. The bar graph on the right of the figure shows mean PEs from within the significant cluster for Val¹⁵⁸ vs. Met¹⁵⁸ homozygotes. Error bars denote standard error of the mean. *** indicates p < 0.000005.