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

Mathieu Jaspar1, 2*, Julien Grandjean1, 2, Eric Salmon1, Pierre Maquet1 and Fabienne Collette1, 2
  • 1 Cyclotron Research Centre - University of Liège, Belgium
  • 2 Cognitive and Behavioral Neuroscience Centre, University of Liège, Belgium

Introduction
Catechol-O-methytransferase (COMT) is an important enzyme which degrades catecholamines, such dopamine, notably in the prefrontal cortex (Männistö & Kaakkola, 1999). Actually, a transition of guanine to adenine at codon 158 of the COMT gene results in a valine to methionine substitution (Lotta & al., 1995). This phenomenon leads to different COMT genotypes, each associated with a different COMT enzymatic activity (Weinshilboum, & al., 1999). A large number of studies reported an effect of COMT on executive functioning. However, most of them used multi-determined executive tasks (e.g., Barnett & al., 2007). We are interested here to determine the effect of COMT Val158Met genotype on the activity of frontal areas (Nee & al., 2007) underlying the specific executive process of proactive control during inhibition.

Methods
Procedure
In an event-related fMRI experiment, a modified form of the Stroop task was administered to 45 young adults (age range: 18-30) separated into three groups according to their COMT Val158Met genotype: 15 homozygous val/val (VV), 15 homozygous met/met (MM) and 15 heterozygotes val/met (VM) carriers. The Stroop task consisted in the presentation of color words printed in various ink colors (e.g the word blue written in red). Subjects were instructed to name ink color as fast and accurately as possible by avoiding reading the word. In this version of the Stroop task, three different contexts were created: (1) a mostly congruent context (MC) with a majority of congruent items (IC, e.g. the word “blue” in “blue”), (2) a mostly incongruent context (MI) with mainly interfering items (II, e.g. the word “blue” in “red”), (3) a neutral context (MN) with mainly neutral items (NI, series of %%% written in different colors).
MRI acquisition
Functional MRI time series were acquired on a 3T head-only scanner operated with the standard transmit-receive quadrature head coil. Multislice T2*-weighted functional images were acquired with a gradient-echo echo-planar imaging sequence using axial slice orientation and covering the whole brain (32 slices, FoV = 220x220 mm², voxel size 3.4x3.4x3 mm³, 30% interslice gap, matrix size 64x64x32, TR = 2130 ms, TE = 40 ms, FA = 90°). Structural images were obtained using a high resolution T1-weighted sequence (3D MDEFT [Deichmann & al., (2004)]; TR = 7.92 ms, TE = 2.4 ms, TI = 910 ms, FA = 15°, FoV = 256 x 224 x 176 mm³, 1 mm isotropic spatial resolution). Preprocessing and statistical analyses were performed with SPM8 (p<.001 uncorrected).

Results
No effect of context [(MI_II + MI_IC + MI_NI) - (MC_II + MC_IC + MC_NI)] was observed for response times (F(1,42) = 3,58 ; p = 0,07). Moreover, no significant between groups differences were observed (F(2,42) = 1,26; p = 0,29).
FMRI results contrasting incongruent vs congruent context (MI - MC) revealed that proactive control is associated with increased activity in the frequently reported anterior cingulate cortex (ACC) in MM and VM groups by comparisons to VV, but also with increased activity in the middle frontal gyrus (MFG) in the VV and VM groups by comparison to MM.

Conclusions
Our results show differential brain activity according to the COMT genotype when subjects are engaged in proactive control process. Indeed, a similar behavioral performance is associated to higher activity in the MFG for carriers of val allele and more characteristically to higher activity in the ACC for carriers of the met allele. This observation, paralleling to the higher cortical dopamine level in met/met individuals, confirms our expectation of a COMT Val158Met genotype modulation of the brain regions underlying proactive control, and this, as suggested by Braver et al. (2007) especially in frontal areas.

Acknowledgements

Cyclotron Research Centre (CRC) ;
Interuniversity Attraction Poles (PAI) ;
Belgian National Funds of Scientific Research (FNRS).

References

Barnett, J. H., Jones, P.B., Robbins, T. W., & Muller, U. (2007), ‘Effects of the cathecol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wiscosin Card Sort Test in schizophrenia and healthy control’, vol. 12, no.5, pp. 502-509.
Braver, T., Gray, J., & Buguess, G.C. (2007), ’Explaining the many varieties of working memory variation: Dual Mechanisms of cognitive control’, in ‘Variations in working memory’, pp. 76-106.
Deichmann, R., Shwarzbauer, C., & Turner, R. (2004), ‘Optimisation of the 3D MDEFT sequence for anatomical brain imaging: technical implications at 1.5 and 3 T’, Neuroimage, vol. 21, pp. 757-767.
Lotta, T., Vidgren, J., Tilgmann, C., Ulmanen, I., Melen, K., Julkunen, I., Taskinen, J., (1995), ‘Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme’, Biochemistry, vol. 34, pp. 4202 - 4210.
Männistö, P.T., & Kaakkola, S. (1999), ‘Catechol-O-methyltransferase (COMT): Biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors’, Pharmacological Reviews, vol. 51, no. 4, pp. 593-628.
Nee, D. E., Wager, T. D., & Jonides, J. (2007), ‘Interference resolution: insights from a meta-analysis of neuroimaging tasks’, vol. 7, no. 1, pp. 1-17.
Weinshilboum, R. M., Otterness, D. M., & Szumlanski, C. L. (1999), ‘Methylation pharmacogenetics: cathecol O-methyltransferase, thiopurine methyltransferase, and histamine N-methytransferase’, Annual Review of Pharmacology and Toxicology, vol. 39, pp. 19-52.

Keywords: COMT, Dopamine, fMRI, attentional control, Stroop Test

Conference: Belgian Brain Council, Liège, Belgium, 27 Oct - 27 Oct, 2012.

Presentation Type: Poster Presentation

Topic: Higher Brain Functions in health and disease: cognition and memory

Citation: Jaspar M, Grandjean J, Salmon E, Maquet P and Collette F (2012). Modulating effect of COMT genotype on the brain regions underlying proactive control process. Conference Abstract: Belgian Brain Council. doi: 10.3389/conf.fnhum.2012.210.00103

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Received: 17 Aug 2012; Published Online: 12 Sep 2012.

* Correspondence: Mr. Mathieu Jaspar, Cyclotron Research Centre - University of Liège, Liège, Belgium, mathieu.jaspar@ulg.ac.be