When control fails: Influence of the prefrontal but not striatal dopaminergic system on behavioural flexibility in a change detection task

Abstract

There is growing interest in understanding the neurobiological foundations of attention. To examine whether attentional processes in a change detection task are modulated by dopamine signalling, we investigated the influence of two polymorphisms, i.e. Val158Met (rs4680) in the catechol-O-methyl transferase (COMT) and a variable number of tandem repeats polymorphism (VNTR, rs28363170) in the dopamine transporter (DAT1).

The COMT Met allele, which results in lower enzyme activity and therefore probably enhanced PFC dopamine signalling, was significantly associated with task-performance and modulated executive control: Homozygous Met/Met allele carriers had difficulties when performing a change detection task, particularly showing the greatest difficulties in case cognitive and behavioural flexibility was necessary and the required reaction was not part of the subject’s primary task set. Contrary, no difference between the two genotype groups were evident, when an attentional conflict emerged and attentional control was needed for adequate responding. No association with variation in DAT1 was observed.

The results indicate a dissociation of the prefrontal and striatal dopamine system for attentional control and behavioural flexibility in a change detection task: While prefrontal dopamine turnover seems to modulate performance, putatively via difficulties in set shifting leading to behavioural inflexibility in COMT Met allele carriers, striatal dopamine turnover seems less important in this regard. With respect to other studies examining mechanisms of attentional functions in different paradigms, the results suggest that behavioural flexibility and attentional control as two executive subprocesses are differentially influenced by genetic polymorphisms within the dopaminergic system.

This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

Introduction

Due to limited cognitive capacities, we are not able to process all stimuli in our surrounding at once. We have to select important stimuli for further processing while suppressing others. Attentional selection might be driven by feature properties of a stimulus (bottom-up driven) (e.g. Theeuwes, 2010, Egeth and Yantis, 1997) or by an individual’s intentions while observing a visual scene (top-down).

Change detection tasks can be used to investigate the interplay between bottom-up and top-down attentional processes, if both kinds of stimuli are presented at once (e.g. Simons and Rensink, 2005). Under certain circumstances, a perceptual conflict between these two sources of information may occur (Wascher and Beste, 2010): It has been suggested that perceptual competition occurs, if two stimuli change concurrently, whereas only one of them is designated as target (Sussman et al., 2003, Wascher and Beste, 2010). Even if the non-target stimulus comprises a very salient feature change as e.g. an orientation change, this feature specific change detection can be counteracted by top-down processes which are in favour of the non salient feature change of the target stimuli, particularly, if the distractor is not part of the primary task set (see also Folk and Remington, 1999, Knudsen, 2007, Maunsell and Treue, 2006, Simons and Rensink, 2005). In broader terms, this top-down control belongs to the executive processes, which consists of several higher order cognitive functions. Two of these are cognitive, respectively behavioural flexibility and attentional top-down control (e.g. Miller and Cohen, 2001).

In our change detection paradigm, behavioural flexibility and attentional control are required for good task-performance. Subjects had to detect a luminance change of a laterally presented bar.

This change could occur alone, or was accompanied by an orientation change at the same location. In those two conditions, change detection is hardly demanding. In 25% of the trials however, the luminance change occurred simultaneously with a more salient orientation change at the opposite location (CONflict trials). Consequently, conflicting information has to be suppressed, which requires high levels of top-down control. In another 25% of the trials only an orientation change occurred with no luminance change in the scene (ORIentation change). Under this condition, subjects were required to disregard the primary task to localize the luminance change and to press a third button to indicate the appearance of an orientation change. By means of this experimental setup, attentional control (CONflict condition) and behavioural flexibility (ORIentation change), as two central executive top-down control functions, can be dissociated.

Several lines of research in health and disease suggest that cognitive control is regulated by the dopaminergic system (e.g. Arnsten and Pliszka, 2011, Van Schouwenburg et al., 2010). Despite a large body of research, to date no task has investigated, how the dopaminergic system modulates top-down control in case of emerging perceptual conflict between stimuli of different saliency levels. Aim of this study was thus to examine whether individual differences related to the COMT and DAT1 polymorphisms influence the performance of subjects in a change detection task, in which high and low salient stimuli compete against each other for detection, perceptual processing and response.

Availability of dopamine (DA) is regulated by two important proteins, the catechol-O-methyl transferase (COMT) and the DA transporter (DAT1). COMT is responsible for the degradation of the catecholamines dopamine and norepinephrine and plays a central role in regulating prefrontal dopamine levels (Dickinson and Elvevåg, 2009, Meyer-Lindenberg and Weinberger, 2006). Studies examining variation in the COMT gene have largely focused on a functional single nucleotide polymorphism (SNP) in exon 4 that leads to an amino acid substitution of valine (Val) by methionine (Met) at amino acid position 158 (Val158Met, rs4680). This polymorphism has been shown to substantially affect COMT enzyme activity, with the Val allele being associated with greater COMT enzyme activity leading to lower synaptic DA levels than the Met allele (Chen et al., 2004, Weinshilboum et al., 1999). It has been demonstrated, that Met allele carriers show enhanced cognitive stability compared to Val allele carriers, who in turn reveal comparably low cognitive stability, but high flexibility (for reviews see: Cools, 2006, Savitz et al., 2006). This assumption has been underlined in several studies with different paradigms (e.g. Egan et al., 2001, Goldberg et al., 2003). Blasi et al. (2005) postulated comparatively enhanced attentional control in subjects homozygous for the Met allele. Furthermore, the Met allele was associated with low performance in a reversal learning task, in which cognitive flexibility was necessary. Along these lines, higher switch costs in a task switching paradigm were evident in Met carriers (Colzato et al., 2010a).

DAT1 regulates the DA reuptake in the synaptic cleft in the striatum (e.g. Uhl, 2003). The mostly studied genetic polymorphism of the DAT1 (SLC6A3) gene is a 40 base pair (bp) variable number of tandem repeats polymorphism (VNTR) in the 3′ untranslated region (rs28363170), (Giros et al., 1992, Mitchell et al., 2000, Vandenberg et al., 1992). The most common alleles are the 9- and 10-repeat alleles, with the 10-repeat allele showing increased gene expression, greater overall DAT activity and corresponding increase in DA reuptake as compared to the 9-repeat allele (Brookes et al., 2007, Mill et al., 2002). Colzato et al. (2010b) showed, that 9-repeat allele carriers displayed enhanced cognitive flexibility in an “Inhibition of return” paradigm which was evident in a more pronounced IOR effect at short SOAs. This result is in line with studies by Cools, 2008, Cools and D’Esposito 2011 and Garcia-Garcia et al. (2010), suggesting that higher DA levels in the striatum facilitate cognitive flexibility.

Based on the findings mentioned above, we hypothesize that dopaminergic polymorphisms modulate executive functions, i.e. behavioural flexibility as well as attentional control similarly: Higher dopamine levels in the PFC of COMT Met allele carriers should lead to excessive top-down control together with diminished behavioural flexibility. This should be reflected by higher error rates, if flexible responding to the seldom occurring orientation change is necessary, especially because the orientation change is not part of the subject’s task set in 75% of their demanded reactions. In contrast to this, these subjects are supposed to perform better than Val allele carriers in the conflict condition, in which attentional control and fixation on their certain task set is important. In summary, Met allele carriers should show enhanced attentional control at the expense of cognitive and behavioural flexibility.

Concerning the effects of DAT1 we hypothesize that 9-repeat carriers would have difficulties in cognitive and behavioural flexibility due to lower striatal DA levels as compared to 10-repeat carriers.