Attentional performance

Twin studies and genome-wide association studies indicate that inherited factors have considerable impact on cognitive performance (Plomin, 2001; Butcher et al., 2008). Candidate gene studies have aimed to identify the genetic underpinnings of the different networks of the information processing system by studying healthy individuals and ADHD patients. The most extensively studied cognitive domains are connected to the attention system. The attention network is responsible for many functions, such as focusing attention, maintaining focus, or dividing attention between two or more stimuli. Attention models distinguish these three networks, with three main neurotransmitter systems responsible for alerting (noradrenergic), orienting (cholinergic), and executive control (dopaminergic) (Raz and Buhle, 2006). The alerting network is responsible for maintaining the alert state, allowing one to respond. The process of selecting information between sensory inputs is mediated by the orienting network. The executive control network includes a set of complex operations responsible for mediating stimulus and response conflicts to control behavior.

The Attention Network Test was developed to measure individual differences in alerting, orienting, and executive attention. A small-scale twin study confirmed the heritability of the executive control network (Fan et al., 2001). This workgroup also studied dopaminergic (DRD4, DAT1, COMT, and MAOA) polymorphisms among healthy individuals. Their results highlighted the importance of dopamine catabolizing enzymes in executive attention: The MAOA low-activity (3-repeat) allele was associated with higher executive attention scores; moreover, a comparison of the groups with low vs. high cortical dopamine levels (i.e., COMT Val/Val + MAOA 4/4 vs. COMT Met/Met + MAOA 3/3) showed a significant difference, as the high dopamine group exhibited better executive attention (Fossella et al., 2002).

The COMT Val158Met polymorphism has been shown to modulate attentional control; better performance was reported in Met-carriers among healthy subjects (Egan et al., 2001) and ADHD children (Sengupta et al., 2008). Because of its importance in the PFC (Tunbridge et al., 2006a), this COMT polymorphism has been widely studied during cognitive tasks over the last few years. However, the results from many studies are not in agreement. For example, the high-activity Val-allele was associated with both better and poorer prefrontal functioning, and a recent meta-analysis showed no main effect of the COMT Val158 Met polymorphism on cognitive functions (Barnett et al., 2008). Based on the tonic-phasic dopamine hypothesis, it was proposed that the Met-variant could be beneficial in working memory and sustained attention tasks for which stability is required; in contrast, the Val-variant facilitates the transition between states and enhances flexibility (Bilder et al., 2004). It is important to note that a cortical COMT effect probably depends on many factors, e.g., the level of stress the individual experiences during the task (see the dopamine systems section for more information). Recent genetic studies include other COMT SNPs in addition to the Val158Met (rs4680) polymorphism to access more precise functional variants. For example, a large scale, population-based study showed an inverted U-shaped association between COMT haplotypes with decreasing enzyme activity and working memory performance among 10-year old children (Barnett et al., 2009). In addition, gene × gene interactions can be also important, as shown by the finding of Reuter et al. (2005): In the Stroop interference test, the COMT Met/Met participants performed significantly better than the Val-allele carriers in the DRD2 A1-allele present group, whereas in the DRD2 A1-allele absent group, subjects with the Met/Met genotyped performed the worst.

Other groups have used computerized continuous performance tests to study attention endophenotypes by response time variability or the number of omission errors (representing inattention). In this type of test, the number of commission errors can be also recorded (indicating impulsivity). Only the DRD5 148-bp allele was associated with all of the main outcome measures in an Israeli ADHD group (Manor et al., 2004). The MAOA uVNTR was associated with the number of commission errors (Manor et al., 2002b), whereas the DRD4 VNTR was associated with both the number of commission errors and the response time variability in this group (Manor et al., 2002a). The attention-related DRD4 findings in the continuous performance test studies are not always in agreement with one another. In two ADHD studies, the DRD4 4-repeat or short allele was associated with a slower reaction time and variable responses (Swanson et al., 2000; Manor et al., 2002a), and only one ADHD study reported the expected result of the DRD4 7-repeat allele carriers making more errors (Kieling et al., 2006). Our group recently confirmed the association between the DRD4 7-repeat allele and slower responses among healthy young adults during verbal tasks, such as word reading or picture naming, but not during simple choice reaction time tasks (Szekely et al., 2011). The DRD4 7-repeat allele might have a special effect in ADHD groups. A study that included control and ADHD children performing the Sustained Attention to Response Task showed that the ADHD 7+ group performed significantly better compared to the 7−group, whereas this genetic effect could not be detected in the control group (Johnson et al., 2008). Also, the previously mentioned MRI study (Shaw et al., 2007) showed that ADHD children carrying the 7-repeat allele had better clinical outcome and showed normalization of the right parietal cortical region compared to the 7-repeat absent ADHD group.

Besides the dopamine receptor genes, the DAT1 gene has been also implicated in sustained attention in clinical groups, such as ADHD. ADHD children with the 10/10 genotype had higher reaction-time variability and more errors compared to those carrying the 9-repeat allele in some but not all studies (Bellgrove and Mattingley, 2008; Rommelse et al., 2008). Whereas continuous performance test analyses of NET polymorphisms conducted among ADHD children gave contradictory results (Cho et al., 2008; Kollins et al., 2008).

Date: 2016-01-03; view: 846