In everyday life, our sensory system is bombarded with visual input and we rely upon attention to select only those inputs that are relevant to behavioural goals. Typically, humans can shift their attention from one visual field to the other with little cost to perception. In cases of ‘unilateral neglect’, however, there is a persistent bias of spatial attention towards the same side as the damaged cerebral hemisphere. We used a visual orienting task to examine the influence of functional polymorphisms of the dopamine transporter gene (DAT1) on individual differences in spatial attention in normally developing children. DAT1 genotype significantly influenced spatial bias. Healthy children who were homozygous for alleles that influence the expression of dopamine transporters in the brain displayed inattention for left-sided stimuli, whereas heterozygotes did not. Our data provide the first evidence in healthy individuals of a genetically mediated bias in spatial attention that is related to dopamine signalling.
Spatial selective attention enhances perceptual processing at specific locations in space, and is subserved by a predominantly right-hemisphere neural network involving frontal, parietal and sub-cortical regions.1, 2 The dominance of the right hemisphere for spatial attention is illustrated by the syndrome of unilateral spatial neglect. Lesions within the right-hemisphere system give rise to a bias of spatial attention towards the ipsilesional side that is more severe and persistent than in cases of left-hemisphere damage.1, 3 This scenario may arise because the right hemisphere controls attention to both the left and right hemifields, whereas the left hemisphere may do so only for the right hemifield.1 Accordingly, stimuli presented in the left hemifield may be more susceptible to disruption. Biases in spatial attention have also been reported in a range of psychiatric conditions, and can be modified through the administration of dopaminergic agents.4, 5 Here we examined whether allelic variation in a dopamine gene was related to individual differences in spatial attention, particularly as a function of hemifield, in normally developing children.
Contemporary accounts of spatial attention emphasize neuromodulation by cholinergic and noradrenergic mechanisms,6, 7, 8, 9 with little contribution from dopamine. Yet there are good reasons to expect that dopamine may play an important role in directed attention, particularly across the hemifields. Lesions of the ascending dopaminergic pathways have been shown to cause neglect-like behaviour in rats,10 while in humans treatment with dopamine agonists reduces the extent of unilateral neglect11 (but see Grujic et al.12). Biases of spatial attention may be induced in healthy subjects through catecholamine agents, such as clonidine, which attenuate task-related brain activity in the posterior parietal cortex during spatial orienting.13 Abnormal spatial attention biases have also been reported in a number of psychiatric disorders where the dopamine system is thought to be important, such as schizophrenia and attention deficit hyperactivity disorder (ADHD).4, 5 In the case of ADHD, left sided inattention is improved by treatment with methylphenidate,5 which inhibits the dopamine transporter (DAT).14
These lines of evidence led us to ask whether individual differences in the lateralized control of spatial attention are related to genotypic differences in potentially functional polymorphisms of the dopamine transporter gene (DAT1). Behaviour genetic studies have demonstrated a genetic contribution to visual cognition,15, 16 but few studies have examined the molecular genetic correlates of spatial attention. Two previous studies have reported an influence of allelic variation within a polymorphism of a nicotinic acetylcholine receptor gene and aspects of spatial attention.17, 18 These authors, however, failed to find an influence of allelic variation in a dopamine gene – dopamine β-hydroxylase – and thus a specific role for dopamine in spatial attention remains uncertain.
We examined the specific attentional role of two variable number of tandem repeat (VNTR) polymorphisms of DAT1, one located in intron 8 and the other in the 3′ untranslated (3′-UTR) region of the gene. The DAT is heavily expressed within human striatum where it serves as the primary means of dopamine re-uptake. In contrast, DAT is relatively sparsely distributed in prefrontal cortex, where dopamine is cleared by other means.19 High densities of DAT-immunoreactive axons have also been found within the posterior parietal cortex.20 This pattern of expression overlaps substantially with the neural substrates of directed attention that include the anterior cingulate, parietal lobe and striatum.1
The gene encoding DAT (SLC6A3) comprises 15 exons spanning a region of 60 kb on chromosome 5p15.32. The 3′-UTR DAT1 polymorphism is a 40 bp VNTR with repeat copy numbers between 3 and 11, with the 10-repeat allele being the most frequent. The 10-repeat allele is thought to be a risk factor for ADHD21, 22 and has been associated with left-sided inattention in that disorder.23, 24 A number of in vitro studies suggest that the 10-repeat allele is associated with increased expression of DAT, relative to other alleles, such as the 9-repeat.25, 26 In vivo studies using neuroimaging in adults and children have shown that the 10-repeat allele is associated with increased transporter density in the human striatum and basal ganglia.27, 28 An additional VNTR within intron 8 has recently been identified and is associated with both cocaine abuse and ADHD.22, 29 A preliminary study using a reporter gene construct found evidence that this VNTR is functional, with the 3-repeat allele showing reduced expression and heightened sensitivity to cocaine, relative to a 2-repeat allele.29 Nevertheless, a regulatory role of the intron 8 VNTR in normally expressing DAT1 cells is yet to be established. Linking variation in the intron 8 marker to individual differences in cognition is an important next step in helping to establish the functional candidacy of this marker. Together, the 3-repeat intron 8 and 10-repeat 3′-UTR alleles form a common DAT1 haplotype (10/3) that appears to confer risk to ADHD with an odds ratio of around 2.6.22 Haplotypes represent sets of closely linked alleles that are inherited as a block of DNA, and can be used to accurately identify a region of a gene that may harbour a causative variant for a trait or disease. To date no studies have examined the association of this haplotype with cognitive ability in non-clinical populations.
We predicted that DNA variants of the DAT1 gene would be associated with individual differences in the control of spatial attention, particularly as a function of hemifield. Mechanisms of spatial attention were probed in 51 healthy children using a covert visual orienting task in which a visual target stimulus was preceded in time by a spatial cue (Figure 1). In different cueing conditions, the cue predicted the target location correctly (validly cued trials), incorrectly (invalidly cued trials) or uninformatively (neutrally cued trials). Such orienting tasks typically yield reaction time (RT) effects that reflect the operation of spatial selective attention. First, when attention is cued validly to a target location, RTs are typically faster than when the target is preceded by a neutral cue. This RT benefit reflects the attentional enhancement of perceptual processing at validly cued locations. In contrast, the disadvantage or cost in RT conferred by invalid cues, relative to neutral cues, reflects the time taken to reorient attention from the invalidly cued location to detect a target in an uncued location.13
We found that DAT1 genotype significantly influenced spatial bias. Healthy children who were homozygous for alleles that influence the expression of DATs in the brain displayed inattention for left-sided stimuli, whereas heterozygotes did not. We found no evidence of association with a polymorphism of the cholinergic system that has previously been linked to spatial attention. Our data provide evidence in healthy individuals of a genetically mediated bias in spatial attention that is related to dopamine signalling. Our data indicate a more prominent role of dopamine in the control of spatial attention, particularly as a function of hemifield, than has hitherto been appreciated.
Materials and methods
Fifty-one normally developing children between the ages of 9 and 16 (M=13.7 years, s.d.=2.1) took part in the study. All had IQ estimates above 80 (M=111, s.d.=12.7) and all scored in the normal range on the Reading Subtest of the Wide Range Achievement Test (WRAT-3) (M=109, s.d.=12). Since ADHD has been associated with spatial attentional bias, all children were screened for ADHD symptomatology using the Conners’ Parent Rating Scale-Revised: Long Version (CPRS-R:L).30 All children had Conners’ Global Index T-scores in the normative range (T<60) (M=45, s.d.=4.3). Forty-eight of these children were right-handed as assessed by the Edinburgh Handedness Inventory. All participants were recruited in accordance with the ethical guidelines of Trinity College Dublin and St James’ Hospital, Dublin, Ireland.
Assessing spatial attention
Participants performed a reflexive orienting task in a single testing session. Participants fixated on a central cross (500 ms duration), which turned from grey to yellow to signal the commencement of a trial. Cues consisted of a 100 ms luminance change (100%) in both placeholders in the same (valid; 33%) or opposite (invalid; 33%) hemifield as the target; or in the case of the neutral cue (33%), in all four placeholders. The stimulus-onset asynchrony (SOA) between the cue and target events was randomly either 200 or 800 ms, and 50% of targets appeared in the left and right hemifields. The target was a 100 ms sine-wave grating that occurred with equal probability within the top or bottom placeholder in one hemifield. Participants used a joystick to indicate whether the target appeared in an upper (forward response) or lower (backward response) location, irrespective of whether it occurred in the left or right hemifield. Participants performed 384 trials representing 32 trials per condition of Target Side, Validity and SOA. The task was performed on a portable computer at a viewing distance of 60 cm. Each task was performed covertly and eye movements were monitored on a trial-by-trial basis. Trials on which a saccade occurred were excluded from analysis.
Genomic DNA was extracted from saliva using Oragene DNA self-collections kits (DNAgenotek, Ottawa, ON, Canada). Polymerase chain reaction (PCR) amplification of the intron 8 marker was performed using the following primers (10 pmol/μl each): (forward: 5′-IndexTermGCTTGGGGAAGGAAGGG-3′; reverse 5′-IndexTermTGTGTGCGTGCATGTGG-3′). The following PCR cycling protocol was adopted: 95°C for 15 min, with 30 cycles of annealing 66°C for 1 min and extension at 72°C for 1 min. A final 10 min extension at 72°C was also added. Amplification products were visualized on 2% agarose gels, denoting the two common repeats as allele 2 and 3 at 339 and 369 bp, respectively. PCR amplification and genotyping of the 3′-DAT1 marker was conducted as described by Cook et al.21 Genotyping of the C1545T marker of the α-4 nicotinic receptor gene was commercially performed by K-Biosciences, Hoddesdon, Hertfordshire, England.
RTs as a function of task condition were normally distributed and thus analysis of variance (ANOVA) could be employed. Omnibus ANOVAs, as a function of DAT1 genotype group (see below), were performed with repeated-measure, factors of Validity (valid, neutral, invalid), Target Side (left, right) and SOA (200, 800 ms). RT costs (Invalid RT−Neutral RT) were only analysed subsequent to a higher-order interaction involving the factor of Validity being present at P<0.05. Interactions were decomposed using analysis of simple main effects with Bonferroni corrections for multiple comparisons. For the intron 8 marker, we compared the performance of 3-repeat homozygotes (3/3) to that of 3-repeat heterozygotes (3R). Equally, for the 3′-UTR marker 10-repeat homozygotes (10/10) were compared to 10-repeat heterozygotes (10R) (Table 1). For the C1545T marker participants possessing at least one C allele (n=35) were compared to those who did not possess this allele (n=16). Genotypes at the DAT1 markers were in Hardy–Weinberg (H–W) equilibrium (see Table 1), as were the genotypes at the C1545T marker (χ2=1.7, P=0.43).
Dopaminergic DNA variants bias spatial attention
Despite both of the DAT1 VNTRs being in strong linkage disequilibrium (LD) the novelty of our approach required us initially to establish the separate influence of each marker on spatial orienting.
3′-UTR DAT1 VNTR
There was no main effect of DAT1 genotype on overall RT (F1,44=1.951, P=0.17). Mean RT was, however, modulated by a three-way interaction between DAT1 genotype, Cue Validity and Target Side (F2,88=3.137, P=0.048, η2=0.07). RT costs and benefits were calculated and analysed using ANOVA with DAT1 3′-UTR genotype as a between-subjects factor and Target Side as a within-subjects factor. Analysis of cuing costs (Invalid RT−Neutral RT) revealed a significant main effect of DAT1 genotype (F1,44=5.491, P=0.024, η2=0.11), indicating that the 10/10 group were slower than the 10/9 group at reorienting attention following an invalid cue. DAT1 genotype tended to interact with Target Side (F1,44=3.014, P=.09, η2=0.06), and pair-wise comparisons indicated significantly greater cuing costs for targets in left hemifield in the 10/10 group than in the 10/9 group (P<0.01; all post hoc comparisons Bonferonni corrected) (Figure 2a). There was a significant correlation between increasing possession of the 10-repeat (1 versus 2 copies) and cuing costs for targets in the left hemifield (r2=0.14, P=0.01) but not right hemifield. This result indicates a genetically mediated slowness in reorienting attention from the right- to left-hemifield.
An analysis of cuing benefits (Valid RT−Neutral RT) revealed an interaction between DAT1 genotype and Target Side that accounted for 15% of task variance (F1,44=7.45, P=0.009, η2=0.15). Pair-wise comparisons revealed an effect of Target Side for the 10/10 group (P<0.05), with a larger difference between RTs to neutral and valid trials in the left, but not right, hemifield. Slower RTs to valid trials indicate slower orienting responses in the 10/10 group. The two groups defined by genotype differed for targets in the left hemifield, with the 10/10 group showing a slower orienting response than the 10/9 group (P=0.05).
Intron 8 DAT1 VNTR
A similar analysis was performed for the DAT1 intron 8 VNTR, comparing 3-repeat homozygotes (3/3) to heterozygotes (3/2). Again, there was no influence of DAT1 genotype on overall RT (F1,48=0.27, P=0.60, η2=0.01), but a reliable interaction was found between DAT1 genotype, Validity and Target Side (F2,96=4.23, P=0.017, η2=0.08). DAT1 genotype group and Target Side interacted for cuing costs and accounted for up to 17% of task variance (F1,48=9.624, P=0.003, η2=0.17) (Figure 2b). Cuing costs were significantly greater for the 3/3, relative to 3/2, group for targets in the left hemifield (P<0.02). Further, there was an asymmetrical pattern of cuing costs for the 3/3 group, with costs being greater for targets in the left, relative to right, hemifield (P<0.02). A significant correlation was observed between possession of the 3-repeat (1 versus 2 copies) and cuing costs for targets in the left (r2=0.12, P=0.01), but not right hemifield. We found no interaction between DAT1 genotype and Target Side for cuing benefits.
10/3 DAT1 haplotype
Given the strong LD between the 3′-UTR and intron 8 markers, we sought to determine whether each of these markers had an independent effect on spatial attentional bias. Using step-wise regression, we examined whether intron 8 genotype explained unique variance in the cuing cost for targets in the left hemifield, after accounting for 3′-UTR genotype. Similarly, we conducted the comparable analysis for 3′-UTR genotype, controlling for the influence of intron 8 genotype. Neither genotype accounted for a significant proportion of the variance in the cuing cost for left targets, after controlling for the other (R2 change=0.06, P=0.1 after controlling for 3′-UTR genotype; R2 change=0.06, P=0.1 after controlling for intron 8 genotype). As anticipated, 10/3 DAT1 haplotype status (homozygous versus heterozygous) interacted with Validity and Target Side (F2,68=3.07, P=0.05, η2=0.08). 10/3 homozyotes exhibited higher cuing costs for targets in left, relative to right, hemifield (P=0.06) (Figure 2c), whereas no significant asymmetry was evident for 10/3 heterozygotes. An analysis of benefits revealed a robust interaction between 10/3 Haplotype Group and Target Side (F1,34=6.114, P=0.019, η2=0.15), with homozygotes having slower orienting responses to targets in the left hemifield than heterozygotes (P<0.05). There was no influence of DAT1 haplotype status on overall RT (F1,34=0.81, P=0.37, η2=0.02).
We also examined the specificity of these effects for the dopaminergic system by testing for association with a cholinergic DNA variant (α-4 nicotinic receptor gene C1545T polymorphism) that was reported to be associated with visuospatial attention in previous work.17, 18 Within this Irish sample, we found no interaction between task factors and C1545T genotype and in particular, no interaction of this factor with Target Side and Validity (F4,96=0.83, P=0.51, η2=0.03) or between Target Side and SOA (F2,48=0.51, P=0.61, η2=0.02).
The findings from the present study demonstrate that genetic variants involved in dopamine signalling influence spatial attention in healthy children. We found that normally developing children who carry potentially functional variants of the DAT1 gene exhibited slower attentional orienting, particularly when required to reorient attention from the right to left hemifield. This left-sided impairment is similar, in a sub-clinical form, to that observed in the neglect syndrome that occurs following damage to the right parietal lobe.31 Evidence of high densities of DAT-immunoreactive axons within the posterior parietal cortex20 suggests a possible neural substrate for the effects reported herein. Since increased expression of DAT, associated for example with the 3′-UTR VNTR, may result in lowered dopamine signalling, our results are consistent with reports that spatial bias is induced by agents that attenuate catecholamine transmission.13 Further, our findings are consistent with reports that persistent left-neglect can be ameliorated by treatment with dopamine agonists11 (but see Grujic et al.12). Our behavioural data imply that DAT expression might vary between the hemispheres, as a function of DAT1 alleles, being higher in the right hemisphere of individuals carrying risk variants (10/3-repeats). This functional asymmetry might affect spatial attentional systems, leading to a subtle orienting bias to the right side, and thus to a relative inattention of left space. It has also been observed, however, that pathological biases of attention, such as left-neglect, are often accompanied by lowered states of alertness or sustained attention.32 This relationship is thought to reflect the close coupling of sustained and spatial attention systems within the right hemisphere of the brain. Even in healthy subjects, lowered states of alertness are sufficient to induce a rightwards shift in spatial attention.33 Whether the results reported herein reflect a primary influence of DAT1 variants on alertness, with secondary effects on spatial attention, will need to be determined in future studies.
Although a number of studies have reported an influence of the 10-repeat allele of the 3′-UTR VNTR on cognitive or physiological measures in both healthy and clinical populations,23, 24, 34, 35, 36, 37 the current report is the first to demonstrate an effect of the 3-repeat intron 8 allele on cognitive measures in healthy children. Linking allelic variation in a polymorphism to cognitive measures is an important way to establish the functional significance of that polymorphism. Our analyses also highlight a novel influence of a frequent haplotype, comprising the 10- and 3-repeat alleles of these markers, on spatial attention. Since neither the association with the 3′-UTR VNTR or intron 8 VNTR and spatial attention remained significant while controlling for the other, these markers are either in strong LD–so that controlling for one cancels the effect of the other–or else they are tagging an as-yet-unknown causal variant. Our analyses suggest that a quantitative trait locus for spatial attentional bias may lie in the region defined by the intron 8 and 3′-UTR markers of the DAT1 gene.
The present findings have direct relevance for genetic studies of ADHD. Meta-analyses suggest that the 10-repeat DAT1 allele confers risk to ADHD. The 10/3 DAT1 haplotype investigated here has also been associated with ADHD in two independent samples.22 Left-sided inattention has been observed in children with ADHD5 and has been reported to be more pronounced in ADHD children who are homozygous for the 10-repeat allele.23, 24 Our results suggest that some of the risk conferred by the 10-repeat allele to ADHD may operate through its effects on the neural networks for spatial attention. A spatial inattention phenotype may improve the power of molecular genetics studies of ADHD to detect associations with genes of relatively small effect.
Only a small number of studies have examined the molecular genetic correlates of spatial attention specifically. An association between a polymorphism (C1545T) of the α-4 nicotinic receptor gene was reported to influence strategic measures of visuospatial attention on both an endogenous cuing and visual search task in healthy adults.17, 18 This association accords well with pharmacological evidence that nicotine improves attentional orienting in both monkey and humans,8 and clinical evidence that disordered cholinergic transmission, for example in Alzheimer's disease, disrupts spatial attention.38, 39 Interestingly, these authors found no association between visuospatial attention and a dopaminergic polymorphism (dopamine β-hydroxylase gene; DBH – G444A), although this variant did influence spatial working memory.18 This apparent dissociation between a role for dopaminergic genes in spatial working memory, but not spatial attention, is potentially important given pharmacological modulations of both processes by dopaminergic agonists40, 41 and their substantially overlapping neuroanatomy.42, 43 In contrast to the substantial influence of dopaminergic variants on spatial attention observed in the current study, we found no influence of the C1545T variant of the α-4 nicotinic receptor gene on spatial attention. Although this suggests a failure to replicate this association within our Irish sample, examination of the genotype frequencies associated with past reports,17, 18 shows significant departure from H–W equilibrium. In contrast, all genotypes associated with the current study were in H–W equilibrium, suggesting that they are representative of population samples. Future studies will need to determine whether dopaminergic and cholinergic variants have common influences on spatial orienting, and whether the lateralized effects reported herein are specific to DAT1 or reflect an influence of dopamine genes more generally.
In summary, this study demonstrates an association between potentially functional polymorphisms of the DAT1 gene and the control of spatial attention in healthy children. Intriguingly, DAT1 variants had a pronounced influence on the control of spatial attention across the hemifields and were associated with poorer directed attention to the left hemifield. Our results indicate a more prominent role for dopamine in the control of spatial attention than has hitherto been appreciated.
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This work was supported by grants from the Irish Health Research Board, Science Foundation Ireland, the Irish Higher Education Authority's Programme for Research in Third-Level Institutions and the Australian Academy of Science (CDC). MAB is supported by an Australian National Health and Medical Research Council Howard Florey Centenary Fellowship. CDC is a David Phillips Fellow of the BBSRC, UK. We thank Jason Mattingley and Rob Hester for helpful discussions.
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Bellgrove, M., Chambers, C., Johnson, K. et al. Dopaminergic genotype biases spatial attention in healthy children. Mol Psychiatry 12, 786–792 (2007). https://doi.org/10.1038/sj.mp.4002022
- spatial attention
- directed attention
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