Bellgrove MA, Hawi Z, Kirley A, Gill M, Robertson IH. Dissecting the attention deficit hyperactivity disorder (ADHD) phenotype: sustained attention, response variability and spatial attentional asymmetries in relation to dopamine transporter (DAT1) genotype. Neuropsychologia 43: 1847-1857

Department of Psychology, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
Neuropsychologia (Impact Factor: 3.3). 02/2005; 43(13):1847-57. DOI: 10.1016/j.neuropsychologia.2005.03.011
Source: PubMed


ADHD is a childhood-onset behavioural disorder with a heterogeneous profile of neuropsychological impairment. Neuropsychological heterogeneity may, in part, reflect underlying genetic differences. Here we examined sustained attention, response variability and spatial attentional asymmetries in a sample of children and adolescents with ADHD (n=22) in relation to dopamine transporter genotype (DAT1) and also controls (n=20). Participants performed the sustained attention to response task (SART) (testing sustained attention and response variability) and the greyscales task (a perceptual measure of attentional bias). The latter has previously been shown to yield a robust leftward attentional asymmetry in healthy subjects. The 10-repeat allele of the DAT1 gene has been associated with ADHD in a number of studies and appears to have biological significance. The ADHD group was sub-divided into those individuals with two copies of the "high-risk" 10-repeat allele (high-risk DAT1) versus those with one or no copies of this allele (low-risk DAT1). The high-risk DAT1 ADHD group displayed greater response variability on the SART than either the low-risk DAT1 group or healthy controls, whereas the latter two groups did not differ. Further, the high-risk DAT1 group showed an attenuated spatial asymmetry, relative to the low-risk DAT1 ADHD group, who showed the typical leftward attentional asymmetry. Our results suggest that the 10-repeat DAT1 allele may mediate neuropsychological impairment in ADHD. The application of molecular genetics may help to define neuropsychological impaired subgroups of ADHD.

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    • "Functional connectivity studies of the ACC have revealed extensive associations with the motor cortex, and superior parietal regions associated with higher order cognitive and attentional processes, as well as subcortical circuits including basal ganglia, thalamus, and cerebellum (Margulies et al., 2007; Shenhav et al., 2013). The ACC receives catecholaminergic innervation arising from midbrain structures, which may provide a neuromodulatory basis for trial-to-trial RT fluctuations (Bellgrove et al., 2005; Cummins et al., 2014; MacDonald et al., 2009a). Within healthy adults, intra-individual RT variability on a set-shifting task was significantly correlated with D2 binding in the ACC (MacDonald et al., 2009a). "
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    ABSTRACT: Within-subject, or intra-individual, variability in reaction time (RT) is increasingly recognised as an important indicator of the efficiency of attentional control, yet there have been few investigations of the neural correlates of trial-to-trial RT variability in healthy adults. We sought to determine the neural correlates of intra-individual RT variability during a go/no-go response inhibition task in 27 healthy, male participants. We found that reduced trial-to-trial RT variability (i.e. greater response stability), was significantly associated with greater activation in the left pregenual anterior cingulate. These results support the role of the left anterior cingulate in the dynamic control of attention and efficient response selection. Greater understanding of intra-individual RT variability and top-down attentional control in healthy adults may help to inform disorders that impact executive/attentional control, such as attention deficit hyperactivity disorder and schizophrenia. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Mar 2015 · Neuropsychologia
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    • "UTR VNTR has been reliably associated with ADHD principally in child populations. Although not unequivocal, in vitro and human in vivo evidence suggests that the 10-, relative to 9-repeat allele may be associated with increased expression of the transporter, smaller brain volumes in key areas of ADHD pathology, such as the caudate, and atypical neurocognitive profiles and brain activation patterns [Bellgrove et al., 2005; Durston et al., 2005, 2008; Fuke et al., 2001]. "
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    ABSTRACT: Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self-reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3'UTR and intron 8 of DAT1, the 10-repeat and 6-repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7-repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS-G and CAARS-H (DSM-IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS-G was also found for the 7-repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Feb 2015 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "rphisms ( El - Hage et al . , 2013 ; Garcia - Garcia et al . , 2011 ; Heinzel et al . , 2013 ) , which when combined with the often low sample size of imaging genetics studies could mas - querade as a main effect of COMT . Likewise , the dopaminergic system is influenced polygenically and other dopamine genes have been shown to be related to ISV ( Bellgrove et al . , 2005b ) , and small studies could fail to isolate the effects of COMT specifically , where other genetic effects con - tribute to dopamine functioning . As the most important and robust genes and epistatic effects affecting ISV and working memory emerge in the lit - erature , however , such problems will hopefully become easier to identify . "
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    ABSTRACT: Intra-subject variability in reaction times (ISV) is a promising endophenotype for several psychiatric conditions, but its neural underpinnings are not yet established. Converging evidence from neuroimaging, molecular genetics, and psychopharmacology suggest that ISV could index catecholaminergically-mediated neural noise. The fine-grained temporal resolution of electroencephalography is ideal for investigating ISV, but only if potential neural correlates of ISV can be assessed in single trials. Based on evidence that ISV is associated with dopaminergic functioning, we apply a recently developed method of single-trial P3b analysis to investigate the association of COMT Val(158)Met genotype with measures of ISV on the behavioural and neural levels at different working memory loads. Greater number of Met alleles was associated with poorer and more intra-individually variable performance on the tasks, and greater latency jitter in single-trial P3bs. These converging results at the behavioural and neurophysiological levels confirm previous observations that prefrontal dopamine availability is associated with stability and accuracy of cognitive performance. Together with previous studies, these data imply pleiotropic cognitive effects of COMT genotype.
    Full-text · Article · Jun 2014 · NeuroImage
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