Neuropsychologia 45 (2007), 630-638

 

Response variability in Attention Deficit Hyperactivity Disorder: Evidence for neuropsychological heterogeneity

 

 

 

a School of Psychology and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

 b Schools of Psychiatry and Genetics and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

 c Cognitive Neurophysiology Laboratory, Nathan S. Kline Institute, Orangeburg, NY 10962, United States

 d Cognitive Neuroscience Laboratory, School of Behavioural Science, University of Melbourne, Australia

 

Abstract

Response time (RT) variability is a common finding in ADHD research. RT variability may reflect frontal cortex function and may be related to deficits in sustained attention. The existence of a sustained attention deficit in ADHD has been debated, largely because of inconsistent evidence of time-on-task effects. A fixed-sequence Sustained Attention to Response Task (SART) was given to 29 control, 39 unimpaired and 24 impaired- ADHD children (impairment defined by the number of commission errors). The response time data were analysed using the Fast Fourier Transform, to define the fast-frequency and slow-frequency contributions to overall response variability. The impaired-ADHD group progressively slowed in RT over the course of the 5.5 min task, as reflected in this group’s greater slow-frequency variability. The fast-frequency trial-to-trial variability was also significantly greater, but did not differentially worsen over the course of the task. The higher error rates of the impaired-ADHD group did not become differentially greater over the length of the task. The progressive slowing in mean RT over the course of the task may relate to a deficit in arousal in the impaired-ADHD group. The consistently poor performance in fast-frequency variability and error rates may be due to difficulties in sustained attention that fluctuate on a trial-to-trial basis.

 

 

Keywords: Sustained attention; Response time; Fast Fourier transform; Frontal cortex; Endophenotype

© 2006 Elsevier Ltd. All rights reserved.

 

Neuropsychlogia 45 (2007) 2234-2245

 

Dissociation in performance of children with ADHD and high-functioning autism on a task of sustained attention

 

Katherine A. Johnson a,b, Ian H. Robertson a, Simon P. Kelly a,c, Timthy J. Silk d, e, f, Edwina Barry b, Aoife Daibhis a, Amy Watchorn a, Michelle Keavey a, Michael Fitzgerald b, Louise Gallagher b, Michael Gill b. Mark A. Bellgrove a,g.

 

a School of Psychology and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

b School of Medicine and Health Sciences and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland.

c Cognitive Neurophysiology Laboratry, Nathan S. Kline Institute, Orangeburg, NY 10962, United States

d Howard Florey Institute and Centre for Neuroscience, University of Melbourne, Australia

e Academic Child Psychiatry Unit, Department of Pediatrics, University of Melbourne, Australia

f Department of Psycholgy, Monash University, Australiag Cognitive Neuroscience Laboratory, School of Psychology and Queensland Brain Institute, University of Queensland, Brisane, Australia

Attention deficit hyperactivity disorder (ADHD) and autism are two neurodevelopmental disorders associated with prominent executive dysfunction, which may be underpinned by disruption within fronto-striatal and fronto-parietal circuits. We probed executive function in these disorders using a sustained attention task with a validated brain-behaviour basis. Twenty-three children with ADHD, 21 children with high-functioning autism (HFA) and 18 control children were tested on the Sustained Attention to Response Task (SART). In a fixed sequence version of the task, children were required to withhold their response to a predictably occurring no-go target (3) in a 1–9 digit sequence; in the random version the sequence was unpredictable. The ADHD group showed clear deficits in response inhibition and sustained attention, through higher errors of commission and omission on both SART versions. The HFA group showed no sustained attention deficits, through a normal number of omission errors on both SART versions. The HFA group showed dissociation in response inhibition performance, as indexed by commission errors. On the Fixed SART, a normal number of errors was made, however when the stimuli were randomised, the HFA group made as many commission errors as the ADHD group. Greater slow-frequency variability in response time and a slowing in mean response time by the ADHD group suggested impaired arousal processes. The ADHD group showed greater fast-frequency variability in response time, indicative of impaired top-down control, relative to the HFA and control groups. These data imply involvement of fronto-parietal attentional networks and sub-cortical arousal systems in the pathology of ADHD and prefrontal cortex dysfunction in children with HFA.

Keywords: Response time; Fast Fourier transform; Variability; Arousal; Response inhibition; Executive function

 

 

 

Neuropsychopharmacology (2005) 30, 2290-2297.

 

Association between Dopamine Transporter (DAT1) Genotype, Left-Sided Inattention, and an Enhanced Response to Methylphenidate in Attention-Deficit Hyperactivity Disorder

 

 

a Department of Psychology and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland. 

b Departments of Psychiatry & Genetics and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland.

 

Abstract:

A polymorphism of the dopamine transporter gene (DAT1, 10-repeat) is associated with attention-deficit hyperactivity disorder (ADHD) and has been linked to an enhanced response to methylphenidate (MPH). One aspect of the attention deficit in ADHD includes a subtle inattention to left space, resembling that seen after right cerebral hemisphere damage. Since left-sided inattention in ADHD may resolve when treated with MPH, we asked whether left-sided inattention in ADHD was related to DAT1 genotype and the therapeutic efficacy of MPH. A total of 43 ADHD children and their parents were genotyped for the DAT1 30 variable number of tandem repeats polymorphism. The children performed the Landmark Test, a well-validated measure yielding a spatial attentional asymmetry index (leftward to rightward attentional bias). Parents rated their child’s response to MPH retrospectively using a three-point scale (no, mediocre or very good response). Additionally, parents used a symptom checklist to rate behavior while on and off medication. A within-family control design determined whether asymmetry indices predicted biased transmission of 10-repeat parental DAT1 alleles and/or response to MPH. It was found that left-sided inattention predicted transmission of the 10-repeat allele from parents to probands and was associated with the severity of ADHD symptomatology. Children rated as achieving a very good response to MPH displayed left-sided inattention, while those rated as achieving a poorer response did not. Our results suggest a subgroup of children with ADHD for whom the 10-repeat DAT1 allele is associated with left-sided inattention. MPH may be most efficacious in this group because it ameliorates a DAT1-mediated hypodopaminergic state.

 

Keywords: DAT1; dopamine; ADHD; methylphenidate; attention; genetics

American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 136B (2005) :81–86

 

DRD4 Gene Variants and Sustained Attention in Attention Deficit Hyperactivity Disorder (ADHD): Effects of Associated Alleles at the VNTR and _521 SNP

 

 

a Department of Psychology and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

b Departments of Psychiatry and Genetics and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

 

Abstract:

Associations between attention deficit hyperactivity disorder (ADHD) and genetic variants within the dopamine D4 receptor gene have been much reported. Variants investigated include the 7-repeat allele of a VNTR within the third exon, and two SNPs (_521 and _616) located with the promoter region.We investigated the relationship between the VNTR, _521, and _616 SNPs and sustained attention performance in 54 ADHD probands, relative to a non-genotyped control group. Participants performed the Sustained Attention to Response Task (SART) in which the response to an unpredictably occurring target digit must be inhibited. This task, therefore, challenged sustained attention and included a response inhibition component. Consistent with previous reports, ADHD participants possessing the 7-repeat allele of the VNTR outperformed those children not possessing this allele, both in terms of errors and response variability. In family based analyses, better performance on the SART tended to predict biased transmission of the 7- repeat allele from heterozygous parents. For the _521 SNP, A allele homozygotes showed greater impairment than heterozygotes or those not possessing this allele, both in terms of total errors and response variability. Family based analysis showed that higher total errors on the SART predicted transmission of theAallele from heterozygous parents. There were no effects of the _616 SNP. Our results suggest dissociable effects of the ‘‘associated alleles’’ of DRD4 gene variants on sustained attention: while the 7-repeat allele of the VNTR is associated with relatively better performance, the A allele of the _521 SNP is associated with poorer performance.

_ 2005 Wiley-Liss, Inc.

 

KEY WORDS: dopamine; DRD4; attention; genetics

Molecular Psychiatry (2007) 1-7

 

Dopaminergic genotype biases spatial attention in healthy children

 

 

a School of Psychology and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

b Departments of Psychiatry and Genetics and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

c Cognitive Neuroscience Laboratory, School of Psychology and Queensland Brain Institute, University of Queensland, Brisane, QLD, Australia

d Institute of Cognitive Neuroscience, University College London, London, UK

 

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 are 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 genetic mediated bias in spatial attention that is related to dopamine signalling.

 

Keywords: dopamine, DAT1, attention, ADHD, spatial attention, directed attention

Cortex (2006) 42, 838-845

 

The Cognitive Genetics of Attention Deficit Hyperactivity Disorder (ADHD): Sustained Attention as a Candidate Phenotype

 

Mark A. Bellgrove a,b, c, Ziarih Hawi b, Ian H. Robertson a, and Michael Gill b.

 

a School of Psychology and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

b Departments of Psychiatry and Genetics and Trinity College Institute of Neuroscience, Trinity College Dublin, -Ireland

c Cognitive Neuroscience Laboratory, University of Melbourne, Victoria, Australia

 

Here we describe the application of cognitive genetics to the study of attention deficit disorder (ADHD). Cognitive genetics owes much to the pioneering work of cognitive neuropsychologists such as John Marshall, whose careful observations of cognitive dissociations between brain-lesioned patients greatly advanced the theoretical understanding of normal cognitive function. These theories have in turn helped to constrain linkages between candidate genes and cognitive processes and thus help to drive the relatively new field of cognitive genetics in a hypothesis-driven catecholamine-related gene, dopamine beta hydroxylase (DBH). DBH encodes the enzyme that converts dopamine to noradrenaline and is crucial to catecholamine regulation. A polymorphism with the DBH gene has been associated with ADHD. In fifty-two children with ADHD, we examined whether variation in the Taq 1 DBH gene polymorphism was related to sustained attention performance. Participants performed the Sustained Attention to Response Test (SART). Performance on the SART discriminates ADHD from control children, and in imaging work, is associated with right fronto-parietal activation. A significant effect of DBH genotype was found on SART performance measures. Children possessing two copies of the ADHD-associated risk allele (A2) had significantly poorer sustained attention than those ADHD children who did not possess this allele or a non-genotyped control group. The DBH gene may contribute to the susceptibility for ADHD, in part because of its varying effects on the development of brain mechanisms mediating sustained attention.

 

Key words: genetics, attention, sustained attention, dopamine, ADHD

 

 
Neuropsychologia 43 (2005) 1847-1857

 

Dissecting the attention deficit hyperactivity disorder (ADHD) phenotype: Sustained attention, response variability and spatial attentional asymmetries in relation to the dopamine transporter (DAT1) genotype.

 

 

a School of Psychology and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

b Departments of Psychiatry and Genetics and Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland

 

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.

Keywords: ADHD, Attention, Genetics, DAT 1, Variability, Neuropsychology

© 2005 Elsevier Ltd. All rights reserved.

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