Abstract
Attention-deficit hyperactivity disorder (ADHD) is a heritable childhood onset disorder that is marked by variability at multiple levels including clinical presentation, cognitive profile, and response to stimulant medications. It has been suggested that this variability may reflect etiological differences, particularly, at the level of underlying genetics. This study examined whether an attentional phenotype-spatial attentional bias could serve as a marker of symptom severity, genetic risk, and stimulant response in ADHD. A total of 96 children and adolescents with ADHD were assessed on the Landmark Task, which is a sensitive measure of spatial attentional bias. All children were genotyped for polymorphisms (3′ untranslated (UTR) and intron 8 variable number of tandem repeats (VNTRs)) of the dopamine transporter gene (DAT1). Spatial attentional bias correlated with ADHD symptom levels and varied according to DAT1 genotype. Children who were homozygous for the 10-repeat allele of the DAT1 3′-UTR VNTR displayed a rightward attentional bias and had higher symptom levels compared to those with the low-risk genotype. A total of 26 of these children who were medication naive performed the Landmark Task at baseline and then again after 6 weeks of stimulant medication. Left-sided inattention (rightward bias) at baseline was associated with an enhanced response to stimulants at 6 weeks. Moreover, changes in spatial bias with stimulant medications, varied as a function of DAT1 genotype. This study suggests an attentional phenotype that relates to symptom severity and genetic risk for ADHD, and may have utility in predicting stimulant response in ADHD.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Angold A, Predergast M, Cox A, Harrington R, Simonoff E, Rutter M (1995). The Child and Adolescent Psychiatric Assessment (CAPA). Psychol Med 25: 739–753.
Asherson P, Brookes K, Franke B, Chen W, Gill M, Ebstein RP et al (2007). Confirmation that a specific haplotype of the dopamine transporter gene is associated with combined-type ADHD. Am J Psychiatry 164: 674–677.
Bellgrove MA, Chambers CD, Johnson KJ, Daibhis A, Daly M, Hawi Z et al (2007). Dopaminergic genotype biases spatial attention in healthy children. Mol Psychiatry 12: 786–792.
Bellgrove MA, Gill M, Hawi Z, Kirley A, Robertson IH (2005a). 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.
Bellgrove MA, Hawi Z, Kirley A, Fitzgerald M, Gill M, Robertson IH (2005b). Association between dopamine transporter (DAT1) genotype, left-sided inattention, and an enhanced response to methylphenidate in attention-deficit hyperactivity disorder. Neuropsychopharmacology 30: 2290–2297.
Binder J, Marshall R, Lazar R, Benjamin J, Mohr JP (1992). Distinct syndromes of hemineglect. Arch Neurol 49: 1187–1194.
Bowers D, Heilman KM (1980). Pseudoneglect: effects of hemispace on a tactile line bisection task. Neuropsychologia 18: 491–498.
Bradshaw JL (1989). Hemispheric Specialisation and Psychological Function. Wiley: New York.
Brookes KJ, Mill J, Guindalini C, Curran S, Xu X, Knight J et al (2006). A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy. Arch Gen Psychiatry 63: 74–81.
Carter CS, Krener P, Chaderjian M, Northcutt C, Wolfe V (1995). Asymmetrical visual-spatial attentional performance in ADHD: evidence for a right hemispheric deficit. Biol Psychiatry 37: 789–797.
Casey BJ, Castellanos FX, Giedd JN, Marsh WL, Hamburger SD, Schubert AB et al (1997). Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 36: 374–383.
Castellanos FX, Giedd JN, Eckburg P, Marsh WL, Vaituzis AC, Kaysen D et al (1994). Quantitative morphology of the caudate nucleus in attention deficit hyperactivity disorder. Am J Psychiatry 151: 1791–1796.
Castellanos FX, Giedd JN, Marsh WL, Hamburger SD, Vaituzis AC, Dickstein DP et al (1996). Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder. Arch Gen Psychiatry 53: 607–616.
Cheon KA, Ryu YH, Kim JW, Cho DY (2005). The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter density in Korean children with attention deficit hyperactivity disorder: relating to treatment response to methylphenidate. Eur Neuropsychopharmacol 15: 95–101.
Cheon KA, Ryu YH, Kim YK, Namkoong K, Kim CH, Lee JD (2003). Dopamine transporter density in the basal ganglia assessed with [123I]IPT SPET in children with attention deficit hyperactivity disorder. Eur J Nucl Med Mol Imaging 30: 306–311.
Cho SC, Hwang JW, Kim BN, Lee HY, Kim HW, Lee JS et al (2006). The relationship between regional cerebral blood flow and response to methylphenidate in children with attention-deficit hyperactivity disorder: comparison between non-responders to methylphenidate and responders. J Psychiatr Res 41: 459–465.
Conners CK (1997). Conners' Rating Scales-Revised: Technical Manual. Multi-Health Systems Inc.: New York.
Cook EH, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE et al (1995). Association of attention-deficit disorder and the dopamine transporter gene. Am J Hum Genet 56: 993–998.
Coull JT, Nobre AC, Frith CD (2001). The noradrenergic alpha2 agonist clonidine modulates behavioural and neuroanatomical correlates of human attentional orienting and alerting. Cereb Cortex 11: 73–84.
Daly G, Hawi Z, Fitzgerald M, Gill M (1999). Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children. Mol Psychiatry 4: 192–196.
Dobler V, Manly T, Atkinson J, Wilson BA, Ioannou K, Robertson IH (2001). Interaction of hand use and spatial selective attention in children. Neuropsychologia 39: 1055–1064.
Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ (1999). Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 354: 2132–2133.
Dresel S, Krause J, Krause KH, LaFougere C, Brinkbaumer K, Kung HF et al (2000). Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment. Eur J Nucl Med 27: 1518–1524.
Efron D, Jarman F, Barker M (1997). Methylphenidate vs dexamphetamine in children with attention deficit hyperactivity disorder: a double-blind, crossover trial. Pediatrics 100: E6.
Epstein JN, Conners CK, Erhardt D, March JS, Swanson JM (1997). Asymmetrical hemispheric control of visual-spatial attention in adults with attention deficit hyperactivity disorder. Neuropsychology 11: 467–473.
Facoetti A, Turatto M, Lorusso ML, Mascetti GG (2001). Orienting of visual attention in dyslexia: evidence for asymmetric hemispheric control of attention. Exp Brain Res 138: 46–53.
Failla CV, Sheppard DM, Bradshaw JL (2003). Age and responding-hand related changes in performance of neurologically normal subjects on the line-bisection and chimeric-faces tasks. Brain Cogn 52: 353–363.
Fink GR, Marshall JC, Shah NJ, Weiss PH, Halligan PW, Grosse-Ruyken M et al (2000). Line bisection judgments implicate right parietal cortex and cerebellum as assessed by fMRI. Neurology 54: 1324–1331.
Fink GR, Marshall JC, Weiss PH, Zilles K (2001). The neural basis of vertical and horizontal line bisection judgments: an fMRI study of normal volunteers. Neuroimage 14 (1 Part 2): S59–S67.
Fleet WS, Valenstein E, Watson RT, Heilman KM (1987). Dopamine agonist therapy for neglect in humans. Neurology 37: 1765–1770.
Fuke S, Suo S, Takahashi N, Koike H, Sasagawa N, Ishiura S (2001). The VNTR polymorphism of the human dopamine transporter (DAT1) gene affects gene expression. Pharmacogenomics J 1: 152–156.
Gilbert DL, Wang Z, Sallee FR, Ridel KR, Merhar S, Zhang J et al (2006). Dopamine transporter genotype influences the physiological response to medication in ADHD. Brain 129 (Part 8): 2038–2046.
Gill M, Daly G, Heron S, Hawi Z, Fitzgerald M (1997). Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism. Mol Psychiatry 2: 311–313.
Heinz A, Goldman D, Jones DW, Palmour R, Hommer D, Gorey JG et al (2000). Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology 22: 133–139.
Holmes J, Lawson D, Langley K, Fitzpatrick H, Trumper A, Pay H et al (2004). The Child Attention-Deficit Hyperactivity Disorder Teacher Telephone Interview (CHATTI): reliability and validity. Br J Psychiatry 184: 74–78.
Iversen SD (1984). Behavioural effects of manipulation of basal ganglia neurotransmitters. Ciba Found Symp 107: 183–200.
Jucaite A, Fernell E, Halldin C, Forssberg H, Farde L (2005). Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity. Biol Psychiatry 57: 229–238.
Kirley A, Lowe N, Hawi Z, Mullins C, Daly G, Waldman I et al (2003). Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD. Am J Med Genet 121B: 50–54.
Konrad K, Neufang S, Hanisch C, Fink GR, Herpertz-Dahlmann B (2006). Dysfunctional attentional networks in children with attention deficit/hyperactivity disorder: evidence from an event-related functional magnetic resonance imaging study. Biol Psychiatry 59: 643–651.
Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K (2000). Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measures by single photon emission computed tomography. Neurosci Lett 285: 107–110.
Langley K, Turic D, Peirce TR, Mills S, Van Den Bree MB, Owen MJ et al (2005). No support for association between the dopamine transporter (DAT1) gene and ADHD. Am J Med Genet B Neuropsychiatr Genet 139: 7–10.
Lewis DA, Melchitzky DS, Sesack SR, Whitehead RE, Auh S, Sampson A (2001). Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol 432: 119–136.
Loo SK, Specter E, Smolen A, Hopfer C, Teale PD, Reite ML (2003). Functional effects of the DAT1 polymorphism on EEG measures in ADHD. J Am Acad Child Adolesc Psychiatry 42: 986–993.
Makris N, Biederman J, Valera EM, Bush G, Kaiser J, Kennedy DN et al (2007). Cortical thinning of the attention and executive function networks in adults with attention-deficit/hyperactivity disorder. Cereb Cortex 17: 1364–1375.
Maruff P, Hay D, Malone V, Currie J (1995). Asymmetries in the covert orienting of visual spatial attention in schizophrenia. Neuropsychologia 33: 1205–1223.
Mehta MA, Owen AM, Sahakian BJ, Mavaddat N, Pickard JD, Robbins TW (2000). Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain. J Neurosci 20: RC65.
Mesulam M-M (1981). A cortical network for directed attention and unilateral neglect. Ann Neurol 10: 309–325.
Mick E, Biederman J, Spencer T, Faraone SV, Sklar P (2006). Absence of association with DAT1 polymorphism and response to methylphenidate in a sample of adults with ADHD. Am J Med Genet B Neuropsychiatr Genet 141: 890–894.
Nigg JT, Swanson JM, Hinshaw SP (1997). Covert visual spatial attention in boys with attention deficit hyperactivity disorder: lateral effects, methylphenidate response, and results for parents. Neuropsychologia 35: 165–176.
Owens EB, Hinshaw SP, Kraemer HC, Arnold LE, Abikoff HB, Cantwell DP et al (2003). Which treatment for whom for ADHD? Moderators of treatment response in the MTA. J Consult Clin Psychol 71: 540–552.
Robertson IH, Marshall JC (eds). (1993). Unilateral Neglect: Clinical and Experimental Studies. Lawrence Erlbaum and Associates: Hillsdale, NJ.
Rohde LA, Roman T, Szobot C, Cunha RD, Hutz MH, Biederman J (2003). Dopamine transporter gene, response to methylphenidate and cerebral blood flow in attention-deficit/hyperactivity disorder: a pilot study. Synapse 48: 87–89.
Roman T, Szobot C, Martins S, Biederman J, Rohde LA, Hutz MH (2002). Dopamine transporter gene and response to methlphenidate in attention-deficit/hyperactivity disorder. Pharmacogenetics 12: 497–499.
Shaw P, Lerch J, Greenstein D, Sharp W, Clasen L, Evans A et al (2006). Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 63: 540–549.
Sheppard DM, Bradshaw JL, Mattingley JB, Lee P (1999). Effects of stimulant medication on the lateralisation of line bisection judgements of children with attention deficit hyperactivity disorder. J Neurol, Neurosurg Psychiatry 66: 57–63.
Silk T, Vance A, Rinehart N, Egan G, O'Boyle M, Bradshaw JL et al (2005). Decreased fronto-parietal activation in attention deficit hyperactivity disorder, combined type (ADHD-CT): an fMRI study. Br J Psychiatry 187: 282–283.
Smith AB, Taylor E, Brammer M, Toone B, Rubia K (2006). Task-specific hypoactivation in prefrontal and temporoparietal brain regions during motor inhibition and task switching in medication-naive children and adolescents with attention deficit hyperactivity disorder. Am J Psychiatry 163: 1044–1051.
Sowell ER, Thompson PM, Welcome SE, Henkenius AL, Toga AW, Peterson BS (2003). Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder. Lancet 362: 1699–1707.
Spencer TJ, Biederman J, Madras BK, Dougherty DD, Bonab AA, Livni E et al (2007). Further evidence of dopamine transporter dysregulation in ADHD: a Controlled PET Imaging Study Using Altropane. Biol Psychiatry 62: 1059–1061.
Stein MA, Waldman ID, Sarampote CS, Seymour KE, Robb AS, Conlon C et al (2005). Dopamine transporter genotype and methylphenidate dose response in children with ADHD. Neuropsychopharmacology 30: 1374–1382.
Stephens M, Donnelly P (2003). A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73: 1162–1169.
Tamm L, Menon V, Reiss AL (2006). Parietal attentional system aberrations during target detection in adolescents with attention deficit hyperactivity disorder: event-related fMRI evidence. Am J Psychiatry 163: 1033–1043.
van der Meulen EM, Bakker SC, Pauls DL, Oteman N, Kruitwagen CL, Pearson PL et al (2005). High sibling correlation on methylphenidate response but no association with DAT1-10R homozygosity in Dutch sibpairs with ADHD. J Child Psychol Psychiatry 46: 1074–1080.
VanNess SH, Owens MJ, Kilts CD (2005). The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density. BMC Genet 6: 55.
Vles JS, Feron FJ, Hendriksen JG, Jolles J, van Kroonenburgh MJ, Weber WE (2003). Methylphenidate down-regulates the dopamine receptor and transporter system in children with attention deficit hyperkinetic disorder (ADHD). Neuropediatrics 34: 77–80.
Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS et al (1998). Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 155: 1325–1331.
Volkow ND, Wang GJ, Newcorn J, Fowler JS, Telang F, Solanto MV et al (2007). Brain dopamine transporter levels in treatment and drug naive adults with ADHD. Neuroimage 34: 1182–1190.
Wilkinson GS (1993). The Wide Range Achievement Test (WRAT3). Wide Range Inc.: Wilmington, Delaware, USA.
Winsberg BG, Comings DE (1999). Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. J Am Acad Child Adolesc Psychiatry 38: 1474–1477.
Acknowledgements
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. MAB is supported by an Australian National Health and Medical Research Council Howard Florey Centenary Fellowship. KAJ is supported by the Health Research Board of Ireland. We thank the referring child and adolescent psychiatrists from the Health Service Executive, South Western, North Eastern, and Midlands areas and the Lucena clinics. We also thank the participating children and their families.
Author information
Authors and Affiliations
Corresponding author
Additional information
Disclosure/Conflict of Interest
Dr Bellgrove, Dr Gill, and Dr Robertson hold a patent within Ireland (Irish Patent no: 84530) on using molecular genetic and attentional markers to predict methylphenidate response in ADHD. The other authors have nothing to disclose.
Rights and permissions
About this article
Cite this article
Bellgrove, M., Barry, E., Johnson, K. et al. Spatial Attentional Bias as a Marker of Genetic Risk, Symptom Severity, and Stimulant Response in ADHD. Neuropsychopharmacol 33, 2536–2545 (2008). https://doi.org/10.1038/sj.npp.1301637
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.npp.1301637
Keywords
This article is cited by
-
Mice with an autism-associated R451C mutation in neuroligin-3 show intact attention orienting but atypical responses to methylphenidate and atomoxetine in the mouse-Posner task
Psychopharmacology (2024)
-
Dopamine influences attentional rate modulation in Macaque posterior parietal cortex
Scientific Reports (2022)
-
Reduced fine motor competence in children with ADHD is associated with atypical microstructural organization within the superior longitudinal fasciculus
Brain Imaging and Behavior (2021)
-
Prefrontal cortical α2A-adrenoceptors and a possible primate model of attention deficit and hyperactivity disorder
Neuroscience Bulletin (2015)
-
Biomarkers in the Diagnosis of ADHD – Promising Directions
Current Psychiatry Reports (2014)
