Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes

Nature Reviews Neuroscience volume 3, pages 617–628 (2002)Cite this article

Key Points

  • Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent and controversial conditions in child psychiatry. Both clinical progress and basic research will benefit from the identification of endophenotypes — intermediate, quantifiable traits that predict an individual's risk of disease and can be linked to the underlying aetiology of the condition. Such endophenotypes should also be anchored in neuroscience.

  • One of the clearest symptoms of ADHD is locomotor hyperactivity. There is evidence for dopaminergic dysfunction in humans with ADHD and, in animals, hyperactivity can be seen in both hypodopaminergic and hyperdopaminergic models. Striatal abnormalities and alterations in dopamine transporter density have been measured in subjects with ADHD, and psychostimulants (which increase the levels of catecholamines at synapses) are effective in treating the symptoms of the disorder.

  • Subjects with ADHD appear to have a deficit in response inhibition. They also manifest delay aversion, including a tendency to choose a small, immediate reward over a larger, delayed one. This can be modelled as a shortened delay gradient (a decline in the effectiveness of reinforcement as the delay between behaviour and reward increases). At least three brain abnormalities that have been observed in ADHD could potentially lead to this endophenotype: striatal abnormalities, alterations in dopamine transporter expression and reduced volume of the cerebellar vermis.

  • Many data lead us to believe that subjects with ADHD show high response variability and inconsistency in performance. They also show deficits in the perception and reproduction of time intervals. Brain abnormalities that could lead to such a deficit include cerebellar dysfunction, striatal lesions and changes in catechol-O-methyltransferase (COMT) activity in the prefrontal cortex.

  • The last proposed endophenotype is an impairment in working memory, which could be linked to delay aversion, executive dysfunction, inattention and phonemic-awareness deficits in ADHD subjects. Potential brain abnormalities that could affect working memory include striatal lesions, alterations in COMT activity and changes in the electroencephalogram (EEG).

  • The endophenotype approach allows researchers and clinicians to avoid some of the problems associated with the use of symptom scales, and should facilitate large-scale collaborative projects that are aimed at clarifying the complex causes of ADHD.

Abstract

Research on attention-deficit/hyperactivity disorder (ADHD), a highly prevalent and controversial condition, has, for the most part, been descriptive and atheoretical. The imperative to discover the genetic and environmental risk factors for ADHD is motivating the search for quantifiable intermediate constructs, termed endophenotypes. In this selective review, we conclude that such endophenotypes should be solidly grounded in the neurosciences. We propose that three such endophenotypes — a specific abnormality in reward-related circuitry that leads to shortened delay gradients, deficits in temporal processing that result in high intrasubject intertrial variability, and deficits in working memory — are most amenable to integrative collaborative approaches that aim to uncover the causes of ADHD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Causal model of shortened delay gradient as a candidate endophenotype.
Figure 2: Selective BOLD fMRI activation during anticipation of a monetary reward.
Figure 3: Causal model of temporal processing as a candidate endophenotype.
Figure 4: Causal model of working memory deficits as a candidate endophenotype.

Similar content being viewed by others

References

  1. Goldman, L. S., Genel, M., Bezman, R. J. & Slanetz, P. J. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Council on Scientific Affairs, American Medical Association. JAMA 279, 1100–1107 (1998).

    CAS  PubMed  Google Scholar 

  2. Barbaresi, W. J. et al. How common is attention-deficit/hyperactivity disorder? Incidence in a population-based birth cohort in Rochester, Minn. Arch. Pediatr. Adolesc. Med. 156, 217–224 (2002).

    PubMed  Google Scholar 

  3. LeFever, G. B., Dawson, K. V. & Morrow, A. L. The extent of drug therapy for attention deficit–hyperactivity disorder among children in public schools. Am. J. Public Health 89, 1359–1364 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Moll, G. H., Hause, S., Ruther, E., Rothenberger, A. & Huether, G. Early methylphenidate administration to young rats causes a persistent reduction in the density of striatal dopamine transporters. J. Child Adolesc. Psychopharmacol. 11, 15–24 (2001).One of the few studies to have examined the effects of stimulants in developing animals. The authors found enduring changes in striatal DATs only when chronic low-dose exposure to methylphenidate was started in young rats (day 25).

    CAS  PubMed  Google Scholar 

  5. Zito, J. M. et al. Trends in the prescribing of psychotropic medications to preschoolers. JAMA 283, 1025–1030 (2000).

    CAS  PubMed  Google Scholar 

  6. Morton, J. & Frith, U. in Developmental Psychopathology (eds Cicchetti, D. & Cohen, D. J.) 357–390 (John Wiley, New York, 1995).

    Google Scholar 

  7. Almasy, L. & Blangero, J. Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. Am. J. Med. Genet. 105, 42–44 (2001).

    CAS  PubMed  Google Scholar 

  8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, Washington DC, 1994).

  9. Swanson, J. M. et al. Seminar: attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet 351, 429–433 (1998).

    CAS  PubMed  Google Scholar 

  10. Landgren, M., Kjellman, B. & Gillberg, C. Deficits in attention, motor control and perception (DAMP): a simplified school entry examination. Acta Paediatr. 89, 302–309 (2000).

    CAS  PubMed  Google Scholar 

  11. Sonuga-Barke, E. J. Psychological heterogeneity in AD/HD — a dual pathway model of behaviour and cognition. Behav. Brain Res. 130, 29–36 (2002).

    PubMed  Google Scholar 

  12. Barkley, R. A. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol. Bull. 121, 65–94 (1997).

    PubMed  Google Scholar 

  13. Sergeant, J., Oosterlaan, J. & Van der Meere, J. in Handbook of Disruptive Behavior Disorders (eds Quay, H. C. & Hogan, A. E.) 75–104 (Plenum, New York, 1999).

    Google Scholar 

  14. Nigg, J. T. Is ADHD a disinhibitory disorder? Psychol. Bull. 127, 571–598 (2001).

    CAS  PubMed  Google Scholar 

  15. Solanto, M. V., Arnsten, A. F. T. & Castellanos, F. X. (eds) Stimulant Drugs and ADHD: Basic and Clinical Neuroscience (Oxford Univ. Press, New York, 2001).

    Google Scholar 

  16. Rutter, M. & Silberg, J. Gene–environment interplay in relation to emotional and behavioral disturbance. Annu. Rev. Psychol. 53, 463–490 (2002).

    PubMed  Google Scholar 

  17. Smalley, S. L. Genetic influences in childhood-onset psychiatric disorders: autism and attention-deficit/hyperactivity disorder. Am. J. Hum. Genet. 60, 1276–1282 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Tannock, R. Attention deficit hyperactivity disorder: advances in cognitive, neurobiological, and genetic research. J. Child Psychol. Psychiatry 39, 65–99 (1998).

    CAS  PubMed  Google Scholar 

  19. Faraone, S. V. & Doyle, A. E. Genetic influences on attention deficit hyperactivity disorder. Curr. Psychiatry Rep. 2, 143–146 (2000).

    CAS  PubMed  Google Scholar 

  20. Swanson, J. M. et al. Dopamine genes and ADHD. Neurosci. Biobehav. Rev. 24, 21–25 (2000).

    CAS  PubMed  Google Scholar 

  21. Faraone, S. V. Report from the third international meeting of the Attention-Deficit Hyperactivity Disorder Molecular Genetics Network. Am. J. Med. Genet. 114, 272–276 (2002).

    Google Scholar 

  22. Fisher, S. E. et al. A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am. J. Hum. Genet. 70, 1183–1196 (2002).This first scan in ADHD, using a sample of 126 affected sibling pairs, did not find any genome-wide statistically significant peaks, although several suggestive peaks were identified and are being explored in greater detail with an enlarged sample.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. International Molecular Genetic Study of Autism Consortium (IMGSAC). A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am. J. Hum. Genet. 69, 570–581 (2001).

  24. Herskovits, E. H. et al. Is the spatial distribution of brain lesions associated with closed-head injury predictive of subsequent development of attention-deficit/hyperactivity disorder? Analysis with brain-image database. Radiology 213, 389–394 (1999).

    CAS  PubMed  Google Scholar 

  25. Max, J. E. et al. Putamen lesions and the development of attention-deficit/hyperactivity symptomatology. J. Am. Acad. Child Adolesc. Psychiatry 41, 563–571 (2002).

    PubMed  Google Scholar 

  26. Kreppner, J. M., O'Connor, T. G. & Rutter, M. Can inattention/overactivity be an institutional deprivation syndrome? J. Abnorm. Child Psychol. 29, 513–528 (2001).This study compared 165 children that were adopted in the United Kingdom after severe deprivation with 52 within-UK adoptees who had not suffered deprivation. Parent and teacher ratings of enduring inattention/overactivity were found in relationship to the extent of early severe deprivation.

    CAS  PubMed  Google Scholar 

  27. Biederman, J. et al. Family-environment risk factors for attention-deficit hyperactivity disorder. A test of Rutter's indicators of adversity. Arch. Gen. Psychiatry 52, 464–470 (1995).

    CAS  PubMed  Google Scholar 

  28. Mick, E., Biederman, J., Faraone, S. V., Sayer, J. & Kleinman, S. Case–control study of attention-deficit hyperactivity disorder and maternal smoking, alcohol use, and drug use during pregnancy. J. Am. Acad. Child Adolesc. Psychiatry 41, 378–385 (2002).

    PubMed  Google Scholar 

  29. Hellstrom-Lindahl, E., Gorbounova, O., Seiger, A., Mousavi, M. & Nordberg, A. Regional distribution of nicotinic receptors during prenatal development of human brain and spinal cord. Brain Res. Dev. Brain Res. 108, 147–160 (1998).

    CAS  PubMed  Google Scholar 

  30. Roy, T. S., Seidler, F. J. & Slotkin, T. A. Prenatal nicotine exposure evokes alterations of cell structure in hippocampus and somatosensory cortex. J. Pharmacol. Exp. Ther. 300, 124–133 (2002).

    CAS  PubMed  Google Scholar 

  31. Lim, D. K. & Kim, H. S. Changes in the glutamate release and uptake of cerebellar cells in perinatally nicotine-exposed rat pups. Neurochem. Res. 26, 1119–1125 (2001).

    CAS  PubMed  Google Scholar 

  32. Oliff, H. S. & Gallardo, K. A. The effect of nicotine on developing brain catecholamine systems. Front. Biosci. 4, D883–D897 (1999).

    CAS  PubMed  Google Scholar 

  33. Fried, P. A. & Watkinson, B. Differential effects on facets of attention in adolescents prenatally exposed to cigarettes and marihuana. Neurotoxicol. Teratol. 23, 421–430 (2001).

    CAS  PubMed  Google Scholar 

  34. Cornblatt, B. A. & Malhotra, A. K. Impaired attention as an endophenotype for molecular genetic studies of schizophrenia. Am. J. Med. Genet. 105, 11–15 (2001).

    CAS  PubMed  Google Scholar 

  35. Quay, H. C. in Handbook of Disruptive Behavior Disorders (eds Quay, H. C. & Hogan, A. E.) 3–21 (Plenum, New York, 1999).

    Google Scholar 

  36. Teicher, M. H., Ito, Y., Glod, C. A. & Barber, N. I. Objective measurement of hyperactivity and attentional problems in ADHD. J. Am. Acad. Child Adolesc. Psychiatry 35, 334–342 (1996).

    CAS  PubMed  Google Scholar 

  37. Teicher, M. H. et al. Functional deficits in basal ganglia of children with attention-deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry. Nature Med. 6, 470–473 (2000).

    CAS  PubMed  Google Scholar 

  38. Anderson, C. M., Polcari, A. M., Lowen, S. B., Renshaw, P. F. & Teicher, M. H. Effects of methylphenidate on functional magnetic resonance relaxometry of the cerebellar vermis in children with ADHD. Am. J. Psychiatry (in the press).

  39. Porrino, L. J. et al. A naturalistic assessment of the motor activity of hyperactive boys. I. Comparison with normal controls. Arch. Gen. Psychiatry 40, 681–687 (1983).

    CAS  PubMed  Google Scholar 

  40. Antrop, I., Roeyers, H., Van Oost, P. & Buysse, A. Stimulation seeking and hyperactivity in children with ADHD. J. Child Psychol. Psychiatry 41, 225–231 (2000).

    CAS  PubMed  Google Scholar 

  41. Corkum, P., Tannock, R., Moldofsky, H., Hogg-Johnson, S. & Humphries, T. Actigraphy and parental ratings of sleep in children with attention-deficit–hyperactivity disorder (ADHD). Sleep 24, 303–312 (2001).

    CAS  PubMed  Google Scholar 

  42. Ferguson, S. A. in Stimulant Drugs and ADHD: Basic and Clinical Neuroscience (eds Solanto, M. V., Arnsten, A. F. T. & Castellanos, F. X.) 209–220 (Oxford Univ. Press, New York, 2001).

    Google Scholar 

  43. Shaywitz, B. A., Yager, R. D. & Klopper, J. H. Selective brain dopamine depletion in developing rats: an experimental model of minimal brain dysfunction. Science 191, 305–308 (1976).

    CAS  PubMed  Google Scholar 

  44. Cardinal, R. N., Pennicott, D. R., Sugathapala, C. L., Robbins, T. W. & Everitt, B. J. Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science 292, 2499–2501 (2001).

    CAS  PubMed  Google Scholar 

  45. Giros, B., Jaber, M., Jones, S. R., Wightman, R. M. & Caron, M. G. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379, 606–612 (1996).

    CAS  PubMed  Google Scholar 

  46. Viggiano, D., Grammatikopoulos, G. & Sadile, A. G. A morphometric evidence for a hyperfunctioning mesolimbic system in an animal model of ADHD. Behav. Brain Res. 130, 181–189 (2002).

    CAS  PubMed  Google Scholar 

  47. Solanto, M. V., Arnsten, A. F. T. & Castellanos, F. X. in Stimulant Drugs and ADHD: Basic and Clinical Neuroscience (eds Solanto, M. V., Arnsten, A. F. T. & Castellanos, F. X.) 355–379 (Oxford Univ. Press, New York, 2001).

    Google Scholar 

  48. Todd, R. D. & Botteron, K. N. Is attention-deficit/hyperactivity disorder an energy deficiency syndrome? Biol. Psychiatry 50, 151–158 (2001).

    CAS  PubMed  Google Scholar 

  49. Castellanos, F. X. in Stimulant Drugs and ADHD: Basic and Clinical Neuroscience (eds Solanto, M. V., Arnsten, A. F. T. & Castellanos, F. X.) 243–258 (Oxford Univ. Press, New York, 2001).

    Google Scholar 

  50. Castellanos, F. X. et al. Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder. Arch. Gen. Psychiatry 58, 289–295 (2001).

    CAS  PubMed  Google Scholar 

  51. Dougherty, D. D. et al. Dopamine transporter density is elevated in patients with attention deficit hyperactivity disorder. Lancet 354, 2132–2133 (1999).The first report of elevated striatal DAT density in adults with ADHD.

    CAS  PubMed  Google Scholar 

  52. Krause, K. H., Dresel, S. H., Krause, J., Kung, H. F. & Tatsch, K. Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measured by single photon emission computed tomography. Neurosci. Lett. 285, 107–110 (2000).

    CAS  PubMed  Google Scholar 

  53. van Dyck, C. H. et al. Unaltered dopamine transporter availability in adult attention deficit hyperactivity disorder. Am. J. Psychiatry 159, 309–312 (2002).

    PubMed  Google Scholar 

  54. Castellanos, F. X. Toward a pathophysiology of attention-deficit/hyperactivity disorder. Clin Pediatr (Phila) 36, 381–393 (1997).

    CAS  Google Scholar 

  55. Ernst, M., Zametkin, A. J., Matochik, J. A., Jons, P. H. & Cohen, R. M. DOPA decarboxylase activity in attention deficit hyperactivity disorder adults. A [fluorine-18]fluorodopa positron emission tomographic study. J. Neurosci. 18, 5901–5907 (1998).

    CAS  PubMed  Google Scholar 

  56. Ernst, M. et al. High midbrain 18F-DOPA accumulation in children with ADHD. Am. J. Psychiatry 156, 1209–1215 (1999).

    CAS  PubMed  Google Scholar 

  57. Pennington, B. F. & Ozonoff, S. Executive functions and developmental psychopathology. J. Child Psychol. Psychiatry 37, 51–87 (1996).

    CAS  PubMed  Google Scholar 

  58. Nigg, J. T. On inhibition/disinhibition in developmental psychopathology: views from cognitive and personality psychology and a working inhibition taxonomy. Psychol. Bull. 126, 220–246 (2000).

    CAS  PubMed  Google Scholar 

  59. Oosterlaan, J., Logan, G. D. & Sergeant, J. A. Response inhibition in AD/HD, CD, comorbid AD/HD + CD, anxious, and control children: a meta-analysis of studies with the stop task. J. Child Psychol. Psychiatry 39, 411–425 (1998).

    CAS  PubMed  Google Scholar 

  60. Solanto, M. V. et al. The ecological validity of delay aversion and response inhibition as measures of impulsivity in AD/HD: a supplement to the NIMH multimodal treatment study of AD/HD. J. Abnorm. Child Psychol. 29, 215–228 (2001).A head-to-head collaborative comparison of experimental measures linked to two competing theories of ADHD pathogenesis.

    CAS  PubMed  Google Scholar 

  61. Logan, G. D., Cowan, W. B. & Davis, K. A. On the ability to inhibit simple and choice reaction time responses: a model and a method. J. Exp. Psychol. Hum. Percept. Perform. 10, 276–291 (1984).

    CAS  PubMed  Google Scholar 

  62. Crosbie, J. & Schachar, R. Deficient inhibition as a marker for familial ADHD. Am. J. Psychiatry 158, 1884–1890 (2001).A preliminary demonstration of the usefulness of a laboratory measure of response inhibition (stop task) as an endophenotype. ADHD was significantly more prevalent in first-degree relatives of children with ADHD who showed poor inhibition (48% versus 19%).

    CAS  PubMed  Google Scholar 

  63. Chhabildas, N., Pennington, B. F. & Willcutt, E. G. A comparison of the neuropsychological profiles of the DSM-IV subtypes of ADHD. J. Abnorm. Child Psychol. 29, 529–540 (2001).

    CAS  PubMed  Google Scholar 

  64. Tripp, G. & Alsop, B. Sensitivity to reward delay in children with attention deficit hyperactivity disorder (ADHD). J. Child Psychol. Psychiatry 42, 691–698 (2001).

    CAS  PubMed  Google Scholar 

  65. Schultz, W. Reward signaling by dopamine neurons. Neuroscientist 7, 293–302 (2001).

    CAS  PubMed  Google Scholar 

  66. Johansen, E. B., Aase, H., Meyer, A. & Sagvolden, T. Attention-deficit/hyperactivity disorder (ADHD) behaviour explained by dysfunctioning reinforcement and extinction processes. Behav. Brain Res. 130, 37–45 (2002).

    PubMed  Google Scholar 

  67. Barkley, R. A., Edwards, G., Laneri, M., Fletcher, K. & Metevia, L. Executive functioning, temporal discounting, and sense of time in adolescents with attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). J. Abnorm. Child Psychol. 29, 541–556 (2001).

    CAS  PubMed  Google Scholar 

  68. Madras, B. K., Miller, G. M. & Fischman, A. J. The dopamine transporter: relevance to attention deficit hyperactivity disorder (ADHD). Behav. Brain Res. 130, 57–63 (2002).

    CAS  PubMed  Google Scholar 

  69. Knutson, B., Adams, C. M., Fong, G. W. & Hommer, D. Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J. Neurosci. 21, RC159 (2001).This was the first human functional study to show selective activation of the nucleus accumbens during reward anticipation but not reward attainment.

    CAS  PubMed  Google Scholar 

  70. Berquin, P. C. et al. The cerebellum in attention-deficit/hyperactivity disorder: a morphometric study. Neurology 50, 1087–1093 (1998).

    CAS  PubMed  Google Scholar 

  71. Mostofsky, S. H., Reiss, A. L., Lockhart, P. & Denckla, M. B. Evaluation of cerebellar size in attention-deficit hyperactivity disorder. J. Child Neurol. 13, 434–439 (1998).

    CAS  PubMed  Google Scholar 

  72. Melchitzky, D. S. & Lewis, D. A. Tyrosine hydroxylase- and dopamine transporter-immunoreactive axons in the primate cerebellum. Evidence for a lobular- and laminar-specific dopamine innervation. Neuropsychopharmacology 22, 466–472 (2000).

    CAS  PubMed  Google Scholar 

  73. Snider, R. S., Maiti, A. & Snider, S. R. Cerebellar pathways to ventral midbrain and nigra. Exp. Neurol. 53, 714–728 (1976).

    CAS  PubMed  Google Scholar 

  74. Dempesy, C. W. et al. Stimulation of the paleocerebellar cortex of the cat: increased rate of synthesis and release of catecholamines at limbic sites. Biol. Psychiatry 18, 127–132 (1983).

    CAS  PubMed  Google Scholar 

  75. Ernst, M. et al. Intravenous dextroamphetamine and brain glucose metabolism. Neuropsychopharmacology 17, 391–401 (1997).

    CAS  PubMed  Google Scholar 

  76. Volkow, N. D. et al. Effects of methylphenidate on regional brain glucose metabolism in humans: relationship to dopamine D2 receptors. Am. J. Psychiatry 154, 50–55 (1997).

    CAS  PubMed  Google Scholar 

  77. Corkum, P. V. & Siegel, L. S. Is the continuous performance test a valuable research tool for use with children with attention-deficit-hyperactivity disorder? J. Child Psychol. Psychiatry 34, 1217–1239 (1993).

    CAS  PubMed  Google Scholar 

  78. Koelega, H. S. Is the continuous performance task useful in research with ADHD children? Comments on a review. J. Child Psychol. Psychiatry 36, 1477–1485 (1995).

    CAS  PubMed  Google Scholar 

  79. Rosvold, H. E., Mirsky, A. F., Sarason, I., Bransome, E. D. & Beck, L. H. A continuous performance test of brain damage. J. Consult. Psychol. 20, 343–350 (1956).

    PubMed  Google Scholar 

  80. Douglas, V. I. in Handbook of Disruptive Behavior Disorders (eds Quay, H. C. & Hogan, A. E.) 105–138 (Plenum, New York, 1999).

    Google Scholar 

  81. Kuntsi, J. & Stevenson, J. Psychological mechanisms in hyperactivity. II. The role of genetic factors. J. Child Psychol. Psychiatry 42, 211–219 (2001).

    CAS  PubMed  Google Scholar 

  82. Kuntsi, J., Oosterlaan, J. & Stevenson, J. Psychological mechanisms in hyperactivity. I. Response inhibition deficit, working memory impairment, delay aversion, or something else? J. Child Psychol. Psychiatry 42, 199–210 (2001).

    CAS  PubMed  Google Scholar 

  83. Barkley, R. A., Koplowitz, S., Anderson, T. & McMurray, M. B. Sense of time in children with ADHD: effects of duration, distraction, and stimulant medication. J. Int. Neuropsychol. Soc. 3, 359–369 (1997).

    CAS  PubMed  Google Scholar 

  84. Barkley, R. A., Murphy, K. R. & Bush, T. Time perception and reproduction in young adults with attention deficit hyperactivity disorder. Neuropsychology 15, 351–360 (2001).

    CAS  PubMed  Google Scholar 

  85. Meck, W. H. Neuropharmacology of timing and time perception. Brain Res. Cogn. Brain Res. 3, 227–242 (1996).

    CAS  PubMed  Google Scholar 

  86. Ivry, R. Cerebellar timing systems. Int. Rev. Neurobiol. 41, 555–573 (1997).

    CAS  PubMed  Google Scholar 

  87. Ivry, R. B. The representation of temporal information in perception and motor control. Curr. Opin. Neurobiol. 6, 851–857 (1996).

    CAS  Google Scholar 

  88. Smith, A., Taylor, E., Rogers, J. W., Newman, S. & Rubia, K. Evidence for a pure time perception deficit in children with ADHD. J. Child Psychol. Psychiatry 43, 529–542 (2002).

    PubMed  Google Scholar 

  89. Nicolson, R. I., Fawcett, A. J. & Dean, P. Developmental dyslexia: the cerebellar deficit hypothesis. Trends Neurosci. 24, 508–511 (2001).

    CAS  PubMed  Google Scholar 

  90. Castellanos, F. X. et al. Quantitative brain magnetic resonance imaging in attention-deficit/hyperactivity disorder. Arch. Gen. Psychiatry 53, 607–616 (1996).

    CAS  PubMed  Google Scholar 

  91. Castellanos, F. X. et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA (in the press).This, the first study to compare medication-naive with previously treated ADHD patients and controls, found that brain volume is globally decreased in ADHD, but that cerebellar volumes are even more diminished than cerebral cortical regions.

  92. Ivry, R. Exploring the role of the cerebellum in sensory anticipation and timing: commentary on Tesche and Karhu. Hum. Brain Mapp. 9, 115–118 (2000).

    CAS  PubMed  Google Scholar 

  93. Egan, M. F. et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc. Natl Acad. Sci. USA 98, 6917–6922 (2001).

    CAS  PubMed  Google Scholar 

  94. Ruskin, D. N., Bergstrom, D. A. & Walters, J. R. Multisecond oscillations in firing rate in the globus pallidus: synergistic modulation by D1 and D2 dopamine receptors. J. Pharmacol. Exp. Ther. 290, 1493–1501 (1999).

    CAS  PubMed  Google Scholar 

  95. Ruskin, D. N. et al. Drugs used in the treatment of attention deficit/hyperactivity disorder affect postsynaptic firing rate and oscillation without preferential autoreceptor action. Biol. Psychiatry 49, 340–350 (2001).A study that addressed the hypothesis that stimulants might function through inhibitory striatal autoreceptors. This study also showed that stimulants in the therapeutic dose range have prominent effects on multisecond oscillations/periodicities (frequency <0.1 Hz) in basal ganglia single-unit recordings.

    CAS  PubMed  Google Scholar 

  96. Ehlers, C. L. & Foote, S. L. Ultradian periodicities in EEG and behavior in the squirrel monkey (Saimiri sciureus). Am. J. Primatol. 7, 381–389 (1984).

    Google Scholar 

  97. Borger, N. & Van der Meere, J. Motor control and state regulation in children with ADHD: a cardiac response study. Biol. Psychol. 51, 247–267 (2000).

    CAS  PubMed  Google Scholar 

  98. Miyake, A. & Shah, P. in Models of Working Memory: Mechanisms of Active Maintenance and Control (eds Miyake, A. & Shah, P.) 442–481 (Cambridge Univ. Press, Cambridge, UK, 1999).

    Google Scholar 

  99. Conway, A. R., Cowan, N. & Bunting, M. F. The cocktail party phenomenon revisited: the importance of working memory capacity. Psychon. Bull. Rev. 8, 331–335 (2001).

    CAS  PubMed  Google Scholar 

  100. de Fockert, J. W., Rees, G., Frith, C. D. & Lavie, N. The role of working memory in visual selective attention. Science 291, 1803–1806 (2001).

    CAS  PubMed  Google Scholar 

  101. Braver, T. S. et al. A parametric study of prefrontal cortex involvement in human working memory. Neuroimage 5, 49–62 (1997).

    CAS  PubMed  Google Scholar 

  102. Carlson, S. et al. Distribution of cortical activation during visuospatial n-back tasks as revealed by functional magnetic resonance imaging. Cereb. Cortex 8, 743–752 (1998).

    CAS  PubMed  Google Scholar 

  103. Arnsten, A. F. T. in Stimulant Drugs and ADHD: Basic and Clinical Neuroscience (eds Solanto, M. V., Arnsten, A. F. T. & Castellanos, F. X.) 185–208 (Oxford Univ. Press, New York, 2001).

    Google Scholar 

  104. Ellis, K. A. & Nathan, P. J. The pharmacology of human working memory. Int. J. Neuropsychopharmacol. 4, 299–313 (2001).

    CAS  PubMed  Google Scholar 

  105. Denney, C. B. & Rapport, M. D. in Stimulant Drugs and ADHD: Basic and Clinical Neuroscience (eds Solanto, M. V., Arnsten, A. F. T. & Castellanos, F. X.) 283–302 (Oxford Univ. Press, New York, 2001).

    Google Scholar 

  106. Welsh, M. C. in Developmental Variations in Learning: Applications to Social, Executive Function, Language, and Reading Skills (eds Molfese, D. L. & Molfese, V. J.) 139–185 (Lawrence Erlbaum, Mahwah, New Jersey, 2002).

    Google Scholar 

  107. Barnett, R. et al. Abnormal executive function in attention deficit hyperactivity disorder: the effect of stimulant medication and age on spatial working memory. Psychol. Med. 31, 1107–1115 (2001).

    CAS  PubMed  Google Scholar 

  108. Kempton, S. et al. Executive function and attention deficit hyperactivity disorder: stimulant medication and better executive function performance in children. Psychol. Med. 29, 527–538 (1999).

    CAS  PubMed  Google Scholar 

  109. Nigg, J. T., Blaskey, L. G., Huang-Pollock, C. L. & Rappley, M. D. Neuropsychological executive functions and DSM-IV ADHD subtypes. J. Am. Acad. Child Adolesc. Psychiatry 41, 59–66 (2002).

    PubMed  Google Scholar 

  110. Schweitzer, J. B. et al. Alterations in the functional anatomy of working memory in adult attention deficit hyperactivity disorder. Am. J. Psychiatry 157, 278–280 (2000).

    CAS  PubMed  Google Scholar 

  111. Sawaguchi, T. The effects of dopamine and its antagonists on directional delay-period activity of prefrontal neurons in monkeys during an oculomotor delayed-response task. Neurosci. Res. 41, 115–128 (2001).

    CAS  PubMed  Google Scholar 

  112. Mattay, V. S. et al. Effects of dextroamphetamine on cognitive performance and cortical activation. Neuroimage 12, 268–275 (2000).

    CAS  PubMed  Google Scholar 

  113. Eisenberg, J. et al. Haplotype relative risk study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): association of the high-enzyme activity val allele with ADHD impulsive–hyperactive phenotype. Am. J. Med. Genet. 88, 497–502 (1999).

    CAS  PubMed  Google Scholar 

  114. Barr, C. L. et al. Linkage study of catechol-O-methyltransferase and attention-deficit hyperactivity disorder. Am. J. Med. Genet. 88, 710–713 (1999).

    CAS  PubMed  Google Scholar 

  115. Hawi, Z., Millar, N., Daly, G., Fitzgerald, M. & Gill, M. No association between catechol-O-methyltransferase (COMT) gene polymorphism and attention deficit hyperactivity disorder (ADHD) in an Irish sample. Am. J. Med. Genet. 96, 282–284 (2000).

    CAS  PubMed  Google Scholar 

  116. Tahir, E. et al. No association between low- and high-activity catecholamine-methyl-transferase (COMT) and attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children. Am. J. Med. Genet. 96, 285–288 (2000).

    CAS  PubMed  Google Scholar 

  117. Castellanos, F. X. & Swanson, J. in Hyperactivity and Attention Disorders in Childhood (ed. Sandberg, S.) 336–366 (Cambridge Univ. Press, Cambridge, UK, 2002).

    Google Scholar 

  118. Monastra, V. J., Lubar, J. F. & Linden, M. The development of a QEEG scanning process for ADHD: reliability and validity studies. Neuropsychology 15, 136–144 (2001).

    CAS  PubMed  Google Scholar 

  119. Clarke, A. R., Barry, R. J., McCarthy, R. & Selikowitz, M. Electroencephalogram differences in two subtypes of attention-deficit/hyperactivity disorder. Psychophysiology 38, 212–221 (2001).

    CAS  PubMed  Google Scholar 

  120. Lazzaro, I. et al. Simultaneous EEG and EDA measures in adolescent attention deficit hyperactivity disorder. Int. J. Psychophysiol. 34, 123–134 (1999).

    CAS  PubMed  Google Scholar 

  121. Raghavachari, S. et al. Gating of human theta oscillations by a working memory task. J. Neurosci. 21, 3175–3183 (2001).

    CAS  PubMed  Google Scholar 

  122. Tesche, C. D. & Karhu, J. Theta oscillations index human hippocampal activation during a working memory task. Proc. Natl Acad. Sci. USA 97, 919–924 (2000).

    CAS  PubMed  Google Scholar 

  123. Offord, D. R. et al. Integrating assessment data from multiple informants. J. Am. Acad. Child Adolesc. Psychiatry 35, 1078–1085 (1996).

    CAS  PubMed  Google Scholar 

  124. Gould, T. D., Bastain, T. M., Israel, M. E., Hommer, D. W. & Castellanos, F. X. Altered performance on an ocular fixation task in attention-deficit/hyperactivity disorder. Biol. Psychiatry 50, 633–635 (2001).

    CAS  PubMed  Google Scholar 

  125. Moll, G. H., Heinrich, H., Trott, G., Wirth, S. & Rothenberger, A. Deficient intracortical inhibition in drug-naive children with attention-deficit hyperactivity disorder is enhanced by methylphenidate. Neurosci. Lett. 284, 121–125 (2000).The first study using transcranial magnetic stimulation to probe the motor system in ADHD. This paper reported isolated deficits in intracortical inhibition.

    CAS  PubMed  Google Scholar 

  126. Heinrich, H., Dickhaus, H., Rothenberger, A., Heinrich, V. & Moll, G. H. Single-sweep analysis of event-related potentials by wavelet networks — methodological basis and clinical application. IEEE Trans. Biomed. Eng. 46, 867–879 (1999).

    CAS  PubMed  Google Scholar 

  127. Cowan, R. L. et al. Sex differences in response to red and blue light in human primary visual cortex: a BOLD fMRI study. Psychiatry Res. 100, 129–138 (2000).Although focused on sex differences in normal adults, this report provides further evidence that the visual-system response to blue light might serve as a marker for central dopamine 'tone' that can be studied non-invasively through fMRI.

    CAS  PubMed  Google Scholar 

  128. Todd, R. D. et al. Familiality and heritability of subtypes of attention deficit hyperactivity disorder in a population sample of adolescent female twins. Am. J. Psychiatry 158, 1891–1898 (2001).

    CAS  PubMed  Google Scholar 

  129. Thapar, A., Hervas, A. & McGuffin, P. Childhood hyperactivity scores are highly heritable and show sibling competition effects: twin study evidence. Behav. Genet. 25, 537–544 (1995).

    CAS  PubMed  Google Scholar 

  130. Simonoff, E. et al. Genetic influences on childhood hyperactivity: contrast effects imply parental rating bias, not sibling interaction. Psychol. Med. 28, 825–837 (1998).

    CAS  PubMed  Google Scholar 

  131. Conners, C. K. Clinical use of rating scales in diagnosis and treatment of attention-deficit/hyperactivity disorder. Pediatr. Clin. North Am. 46, 857–870 (1999).

    CAS  PubMed  Google Scholar 

  132. Frick, P. J. et al. DSM-IV field trials for the disruptive behavior disorders: symptom utility estimates. J. Am. Acad. Child Adolesc. Psychiatry 33, 529–539 (1994).

    CAS  PubMed  Google Scholar 

  133. Angold, A. & Costello, E. J. The child and adolescent psychiatric assessment (CAPA). J. Am. Acad. Child Adolesc. Psychiatry 39, 39–48 (2000).

    CAS  PubMed  Google Scholar 

  134. Mota, V. L. & Schachar, R. J. Reformulating attention-deficit/hyperactivity disorder according to signal detection theory. J. Am. Acad. Child Adolesc. Psychiatry 39, 1144–1151 (2000).

    CAS  PubMed  Google Scholar 

  135. Cook, E. H. Jr et al. Association of attention deficit disorder and the dopamine transporter gene. Am. J. Hum. Genet. 56, 993–998 (1995).The first replicated report of a gene locus associated with ADHD.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Faraone, S. V., Doyle, A. E., Mick, E. & Biederman, J. Meta-analysis of the association between the 7-repeat allele of the dopamine D4 receptor gene and attention deficit hyperactivity disorder. Am. J. Psychiatry 158, 1052–1057 (2001).

    CAS  PubMed  Google Scholar 

  137. Scheres, A., Oosterlaan, J. & Sergeant, J. A. Response execution and inhibition in children with AD/HD and other disruptive disorders: the role of behavioural activation. J. Child Psychol. Psychiatry 42, 347–357 (2001).

    CAS  PubMed  Google Scholar 

  138. Tannock, R. in Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder: an Evidence-Based Approach (eds Jensen, P. & Cooper, J.) (American Medical Association Press, New York, in the press).

  139. Casey, B. J. et al. Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 36, 374–383 (1997).

    CAS  PubMed  Google Scholar 

  140. Rubia, K. et al. Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. Am. J. Psychiatry 156, 891–896 (1999).

    CAS  PubMed  Google Scholar 

  141. Saunders, C. et al. Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc. Natl Acad. Sci. USA 97, 6850–6855 (2000).

    CAS  PubMed  Google Scholar 

  142. Swanson, J. & Volkow, N. D. in Stimulant Drugs and ADHD: Basic and Clinical Neuroscience (eds Solanto, M. V., Arnsten, A. F. T. & Castellanos, F. X.) 259–282 (Oxford Univ. Press, New York, 2001).

    Google Scholar 

  143. Arnold, L. E. Responders and nonresponders. J. Am. Acad. Child Adolesc. Psychiatry 35, 1569–1570 (1996).

    CAS  PubMed  Google Scholar 

  144. Volkow, N. D. et al. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in human brain. Arch. Gen. Psychiatry 52, 456–463 (1995).A provocatively titled study that highlights the importance of pharmacokinetic differences for abuse potential and subjective effects of stimulants in humans.

    CAS  PubMed  Google Scholar 

  145. Andersen, S. L., Arvanitogiannis, A., Pliakas, A. M., LeBlanc, C. & Carlezon, W. A. Jr. Altered responsiveness to cocaine in rats exposed to methylphenidate during development. Nature Neurosci. 5, 13–14 (2002).A study showing that conditioned place preference for cocaine is decreased in rats that are exposed to methylphenidate as juveniles, but not as adults.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. New York University Child Study Center, 577 First Avenue, CSC 204, New York, 10016-6404, New York, USA

    F. Xavier Castellanos

  2. The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Rosemary Tannock

Authors
  1. F. Xavier Castellanos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rosemary Tannock
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

LocusLink

COMT

D1

D2

D4

DAT

nAChRs

Medscape DrugInfo

methylphenidate

OMIM

attention-deficit/hyperactivity disorder

developmental dyslexia

FURTHER INFORMATION

ADHD.net

ADHD.net

Encyclopedia of Life Sciences

attention deficit–hyperactivity disorder

cocaine and amphetamines

dopamine

learning and memory

MIT Encyclopedia of Cognitive Sciences

attention

electrophysiology, electric and magnetic evoked fields

magnetic resonance imaging

positron emission tomography

working memory

working memory, neural basis of

Glossary

WORKING MEMORY

The representation of items held in consciousness during experiences or after retrieval of memories. Working memory is short-lasting and associated with the active rehearsal or manipulation of information.

BASAL GANGLIA

A group of interconnected subcortical nuclei in the forebrain and midbrain that includes the striatum, globus pallidus, subthalamic nucleus, ventral tegmental area and substantia nigra.

EFFECT SIZE

A measure of effect that is adopted when different scales are used to measure an outcome. It is usually defined as the difference in means between the experimental and control groups, divided by the standard deviation of the control or both groups. As effect size is a standardized measure, it allows us to compare and/or combine the effects found in different studies of the same phenomenon.

STRIATUM

Part of the subpallidum and one of the components of the striatopallidal complex. It comprises deep (caudate nucleus, putamen and nucleus accumbens) and superficial (olfactory tubercle) parts.

SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY

A method in which images are generated by using radionuclides that emit single photons of a given energy. Images are captured at multiple positions by rotating the sensor around the subject; the three-dimensional distribution of radionuclides is then used to reconstruct the images. SPECT can be used to observe biochemical and physiological processes, as well as the size and volume of structures. Unlike positron emission tomography, SPECT uses many fewer detectors, resulting in the loss of many available photons and the degradation of the image.

EXECUTIVE FUNCTION

A cluster of high-order capacities, which include selective attention, behavioural planning and response inhibition, and the manipulation of information in problem-solving tasks.

ANTISACCADE TASKS

Tasks in which subjects are required to suppress the automatic response of making a saccade towards a target and, instead, produce an eye movement in the opposite direction.

GO/NO-GO TASK

A task in which the subject must produce a motor response for one class of stimulus while ignoring others.

POLYMORPHISM

The simultaneous existence in the same population of two or more genotypes in frequencies that cannot be explained by recurrent mutations.

VENTRAL TEGMENTAL AREA

A nucleus of the midbrain. The main supplier of dopamine to the cortex.

LOCUS COERULEUS

A nucleus of the brainstem. The main supplier of noradrenaline to the brain.

P300 COMPONENT

A positive-going waveform in the electroencephalogram that occurs approximately 300 ms after the onset of a stimulus, and is related to the attentional and working memory demands of a task.

THETA/BETA POWER RATIO

A ratio that compares the power output in the theta (4–8 Hz) versus the beta (13–21 Hz) frequency bands of the electroencephalogram.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Castellanos, F., Tannock, R. Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 3, 617–628 (2002). https://doi.org/10.1038/nrn896

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn896

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing