Nervenheilkunde 2006; 25(06): 421-429
DOI: 10.1055/s-0038-1626480
Originaler Artikel
Schattauer GmbH

Genetik und Bildgebung bei Aufmerksamkeitsdefizit-/Hyperaktivitätsstörungen

Genetic and neuroimaging studies in attention deficit hyperactivity disorder
S. Walitza
1   Klinik und Poliklinik für Kinder- und Jugendpsychiatrie und Psychotherapie, Universität Würzburg (Direktor: Prof. Dr. A. Warnke)
,
T. Renner
1   Klinik und Poliklinik für Kinder- und Jugendpsychiatrie und Psychotherapie, Universität Würzburg (Direktor: Prof. Dr. A. Warnke)
,
M. Romanos
1   Klinik und Poliklinik für Kinder- und Jugendpsychiatrie und Psychotherapie, Universität Würzburg (Direktor: Prof. Dr. A. Warnke)
,
L. Mecklinger
2   Institut für Experimentelle Psychologie, Universität Regensburg (Direktor: Prof. Dr. K. W. Lange)
,
O. Tucha
2   Institut für Experimentelle Psychologie, Universität Regensburg (Direktor: Prof. Dr. K. W. Lange)
,
M. Gerlach
1   Klinik und Poliklinik für Kinder- und Jugendpsychiatrie und Psychotherapie, Universität Würzburg (Direktor: Prof. Dr. A. Warnke)
,
K. W. Lange
2   Institut für Experimentelle Psychologie, Universität Regensburg (Direktor: Prof. Dr. K. W. Lange)
› Author Affiliations
Further Information

Publication History

Publication Date:
19 January 2018 (online)

Zusammenfassung

Formalgenetische Untersuchungen zeigen, dass die Aufmerksamkeitsdefizit-/Hyperaktivitäts-Störung (ADHS) eine hohe Erblichkeit aufweist, wobei wahrscheinlich zahlreiche Gene mit jeweils moderatem Effekt beteiligt sind. Es werden die am häufigsten replizierten Befunde molekulargenetischer Studien zusammengefasst. Die Ergebnisse von bisherigen Genomscans ergeben Hinweise auf mehrere relevante Genorte, vorangestellt Chromosom 5p13, in dessen Nähe das Gen des Dopamintransporters (DAT1) lokalisiert ist. Assoziationsstudien zeigen Zusammenhänge zwischen Varianten in dopaminergen (DRD4, DAT1) bzw. serotonergen Genen (SERT) und dem Vorliegen einer ADHS. Neuroanatomische Hirnveränderungen bei ADHS finden sich vornehmlich im Bereich von fronto-striatalen Strukturen. Weiterhin treten weit verbreitet Auffälligkeiten in anderen kortikalen Arealen und dem Zerebellum auf. Funktionell-bildgebende Studien legen nahe, dass eine Dysfunktion frontostriataler Schleifen an der Pathophysiologie der ADHS beteiligt ist. Der Dopamintransporter ist ein wichtiges Element dopaminerger Neurotransmission; Neurorezeptorstudien zeigen eine erhöhte Dopamintransporter-Bindung radioaktiver Liganden bei ADHS sowie eine Reduktion dieser Bindung unter Methylphenidat-Behandlung.

Summary

Formal genetic and molecular genetic studies indicate that attention deficit hyperactivity disorder (ADHD) is highly heritable, involving multiple genes of moderate effect. Four genome-wide linkage studies and the most frequently reported positive results of association studies are reviewed. Linkage studies have detected chromosome 5p13 as a relevant region, which is in the vicinity of the location of the dopamine transporter gene (DAT1). The most frequently replicated findings in the candidate gene approach refer to polymorphisms in dopaminergic (DRD4, DAT1) and serotonergic genes (SERT). Neuroimaging studies show that ADHD involves structural brain abnormalities in fronto-striatal regions, other cortical regions and the cerebellum. Functional neuroimaging have implicated dysfunction of the fronto-striatal circuitry as likely contributing to the pathophysiology of ADHD. The dopamine transporter isa key regulator of dopamine. In vivo neuroreceptor imaging has shown increased dopamine transporter binding in ADHD anda decrease following methylphenidate treatment.

 
  • Literatur

  • 1 Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986; 09: 357-81.
  • 2 Arcos-Burgos M. et al. Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11. Am J Hum Genet 2004; 75: 998-1014.
  • 3 Aylward EH, Reiss AL, Reader MJ, Singer HS, Brown JE, Denckla MB. Basal ganglia volumes in children with attention-deficit hyperactivity disorder. J Child Neurol 1996; 11: 112-5.
  • 4 Bakker SC. et al. A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet 2003; 72: 1251-60.
  • 5 Barkley RA. ADHD and the nature of self-control. New York: Guilford; 1997
  • 6 Barkley RA, 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 2001; 29: 541-56.
  • 7 Berquin PC. et al. Cerebellum in attention-deficit hyperactivity disorder: a morphometric MRI study. Neurology 1998; 50: 1087-93.
  • 8 Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005; 366: 237-48.
  • 9 Biederman J. et al. Patterns of psychiatric comorbidity, cognition, and psychosocial functioning in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1993; 150: 1792-8.
  • 10 Bobb AJ, Castellanos FX, Addington AM, Rapoport JL. Molecular genetic studies of ADHD: 1991 to 2004. Am J Med Genet. 2004
  • 11 Bradley JD, Golden CJ. Biological contributions to the presentation and understanding of attentiondeficit/hyperactivity disorder: a review. Clin Psychol Rev 2001; 21: 907-29.
  • 12 Canli T, Congdon E, Gutknecht L, Constable RT, Lesch KP. Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation. J Neural Transm 2005; 112: 1479-85.
  • 13 Casey BJ. et al. Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1997; 36: 374-83.
  • 14 Castellanos FX, Giedd JN, Berquin PC, Walter JM, Sharp W, Tran T. et al. Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2001; 58: 289-95.
  • 15 Castellanos FX. et al. Quantitative morphology of the caudate nucleus in attention deficit hyperactivity disorder. Am J Psychiatry 1994; 151: 1791-6.
  • 16 Castellanos FX, Giedd JN, Hamburger SD, Marsh WL, Rapoport JL. Brain morphometry in Tourette’s syndrome: the influence of comorbid attention-deficit/hyperactivity disorder. Neurology 1996; 47: 1581-3.
  • 17 Castellanos FX. et al. Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1996; 53: 607-16.
  • 18 Castellanos FX. et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA 2002; 288: 1740-8.
  • 19 Chen CK, Chen SL, Mill J, Huang YS, Lin SK, Curran S. et al. The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample. Mol Psychiatry 2003; 08: 393-6.
  • 20 Cheon KA, Ryu YH, Kim YK, Namkoong K, Kim CH, Lee JD. 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 2003; 30: 306-11.
  • 21 Coolidge FL, Thede LL, Young SE. Heritability and the comorbidity of attention deficit hyperactivity disorder with behavioral disorders and executive function deficits: a preliminary investigation. Dev Neuropsychol 2000; 17: 273-87.
  • 22 Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ. Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 1999; 354: 2132-3.
  • 23 Dresel S, Krause J, Krause KH, LaFougere C, Brinkbaumer K, Kung HF. et al. Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment. Eur J Nucl Med 2000; 27: 1518-24.
  • 24 Dulawa SC, Grandy DK, Low MJ, Paulus MP, Geyer MA. Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J Neurosci 1999; 19: 9550-6.
  • 25 Durston S, Thomas KM, Yang Y, Ulug AM, Zimmerman RD, Casey BJ. The development of neural systems involved in overriding behavioral responses: an event-related fMRI study. Dev Sci 2002; 05: F9-F16.
  • 26 Durston S, Tottenham NT, Thomas KM, Davidson MC, Eigsti IM, Yang Y. et al. Differential patterns of striatal activation in young children with and without ADHD. Biol Psychiatry 2003; 53: 871-8.
  • 27 Epstein JN. et al. Familial aggregation of ADHD characteristics. J Abnorm Child Psychol 2000; 28: 585-94.
  • 28 Ernst M, Liebenauer LL, King AC, Fitzgerald GA, Cohen RM, Zametkin AJ. Reduced brain metabolism in hyperactive girls. J Am Acad Child Adolesc Psychiatry 1994; 33: 858-68.
  • 29 Ernst M, Zametkin AJ, Phillips RL, Cohen RM. Age-related changes in brain glucose metabolism in adults with attention-deficit/hyperactivity disorder and control subjects. J Neuropsychiatry Clin Neurosci 1998; 10: 168-77.
  • 30 Faraone SV, Biederman J. Neurobiology of attention-deficit hyperactivity disorder. Biol Psychiatry 1998; 44: 951-8.
  • 31 Faraone SV, Biederman J. Neurobiology of attention deficit hyperactivity disorder. In: Charney DS, Nestler EJ. (eds). Neurobiology of Mental Illness. New York: Oxford University Press; 2004
  • 32 Faraone SV, Biederman J, Spencer T, Wilens T, Seidman LJ, Mick E. et al. Attention-deficit/hyperactivity disorder in adults: an overview. Biol Psychiatry 2000; 48: 9-20.
  • 33 Faraone SV, Doyle AE, Mick E, Biederman J. Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. Am J Psychiatry 2001; 158: 1052-7.
  • 34 Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA. et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; 57: 1313-23.
  • 35 Filipek PA, Semrud-Clikeman M, Steingard RJ, Renshaw PF, Kennedy DN, Biederman J. Volumetric MRI analysis comparing subjects having attention-deficit hyperactivity disorder with normal controls. Neurology 1997; 48: 589-601.
  • 36 Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, Macphie IL. et al. A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am J Hum Genet 2002; 70: 1183-96.
  • 37 Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 1999; 283: 397-401.
  • 38 Gerlach M. Pharmakologie von Methylphenidat. In: Schulte-Markwort M, Warnke A. (eds). Methylphenidat. Stuttgart: Thieme; 2004
  • 39 Giedd JN, Blumenthal JD, Molloy E, Castellanos FX. Brain imaging of attention deficit/hyperactivity disorder. Ann NY Acad Sci 2001; 931: 33-49.
  • 40 Goodman R, Stevenson J. A twin study of hyperactivity I. An examination of hyperactivity scores and categories derived from Rutter teacher and parent questionnaires. J Child Psychol Psychiatry 1989; 30: 671-89.
  • 41 Goodman R, Stevenson J. A twin study of hyperactivity II. The aetiological role of genes, family relationships and perinatal adversity. J Child Psychol Psychiatry 1989; 30: 691-709.
  • 42 Hebebrand J, Dempfle A, Saar K, Thiele H, Herpertz-Dahlmann B, Linder M. et al. A genome-wide scan for attention-deficit/hyperactivity disorder in 155 german sib-pairs. Mol Psychiatry. 2005
  • 43 Hesslinger B, Tebartz vE, Thiel T, Haegele K, Hennig J, Ebert D. Frontoorbital volume reductions in adult patients with attention deficit hyperactivity disorder. Neurosci Lett 2002; 328: 319-21.
  • 44 Johansen EB, Aase H, Meyer A, Sagvolden T. Attention-deficit/hyperactivity disorder (ADHD) behaviour explained by dysfunctioning reinforcement and extinction processes. Behav Brain Res 2002; 130: 37-45.
  • 45 Kim BN, Lee JS, Cho SC, Lee DS. Methylphenidate increased regional cerebral blood flow in subjects with attention deficit/hyperactivity disorder. Yonsei Med J 2001; 42: 19-29.
  • 46 Konishi S, Nakajima K, Uchida I, Kikyo H, Kameyama M, Miyashita Y. Common inhibitory mechanism in human inferior prefrontal cortex revealed by event-related functional MRI. Brain 1999; 122: 981-91.
  • 47 Konishi S, Nakajima K, Uchida I, Sekihara K, Miyashita Y. No-go dominant brain activity in human inferior prefrontal cortex revealed by functional magnetic resonance imaging. Eur J Neurosci 1998; 10: 1209-13.
  • 48 Krause J, la Fougere Ch, Krause K-H, Ackenheil M, Dresel StH. Influence of striatal dopamine transporter availability on the response to methylphenidate in adult patients with ADHD. European Archives of Psychiatry and Clinical Neuroscience. 2005
  • 49 Krause KH, Dresel SH, Krause J, Kung HF, 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 2000; 285: 107-10.
  • 50 Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527-31.
  • 51 Lou HC, Henriksen L, Bruhn P. Focal cerebral hypoperfusion in children with dysphasia and/or attention deficit disorder. Arch Neurol 1984; 41: 825-9.
  • 52 Lou HC, Henriksen L, Bruhn P. Focal cerebral dysfunction in developmental learning disabilities. Lancet 1990; 335: 8-11.
  • 53 Lou HC, Henriksen L, Bruhn P, Borner H, Nielsen JB. Striatal dysfunction in attention deficit and hyperkinetic disorder. Arch Neurol 1989; 46: 48-52.
  • 54 Mannuzza S, Klein RG, Bessler A, Malloy P, La-Padula M. Adult outcome of hyperactive boys. Educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry 1993; 50: 565-76.
  • 55 Matochik JA, Liebenauer LL, King AC, Szymanski HV, Cohen RM, Zametkin AJ. Cerebral glucose metabolism in adults with attention deficit hyperactivity disorder after chronic stimulant treatment. Am J Psychiatry 1994; 151: 658-64.
  • 56 Matochik JA, Nordahl TE, Gross M, Semple WE, King AC, Cohen RM. et al. Effects of acute stimulant medication on cerebral metabolism in adults with hyperactivity. Neuropsychopharmacology 1993; 08: 377-86.
  • 57 Mick E, Biederman J, Prince J, Fischer MJ, Faraone SV. Impact of low birth weight on attention-deficit hyperactivity disorder. J Dev Behav Pediatr 2002; 23: 16-22.
  • 58 Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci 2001; 24: 167-202.
  • 59 Miyake A, Friedman NP, Emerson MJ, Witzki AH, Howerter A, Wager TD. The unity and diversity of executive functions and their contributions to complex “Frontal Lobe” tasks: a latent variable analysis. Cognit Psychol 2000; 41: 49-100.
  • 60 Mostofsky SH, Reiss AL, Lockhart P, Denckla MB. Evaluation of cerebellar size in attention-deficit hyperactivity disorder. J Child Neurol 1998; 13: 434-9.
  • 61 Ogdie MN, Macphie IL, Minassian SL, Yang M, Fisher SE, Francks C. et al. A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. Am J Hum Genet 2003; 72: 1268-79.
  • 62 Robbins TW, James M, Owen AM, Sahakian BJ, Lawrence AD, McInnes L. et al. A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: implications for theories of executive functioning and cognitive aging.Cambridge Neuropsychological Test Automated Battery. J Int Neuropsychol Soc 1998; 04: 474-90.
  • 63 Rubia K, Russell T, Overmeyer S, Brammer MJ, Bullmore ET, Sharma T. et al. Mapping motor inhibition: Conjunctive brain activations across different versions of go/no-go and stop tasks. Neuroimage 2001; 13: 250-61.
  • 64 Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G. et al. Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 1997; 90: 991-1001.
  • 65 Saß H, Wittchen H-U, Zaudig M, Houben I. Diagnostisches und Statistisches Manual Psychischer Störungen –Textrevision DSM-IV-TR. Göttingen. Hogrefe. 2003
  • 66 Schneider JS, Sun ZQ, Roeltgen DP. Effects of dopamine agonists on delayed response performance in chronic low-dose MPTP-treated monkeys. Pharmacol Biochem Behav 1994; 48: 235-40.
  • 67 Seidman LJ, Biederman J, Weber W, Hatch M, Faraone SV. Neuropsychological function in adults with attention-deficit hyperactivity disorder. Biol Psychiatry 1998; 44: 260-8.
  • 68 Seidman LJ, Doyle A, Fried R, Valera E, Crum K, Matthews L. Neuropsychological function in adults with attention-deficit/hyperactivity disorder. Psychiatr Clin North Am 2004; 27: 261-82.
  • 69 Seidman LJ, Valera EM, Bush G. Brain function and structure in adults with attention-deficit/hyperactivity disorder. Psychiatr Clin North Am 2004; 27: 323-47.
  • 70 Semrud-Clikeman M, Filipek PA, Biederman J, Steingard R, Kennedy D, Renshaw P. et al. Attention-deficit hyperactivity disorder: magnetic resonance imaging morphometric analysis of the corpus callosum. J Am Acad Child Adolesc Psychiatry 1994; 33: 875-81.
  • 71 Semrud-Clikeman M, Steingard RJ, Filipek P, Biederman J, Bekken K, Renshaw PF. Using MRI to examine brain-behavior relationships in males with attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 2000; 39: 477-84.
  • 72 Sergeant JA, Geurts H, Huijbregts S, Scheres A, Oosterlaan J. The top and the bottom of ADHD: a neuropsychological perspective. Neurosci Biobehav Rev 2003; 27: 583-92.
  • 73 Shaywitz SE, Cohen DJ, Shaywitz BA. The biochemical basis of minimal brain dysfunction. J Pediatr 1978; 92: 179-87.
  • 74 Slaats-Willemse D, Swaab-Barneveld H, de Sonneville L, van der ME, Buitelaar J. Deficient response inhibition as a cognitive endophenotype of ADHD. J Am Acad Child Adolesc Psychiatry 2003; 42: 1242-8.
  • 75 Smalley SL. Genetic influences in childhood-onset psychiatric disorders: autism and attention-deficit/hyperactivity disorder. Am J Hum Genet 1997; 60: 1276-82.
  • 76 Smalley SL, Kustanovich V, Minassian SL, Stone JL, Ogdie MN, McGough JJ. et al. Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism. Am J Hum Genet 2002; 71: 959-63.
  • 77 Smalley SL, McGough JJ, Del’Homme M, NewDelman J, Gordon E, Kim T. et al. Familial clustering of symptoms and disruptive behaviors in multiplex families with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2000; 39: 1135-43.
  • 78 Sobanski E, Alm B. [Attention deficit hyperactivity disorder in adults. An overview]. Nervenarzt 2004; 75: 697-715.
  • 79 Sonuga-Barke EJ, Dalen L, Daley D, Remington B. Are planning, working memory, and inhibition associated with individual differences in preschool ADHD symptoms?. Dev Neuropsychol 2002; 21: 255-72.
  • 80 Sowell ER, Thompson PM, Welcome SE, Henkenius AL, Toga AW, Peterson BS. Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder. Lancet 2003; 362: 1699-707.
  • 81 Sprich S, Biederman J, Crawford MH, Mundy E, Faraone SV. Adoptive and biological families of children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry 2000; 39: 1432-7.
  • 82 Thapar A, Harrington R, McGuffin P. Examining the comorbidity of ADHD-related behaviours and conduct problems using a twin study design. Br J Psychiatry 2001; 179: 224-9.
  • 83 Tucha O, Mecklinger L, Laufkötter R, Kaunzinger I, Paul GM, Klein HE. et al. Clustering and switching on verbal and figural fluency functions in adults with attention deficit hyperactivity disorder. Cognitive Neuropsychiatry 2005; 10: 231-48.
  • 84 Vaidya CJ, Austin G, Kirkorian G, Ridlehuber HW, Desmond JE, Glover GH. et al. Selective effects of methylphenidate in attention deficit hyperactivity disorder: a functional magnetic resonance study. Proc Natl Acad Sci USA 1998; 95: 14494-9.
  • 85 van Dyck CH, Quinlan DM, Cretella LM, Staley JK, Malison RT, Baldwin RM. et al. Unaltered dopamine transporter availability in adult attention deficit hyperactivity disorder. Am J Psychiatry 2002; 159: 309-12.
  • 86 Vles JS, Feron FJ, Hendriksen JG, Jolles J, van Kroonenburgh MJ, Weber WE. Methylphenidate down-regulates the dopamine receptor and transporter system in children with attention deficit hyperkinetic disorder (ADHD). Neuropediatrics 2003; 34: 77-80.
  • 87 Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS. et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 1998; 155: 1325-31.
  • 88 Walitza S, Renner TJ, Dempfle A, Konrad K, Wewetzer C, Halbach A. et al. Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 2005; 10: 1126-32.
  • 89 Willcutt EG, Brodsky K, Chhabildas N. The neuropsychology of attention deficit hyperactivity disorder: validity of the executive function hypothesis. In: Gozal D, Molfese D. (eds). Attention deficit hyperactivity disorder from genes to patients. Totowa, NJ: Humana Press; 2005
  • 90 Zametkin AJ, Liebenauer LL, Fitzgerald GA, King AC, Minkunas DV, Herscovitch P. et al. Brain metabolism in teenagers with attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1993; 50: 333-40.
  • 91 Zametkin AJ, Nordahl TE, Gross M, King AC, Semple WE, Rumsey J. et al. Cerebral glucose metabolism in adults with hyperactivity of childhood onset. N Engl J Med 1990; 323: 1361-6.