Zusammenfassung
Das Aufmerksamkeitsdefizit-/Hyperaktivitätssyndrom (ADHS) ist eine klinisch heterogene Störung der Gehirnentwicklung unter Beteiligung zahlreicher genetischer und umweltbedingter Risikofaktoren. Ziel der interdisziplinär und translational ausgerichteten neurobiologischen Forschung ist, die wechselseitige Beziehung zwischen molekularen Mechanismen und strukturell-funktionellen Substraten in der Pathogenese des ADHS und ihre Bedeutung für den Langzeitverlauf der Erkrankung aufzuklären. Die Auseinandersetzung mit ADHS-spezifischen molekulargenetischen und entwicklungsbiologischen Grundlagen der Gehirnfunktion sowie strukturell-funktionellen Anlagen des Verhaltens verspricht, zur Entwicklung von Prädiktoren und differenziellen Strategien für die therapeutische Beeinflussung schwerer und chronischer Verläufe des ADHS beizutragen. Um evolutionär konservierte ADHS-relevante Prinzipien der Funktion und Struktur des Gehirns sowie des syndromtypischen Verhaltens zu definieren, ist ein integrierter Ansatz zur Aufklärung spezifischer neuro- und psychobiologischer Mechanismen und damit der systemischen Pathophysiologie des ADHS notwendig. Pathophysiologische Modelle des ADHS, insbesondere aber die syndromalen und komorbiden Dimensionen, benötigen daher die Kombination von molekulargenetischen, funktionell-bildgebenden, neuropsychologischen, verhaltensbiologischen und psychosozialen Strategien zur Erklärung vollständiger Kausalketten unter dem Gesichtspunkt einer gestörten Gehirnentwicklung.
Summary
Attention-deficit hyperactivity disorder (ADHD) is defined as a clinically heterogeneous neurodevelopmental syndrome with the contribution of numerous genetic and environmental risk factors. The goal of interdisciplinary and translational neurobiological research is to clarify the interdependent relationship between molecular mechanisms and structural-functional substrates in the pathogenesis of ADHD and its significance to the disorder’s long-term course. Work on ADHD-specific molecular genetic and developmental biological essentials of brain function and on the structural-functional basis of behavior holds the promise of developing predictors and differential strategies for effective therapy of severe and chronic courses of ADHD. To define evolutionary conserved ADHD-relevant principles of structure and function of the brain and behavior typical to the syndrome, an integrated approach in the elucidation of specific neuro- and psychobiological mechanisms and thus systemic pathophysiology of ADHD is crucial. Regarding compromised neurodevelopment, pathophysiological models of ADHD, particularly its syndromal and comorbid dimensions, therefore require the combination of molecular genetic, neuroimaging, neuropsychology, behavioral, and psychosocial strategies to explain complete causal chains.
Literatur
Biederman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366: 237–248
Jacob CP, Romanos J, Dempfle A et al. (2007) Co-morbidity of adult attention-deficit/hyperactivity disorder with focus on personality traits and related disorders in a tertiary referral center. Eur Arch Psychiatry Clin Neurosci 257: 309–317
Lesch KP (2008) Attention-deficit/hyperactivity disorder (ADHD). In: Lang F (ed) Encyclopedia of molecular mechanisms of disease. Springer, Heidelberg New York (im Druck)
Arcos-Burgos M, Castellanos FX, Pineda D et al. (2004) Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11. Am J Hum Genet 75: 998–1014
Muenke M (2007) Neurobiology of attention-deficit/hyperactivity disorder: a common and ancestral variant of latrophilin 3 (LPHN3) confers susceptibility to attention-deficit/hyperactivity disorder (Abstract, 1st International Congress on ADHD). J Neural Transm 114: XLVI
Friedel S, Saar K, Sauer S et al. (2007) Association and linkage of allelic variants of the dopamine transporter gene in ADHD. Mol Psychiatry 12: 923–933
Asherson P, Zhou K, Anney RJ et al. (2008) A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16. Mol Psychiatry (im Druck)
Romanos M, Freitag C, Jacob C et al. (2008) Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12. Mol Psychiatry (im Druck)
Walitza S, Renner TJ, Dempfle A et al. (2005) Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 10: 1126–1132
Baehne CG, Ehlis AC, Plichta MM et al. (2008) Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals. Mol Psychiatry (im Druck)
Guindalini C, Howard M, Haddley K et al. (2006) A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample. Proc Natl Acad Sci U S A 103: 4552–4557
Mill J, Caspi A, Williams BS et al. (2006) Prediction of heterogeneity in intelligence and adult prognosis by genetic polymorphisms in the dopamine system among children with attention-deficit/hyperactivity disorder: evidence from 2 birth cohorts. Arch Gen Psychiatry 63: 462–469
Sonuga-Barke EJ, Brookes KJ, Buitelaar J et al. (2008) Intelligence in DSM-IV combined type attention-deficit/hyperactivity disorder is not predicted by either dopamine receptor/transporter genes or other previously identified risk alleles for attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 147: 316–319
Herrmann MJ, Huter T, Muller F et al. (2007) Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing. Cereb Cortex 17: 1160–1163
Congdon E, Lesch KP, Canli T (2008) Analysis of DRD4 and DAT polymorphisms and behavioral inhibition in healthy adults: implications for impulsivity. Am J Med Genet B Neuropsychiatr Genet 147: 27–32
Canli T, Congdon E, Todd Constable R et al. (2008) Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on neural correlates of affective processing. Biol Psychol (im Druck)
Polanczyk G, Zeni C, Genro JP et al. (2005) Attention-deficit/hyperactivity disorder: advancing on pharmacogenomics. Pharmacogenomics 6: 225–234
Kooij JS, Boonstra AM, Vermeulen SH et al. (2008) Response to methylphenidate in adults with ADHD is associated with a polymorphism in SLC6A3 (DAT1). Am J Med Genet B Neuropsychiatr Genet 147: 201–208
Kereszturi E, Tarnok Z, Bognar E et al. (2008) Catechol-O-methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children. Am J Med Genet B Neuropsychiatr Genet (in press)
Mill J, Sagvolden T, Asherson P (2005) Sequence analysis of Drd2, Drd4, and Dat1 in SHR and WKY rat strains. Behav Brain Funct 1: 24
Arnsten AF (2006) Fundamentals of attention-deficit/hyperactivity disorder: circuits and pathways. J Clin Psychiatry [Suppl 8] 67: 7–12
Murphy DL, Lesch KP (2008) Targeting the murine serotonin transporter: insights into human neurobiology. Nat Rev Neurosci 9: 85–96
Sora I, Hall FS, Andrews AM et al. (2001) Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Natl Acad Sci U S A 98: 5300–5305
Kostrzewa RM, Kostrzewa JP, Kostrzewa RA et al. (2008) Pharmacological models of ADHD. J Neural Transm 115: 287–298
Carola V, Frazzetto G, Pascucci T et al. (2008) Identifying molecular substrates in a mouse model of the 5-HTT-by-environment risk factor for anxiety and depression. Biol Psychiatry (in press)
Stevens SE, Sonuga-Barke EJ, Kreppner JM et al. (2008) Inattention/overactivity following early severe institutional deprivation: presentation and associations in early adolescence. J Abnorm Child Psychol 36: J 385–J 398
MTA Cooperative Group (2004) National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: 24-month outcomes of treatment strategies for attention-deficit/hyperactivity disorder. Pediatrics 113: 754–761
Krain AL, Castellanos FX (2006) Brain development and ADHD. Clin Psychol Rev 26: 433–444
Swanson JM, Hinshaw SP, Arnold LE et al. (2007) Secondary evaluations of MTA 36-month outcomes: propensity score and growth mixture model analyses. J Am Acad Child Adolesc Psychiatry 46: 1003–1014
Sagvolden T, Johansen EB, Aase H et al. (2005) A dynamic developmental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes. Behav Brain Sci 28: 397–419; discussion 419–468
Fallgatter AJ, Ehlis AC, Seifert J et al. (2004) Altered response control and anterior cingulate function in attention-deficit/hyperactivity disorder boys. Clin Neurophysiol 115: 973–981
Sowell ER, Thompson PM, Welcome SE et al. (2003) Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder. Lancet 362: 1699–1707
Canli T, Lesch KP (2007) Long story short: the serotonin transporter in emotion regulation and social cognition. Nat Neurosci 10: 1103–1109
Canli T, Qiu M, Omura K et al. (2006) Neural correlates of epigenesis. Proc Natl Acad Sci U S A 103: 16033–16038
Fallgatter AJ, Ehlis AC, Rösler M et al. (2005) Diminished prefrontal brain function in adults with attention deficit hyperactivity disorder (ADHD) related psychopathology in childhood. Psychiatry Res Neuroimaging 138: 157–169
Seidman LJ, Valera EM, Makris N et al. (2006) Dorsolateral prefrontal and anterior cingulate cortex volumetric abnormalities in adults with attention-deficit/hyperactivity disorder identified by magnetic resonance imaging. Biol Psychiatry 60: 1071–1080
Durston S, Fossella JA, Mulder MJ et al. (2008) Dopamine transporter genotype conveys familial risk of attention-deficit/hyperactivity disorder through striatal activation. J Am Acad Child Adolesc Psychiatry 47: 61–67
Krause J, Krause KH, Dresel SH et al. (2006) ADHD in adolescence and adulthood, with a special focus on the dopamine transporter and nicotine. Dialogues Clin Neurosci 8: 29–36
Castellanos FX, Tannock R (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 3: 617–628
Danksagung
Die Forschung der Autoren wird durch die Deutsche Forschungsgemeinschaft (KFO 125 ADHS) und das Bundesministerium für Bildung und Forschung (01GV0605) unterstützt.
Interessenkonflikt
Die korrespondierenden Autoren geben an, dass kein Interessenkonflikt besteht.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Renner, T., Gerlach, M., Romanos, M. et al. Neurobiologie des Aufmerksamkeitsdefizit-/Hyperaktivitätssyndroms. Nervenarzt 79, 771–781 (2008). https://doi.org/10.1007/s00115-008-2513-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00115-008-2513-3
Schlüsselwörter
- Aufmerksamkeitsdefizit-/Hyperaktivitätssyndrom
- Aufmerksamkeitsdefizit
- Hyperaktivität
- Komorbidität
- Neurobiologie