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The neurobiological component of attention-deficit hyperactivity disorder (ADHD), or hyperkinetic disorder (HKD), has received much attention in recent years. Evidence exists for the association between ADHD and possible structural,1-12 functional13-20 and neurotransmitter21-27 alterations in various regions of the brain in children, adolescents and adults with ADHD.

ADHD is acknowledged to have an underlying genetic component,28,29 with the heritability of ADHD estimated to be up to 76%,28-30 and the involvement of specific candidate genes reported.31

Several environmental risk factors have been associated with the potential development of ADHD,32-36 and combinations of specific polymorphisms and environmental risk factors may increase the likelihood of some ADHD symptoms.37-45

  1. Proal E, Reiss PT, Klein RG, et al. Brain gray matter deficits at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood. Arch Gen Psychiatry 2011; 68: 1122-1134.
  2. Nakao T, Radua J, Rubia K, et al. Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication. Am J Psychiatry 2011; 168: 1154-1163.
  3. Ellison-Wright I, Ellison-Wright Z, Bullmore E. Structural brain change in attention deficit hyperactivity disorder identified by meta-analysis. BMC Psychiatry 2008; 8: 51.
  4. Davenport ND, Karatekin C, White T, et al. Differential fractional anisotropy abnormalities in adolescents with ADHD or schizophrenia. Psychiatry Res 2010; 181: 193-198.
  5. Shaw P, Sudre G, Wharton A, et al. White matter microstructure and the variable adult outcome of childhood attention deficit hyperactivity disorder. Neuropsychopharmacology 2015; 40: 746-754.
  6. Valera EM, Faraone SV, Murray KE, et al. Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 61: 1361-1369.
  7. Ivanov I, Bansal R, Hao X, et al. Morphological abnormalities of the thalamus in youths with attention deficit hyperactivity disorder. Am J Psychiatry 2010; 167: 397-408.
  8. Hoogman M, Rijpkema M, Janss L, et al. Current self-reported symptoms of attention deficit/hyperactivity disorder are associated with total brain volume in healthy adults. PLoS One 2012; 7: e31273.
  9. Shaw P, Lerch J, Greenstein D, et al. Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2006; 63: 540-549.
  10. Shaw P, Eckstrand K, Sharp W, et al. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci U S A 2007; 104: 19649-19654.
  11. Shaw P, Malek M, Watson B, et al. Development of cortical surface area and gyrification in attention-deficit/hyperactivity disorder. Biol Psychiatry 2012; 72: 191-197.
  12. Makris N, Biederman J, Valera EM, et al. Cortical thinning of the attention and executive function networks in adults with attention-deficit/hyperactivity disorder. Cereb Cortex 2007; 17: 1364-1375.
  13. Purper-Ouakil D, Ramoz N, Lepagnol-Bestel AM, et al. Neurobiology of attention deficit/hyperactivity disorder. Pediatr Res 2011; 69: 69R-76R.
  14. Cortese S, Kelly C, Chabernaud C, et al. Toward systems neuroscience of ADHD: a meta-analysis of 55 fMRI studies. Am J Psychiatry 2012; 169: 1038-1055.
  15. Morein-Zamir S, Dodds C, van Hartevelt TJ, et al. Hypoactivation in right inferior frontal cortex is specifically associated with motor response inhibition in adult ADHD. Hum Brain Mapp 2014; 35: 5141-5152.
  16. Karch S, Voelker JM, Thalmeier T, et al. Deficits during voluntary selection in adult patients with ADHD: new insights from single-trial coupling of simultaneous EEG/fMRI. Front Psychiatry 2014; 5: 41.
  17. Dickstein SG, Bannon K, Castellanos FX, et al. The neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis. J Child Psychol Psychiatry 2006; 47: 1051-1062.
  18. Cubillo A, Halari R, Giampietro V, et al. Fronto-striatal underactivation during interference inhibition and attention allocation in grown up children with attention deficit/hyperactivity disorder and persistent symptoms. Psychiatry Res 2011; 193: 17-27.
  19. Peterson BS, Potenza MN, Wang Z, et al. An FMRI study of the effects of psychostimulants on default-mode processing during Stroop task performance in youths with ADHD. Am J Psychiatry 2009; 166: 1286-1294.
  20. Liddle EB, Hollis C, Batty MJ, et al. Task-related default mode network modulation and inhibitory control in ADHD: effects of motivation and methylphenidate. J Child Psychol Psychiatry 2011; 52: 761-771.
  21. Economidou D, Theobald DE, Robbins TW, et al. Norepinephrine and dopamine modulate impulsivity on the five-choice serial reaction time task through opponent actions in the shell and core sub-regions of the nucleus accumbens. Neuropsychopharmacology 2012; 37: 2057-2066.
  22. Volkow ND, Wang GJ, Newcorn J, et al. Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2007; 64: 932-940.
  23. Liu YP, Lin YL, Chuang CH, et al. Alpha adrenergic modulation on effects of norepinephrine transporter inhibitor reboxetine in five-choice serial reaction time task. J Biomed Sci 2009; 16: 72.
  24. Del Campo N, Chamberlain SR, Sahakian BJ, et al. The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biol Psychiatry 2011; 69: e145-157.
  25. Seeger G, Schloss P, Schmidt MH. Functional polymorphism within the promotor of the serotonin transporter gene is associated with severe hyperkinetic disorders. Mol Psychiatry 2001; 6: 235-238.
  26. Maltezos S, Horder J, Coghlan S, et al. Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study. Transl Psychiatry 2014; 4: e373.
  27. Perlov E, Philipsen A, Hesslinger B, et al. Reduced cingulate glutamate/glutamine-to-creatine ratios in adult patients with attention deficit/hyperactivity disorder — a magnet resonance spectroscopy study. J Psychiatr Res 2007; 41: 934-941.
  28. Larsson H, Chang Z, D’Onofrio BM, et al. The heritability of clinically diagnosed attention deficit hyperactivity disorder across the lifespan. Psychol Med 2014; 44: 2223-2229.
  29. Larsson H, Asherson P, Chang Z, et al. Genetic and environmental influences on adult attention deficit hyperactivity disorder symptoms: a large Swedish population-based study of twins. Psychol Med 2013; 43: 197-207.
  30. Faraone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; 57: 1313-1323.
  31. Faraone SV, Bonvicini C, Scassellati C. Biomarkers in the diagnosis of ADHD–promising directions. Curr Psychiatry Rep 2014; 16: 497.
  32. Galéra C, Côté SM, Bouvard MP, et al. Early risk factors for hyperactivity-impulsivity and inattention trajectories from age 17 months to 8 years. Arch Gen Psychiatry 2011; 68: 1267-1275.
  33. Langley K, Holmans PA, van den Bree MB, et al. Effects of low birth weight, maternal smoking in pregnancy and social class on the phenotypic manifestation of attention deficit hyperactivity disorder and associated antisocial behaviour: investigation in a clinical sample. BMC Psychiatry 2007; 7: 26.
  34. Froehlich TE, Lanphear BP, Auinger P, et al. Association of tobacco and lead exposures with attention-deficit/hyperactivity disorder. Pediatrics 2009; 124: e1054-e1063.
  35. Hjern A, Weitoft GR, Lindblad F. Social adversity predicts ADHD-medication in school children–a national cohort study. Acta Paediatr 2010; 99: 920-924.
  36. Rowland AS, Skipper BJ, Rabiner DL, et al. Attention-deficit/hyperactivity disorder (ADHD): interaction between socioeconomic status and parental history of ADHD determines prevalence. J Child Psychol Psychiatry 2018; 59: 213-222.
  37. Brookes KJ, Mill J, Guindalini C, et al. 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 2006; 63: 74-81.
  38. Grizenko N, Fortier ME, Zadorozny C, et al. Maternal stress during pregnancy, ADHD symptomatology in children and genotype: gene-environment interaction. J Can Acad Child Adolesc Psychiatry 2012; 21: 9-15.
  39. Kahn RS, Khoury J, Nichols WC, et al. Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors. J Pediatr 2003; 143: 104-110.
  40. Neuman RJ, Lobos E, Reich W, et al. Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype. Biol Psychiatry 2007; 61: 1320-1328.
  41. Sánchez-Mora C, Richarte V, Garcia-Martínez I, et al. Dopamine receptor DRD4 gene and stressful life events in persistent attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2015; 168: 480-491.
  42. Jacob CP, Nguyen TT, Dempfle A, et al. A gene-environment investigation on personality traits in two independent clinical sets of adult patients with personality disorder and attention deficit/hyperactive disorder. Eur Arch Psychiatry Clin Neurosci 2010; 260: 317-326.
  43. Retz W, Freitag CM, Retz-Junginger P, et al. A functional serotonin transporter promoter gene polymorphism increases ADHD symptoms in delinquents: interaction with adverse childhood environment. Psychiatry Res 2008; 158: 123-131.
  44. Martel MM, Nikolas M, Jernigan K, et al. The dopamine receptor D4 gene (DRD4) moderates family environmental effects on ADHD. J Abnorm Child Psychol 2011; 39: 1-10.
  45. Nikolas M, Friderici K, Waldman I, et al. Gene x environment interactions for ADHD: synergistic effect of 5HTTLPR genotype and youth appraisals of inter-parental conflict. Behav Brain Funct 2010; 6: 23.
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