Elsevier

Biological Psychiatry

Volume 44, Issue 10, 15 November 1998, Pages 951-958
Biological Psychiatry

Review Articles
Neurobiology of attention-deficit hyperactivity disorder

https://doi.org/10.1016/S0006-3223(98)00240-6Get rights and content

Abstract

Attention-deficit hyperactivity disorder (ADHD) is an early-onset, clinically heterogeneous disorder of inattention, hyperactivity, and impulsivity. Family, twin, adoption, segregation analysis, and molecular genetic studies show that is has a substantial genetic component. Although their results are still tentative, molecular genetic studies suggest that three genes may increase the susceptibility to ADHD: the D4 dopamine receptor gene, the dopamine transporter gene, and the D2 dopamine receptor gene. Studies of environmental adversity have implicated pregnancy and delivery complications, marital distress, family dysfunction, and low social class. The pattern of neuropsychological deficits found in ADHD children implicate executive functions and working memory; this pattern is similar to what has been found among adults with frontal lobe damage, which suggests that the frontal cortex or regions projecting to the frontal cortex are dysfunctional in at least some ADHD children. Moreover, neuroimaging studies implicate frontosubcortical pathways in ADHD. Notably, these pathways are rich in catecholamines, which have been implicated in ADHD by the mechanism of action of stimulants—the class of drugs that effectively treats many ADHD children. Yet human studies of the catecholamine hypothesis of ADHD have produced conflicting results, perhaps due to the insensitivity of peripheral measures.

Introduction

Attention-deficit hyperactivity disorder (ADHD) is an early-onset, clinically heterogeneous disorder of inattention, hyperactivity, and impulsivity. Its impact on society is enormous in terms of its financial cost, stress to families, adverse academic and vocational outcomes, and negative effects on self-esteem. In this article we provide an overview of what is known about the neurobiology of ADHD by examining studies of genetics, environmental adversity, neuropsychology, neuroimaging, and neuropharmacology.

Section snippets

Family, twin, adoption, and segregation analysis studies

As we have reviewed in detail elsewhere, family studies derived from clinically referred samples consistently support the assertion that ADHD runs in families Faraone and Biederman 1994a, Faraone and Biederman 1994b. There is agreement on this point between early studies of hyperactivity and subsequent studies of DSM-III attention deficit disorder (ADD) and DSM-IV ADHD. These studies find the parents of ADHD children to have a 2- to 8-fold increase in the risk for ADHD. Thus, they confirm the

Environmental risk and protective factors for ADHD

Numerous aspects of the biological and psychosocial environment have been examined as potential risk or protective factors for ADHD. Although several factors have been implicated in the etiology of the disorder, none has emerged as a necessary and sufficient cause that can account for most cases of ADHD.

ADHD and the brain

Satterfield and Dawson (1971) were among the first to propose that ADHD symptoms were caused by frontolimbic dysfunction. They suggested that weak frontal cortical inhibitory control over limbic functions might lead to ADHD. The success of stimulant medications, and animal models implicating dopamine pathways were taken as support for this model. A review of the neurological literature (Mattes 1980) articulating the similarities between adult patients with frontal lobe damage and children with

Summary and conclusions

Few would argue with the idea that ADHD is a disorder of the brain that has multiple causes: genes, biological adversity, and psychosocial adversity. But the details of how these components combine to cause ADHD are unknown. Moreover, the available data provide support for the etiologic and pathophysiologic heterogeneity of the disorder. We are not likely to find a necessary and sufficient cause that explains a substantial fraction of ADHD cases. Instead, the challenge for future research is to

References (84)

  • D.R Offord et al.

    Outcome, prognosis and risk in a longitudinal follow-up study

    J Am Acad Child Adolesc Psychiatry

    (1992)
  • S Pliszka et al.

    Catecholamines in attention-deficity hyperactivity disorderCurrent perspectives

    J Am Acad Child Adolesc Psychiatry

    (1996)
  • T.A Slotkin et al.

    Impact of fetal nicotine exposure on development of rat brain regionsCritical sensitive periods or effects of withdrawal?

    Brain Res Bull

    (1993)
  • S Sprich-Buckminster et al.

    Are perinatal complications relevant to the manifestation of ADD? Issues of comorbidity and familiality

    J Am Acad Child Adolesc Psychiatry

    (1993)
  • R Weiss et al.

    Attention-deficit hyperactivity disorder and thyroid function

    J Pediatr

    (1993)
  • A.J Zametkin et al.

    Neurobiology of attention deficit disorder with hyperactivityWhere have we come in 50 years?

    J Am Acad Child Adolesc Psychiatry

    (1987)
  • J.N Bailey et al.

    Segregation analysis of attention deficit hyperactivity disorder

    Genet Epidemiol

    (1997)
  • J.N Bailey et al.

    DRD4 gene and susceptibility to attention deficit hyperactivity disorderDifferences in familial and sporadic cases

    Am J Med Genet Neuropsychiatr Genet

    (1997)
  • R.A Barkley

    Attention Deficit Hyperactivity DisorderA Handbook for Diagnosis and Treatment

    (1990)
  • R.A Barkley

    ADHD and the Nature of Self-Control

    (1997)
  • J Benjamin et al.

    Population and familial association between the D4 dopamine receptor gene and measures of novelty seeking

    Nat Genet

    (1996)
  • J Biederman et al.

    Familial association between attention deficit disorder and anxiety disorders

    Am J Psychiatry

    (1991)
  • J Biederman et al.

    Evidence of familial association between attention deficit disorder and major affective disorders

    Arch Gen Psychiatry

    (1991)
  • J Biederman et al.

    Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder (ADHD)Patterns of comorbidity in probands and relatives in psychiatrically and pediatrically referred samples

    Arch Gen Psychiatry

    (1992)
  • J Biederman et al.

    Family-environment risk factors for ADHDA test of Rutter’s indicators of adversity

    Arch Gen Psychiatry

    (1995)
  • J Biederman et al.

    Impact of adversity on functioning and comorbidity in children with attention-deficit hyperactivity disorder

    J Am Acad Child Adolesc Psychiatry

    (1995)
  • K Blum et al.

    Association of polymorphisms of dopamine D2 receptor (DRD2), and dopamine transporter (DAT1) genes with schizoid/avoidant behaviors (SAB)

    Mol Psychiatry

    (1997)
  • D.P Cantwell

    Genetics of hyperactivity

    J Child Psychol Psychiatry

    (1975)
  • F.X Castellanos et al.

    Evidence that a D4DR∗7R dopamine receptor polymorphism is not correlated with attention deficit/hyperactivity disorder

    Am J Med Genet Neuropsyhiatr Genet

    (1997)
  • F.M Chang et al.

    The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus

    Hum Genet

    (1996)
  • P Clarke

    Dopaminergic mechanisms in the locomotor stimulant effects of nicotine

    Biochem Pharmacol

    (1990)
  • R Coger et al.

    Attention deficit disorder in adults and nicotine dependencePsychobiological factors in resistance to recovery?

    J Psychoactive Drugs

    (1996)
  • D.E Comings et al.

    The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders

    JAMA

    (1991)
  • C.K Conners

    Food Additives and Hyperactive Children

    (1980)
  • C Conners et al.

    Nicotine and attention deficit hyperactivity disorder (ADHD)

    Psychopharmocol Bull

    (1996)
  • E.H Cook et al.

    Association of attention deficit disorder and the dopamine transporter gene

    Am J Hum Genet

    (1995)
  • L Eaves et al.

    Genes, personality, and psychopathologyA latent class analysis of liability to symptoms of attention-deficit hyperactivity disorder in twins

  • R.P Ebstein et al.

    Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of novelty seeking

    Nat Genet

    (1996)
  • Edelbrock C, Rende RD, Plomin R, Thompson LA (1992): A twin study of behavior problems in early adolescence. Paper...
  • S Faraone et al.

    Genetics of attention-deficit hyperactivity disorder

    Child Adolesc Psychiatr Clin North Am

    (1994)
  • S Faraone et al.

    Is attention deficit hyperactivity disorder familial?

    Harvard Rev Psychiatry

    (1994)
  • S Faraone et al.

    Do attention deficit hyperactivity disorder and major depression share familial risk factors?

    J Nerv Ment Dis

    (1997)
  • Cited by (0)

    View full text