Attention Deficit Hyperactivity Disorder 1

Attention Deficit Hyperactivity Introductory article

Disorder
James M Swanson, University of California, Irvine, California, USA
Nora D Volkow, Brookhaven National Laboratory, Upton, New York, USA
Jeffrey Newcorn, Mount Sinai School of Medicine, New York City, New York, USA
BJ Casey, Sackler Institute, Weill College of Medicine at Cornell University,
New York City, New York, USA
Robert Moyzis, University of California, Irvine, California, USA
David Grandy, University of Oregon Health Sciences Center, Portland, Oregon, USA
Michael Posner, University of Oregon, Eugene, Oregon, USA

CONTENTS
Introduction Etiology
Onset and course Neural correlates of ADHD
Treatment Conclusion

Attention deficit hyperactivity disorder is a childhood tom domains must be present and contribute to
syndrome characterized by developmentally in- impairment. Partial syndromes (ADHD–inatten-
appropriate inattention, impulsivity, and hyperactiv- tive type or ADHD–hyperactive/impulsive type)
ity which produces impairment at home and school. are diagnosed if symptoms in only one
Long-term outcome is poor, but treatment with
domain are present, and comorbid conditions
stimulant medication and behavior modification is
(such as anxiety and depression) are diagnosed if
effective. Investigations of the disorder and its treat-
ments suggest a dopamine deficit exists that may they are also present. Based on these criteria, about
be corrected by stimulant medication. 3–5% of the population of children in American
elementary schools are diagnosed and treated for
ADHD.
INTRODUCTION
The identification of a specific cognitive deficit
The combination of inattentive, hyperactive, and unique to ADHD has been elusive. Some research-
impulsive behavior in children has been recog- ers have suggested that deficiencies of children
nized as a syndrome since the start of the twentieth with ADHD are due to their inability to control
century, dating back to Still’s description in 1902 of their behavior, rather than a structural deficit of
children with ‘marked inability to concentrate and attention. Others have concluded that there is no
sustain attention’ and impaired ‘inhibitory vol- attentional deficit in ADHD, but instead that the
ition’. The term now used as a label for this syn- core deficit is in behavioral inhibition. However,
drome, attention deficit hyperactivity disorder ADHD children do clearly have abnormal perform-
(ADHD), is defined in the fourth edition of the ance on several tasks such as the Stroop color-word
Diagnostic and Statistical Manual of Mental Disorders naming task, the Matching Familar Figures test of
(DSM-IV), published by the American Psychiatric comparison of almost identical complex figures,
Association. The DSM-IV definition lists 18 behav- the Tower of Hanoi test of planning and stacking
iors as grounds for diagnosis (Table 1), which colored rings to match a pattern, and the Trails B
fall into two domains: inattention, and hyperactiv- test of search for characters on a page in the face of
ity/impulsivity. These are behaviors of normal distraction.
childhood when they occur infrequently or at a Advances in the field of cognitive neuroscience
low intensity, so they represent symptoms of a led to new concepts of attention linked to specific
psychiatric disorder only when they are develop- brain circuitry. For example, Posner and Raichle’s
mentally inappropriate, severe, and produce sig- neuroanatomical network theory of attention is
nificant impairment in multiple settings. For a based on the concepts of alerting (supressing back-
diagnosis of ADHD–combined type, both symp- ground neural noise by inhibiting ongoing or
2 Attention Deficit Hyperactivity Disorder

Table 1. Alignment of symptom domains, cognitive processes and neural networks

Symptom domain Cognitive process Neural network

Inattentive – Alerting Sustained attention Alerting
difficulty sustaining attention vigilance level/decrement cortical: right frontal
fails to finish persistence midbrain: locus ceruleus
avoids sustained effort performance thalamic:?
Inattentive – Orienting Selective attention Orienting
distracted by stimuli visual cueing cortical: parietal
does not seem to listen auditory cueing thalamic: pulvinar
fails to give close attention visual search other:?
Inattentive – Memory Memory/planning Executive control
has difficulty organizing tasks planning cortical: prefrontal
loses things memory for objects striatal: basal ganglia
is forgetful memory for time other:?
Impulsivity – Executive control Cognitive regulation Executive control
blurts out answers conflict resolution cortical: anterior cingulate
interrupts or intrudes behavioral inhibition striatal: nucleus accumbens
cannot wait delay aversion other:?
Hyperactivity – Fine motor Motor/vocal control Fine motor control
fidgets fine motor control cortical: left frontal
cannot play quietly nonverbal control striatal: cerebellar vermis
talks excessively verbal other:?
Hyperactivity – Gross motor Activation level Gross motor control
leaves seat gross motor control cortical: right frontal
runs about and climbs novelty seeking striatal: caudate
always on the go arousal level other:?

irrevevant activity or mental effort to establish a ONSET AND COURSE

state of vigilance), orienting (mobilizing specific
neural resources toward a source of sensory stimu- The DSM-IV diagnostic criteria specify the onset of
lation), and executive control (coordinating mul- symptoms by the age of 7 years, but in most cases
tiple specialized neural processes by detecting the symptoms of ADHD are present much earlier.
targets, starting and stopping mental operations, Impairment tends to increase during the elemen-
and resolving conflict among responses), each tary-school years in response to the cognitive and
with a well-defined neural circuitry (anterior cin- behavioral demands of the classroom setting, and
gulated, prefrontal cortex and basal ganglia). This this is when most diagnoses are made. At this age,
cognitive neuroscience approach can be used to more boys than girls are recognized and treated for
constrain the definition of attention, and it offers ADHD (reported male to female ratios range from
modern terminology for describing its components. 3:1 to 9:1), but this may be due to referral biases
The application of three levels of analysis (behav- related to disruptive behaviors (aggression, oppos-
ioral, cognitive, and neural) may provide some new ition, and defiance) that often coexist in boys. In
insights about the cognitive component of this dis- most cases, ADHD symptoms decline with age,
order. Each symptom can be classified based on its especially for the domain of hyperactivity and
relationship to alerting, orienting, and executive impulsivity. When symptoms no longer produce
control (see Table 1). The nine symptoms of inatten- impairment, the diagnostic label changes to
tion listed in Table 1 logically split into three ADHD–residual type. In about one-third of the
groups when aligned with the three concepts of cases, the full criteria are still met in adulthood,
attention and the underlying neural networks. and in another third symptoms are present but at
The three symptoms of impulsivity are behavioral a subthreshold level.
manifestations of deficits in self-regulation, which The subjective nature of the assessment process
align with the executive control network, and the raises legitimate questions about the validity of the
six symptoms of hyperactivity fall into two groups diagnosis of ADHD, but evidence for validity has
based on deficits in fine motor and gross motor accumulated from follow-up studies showing that
control. a childhood diagnosis of ADHD is associated with
 Attention Deficit Hyperactivity Disorder 3

extremely poor outcome in many areas, including inappropriate behaviors (e.g. getting out of seat,
juvenile delinquency. Children identified by the talking without permission).
ADHD diagnosis have a serious disorder that The most recent information on treatment comes
demands recognition and deserves treatment. from the Multimodality Treatment of ADHD
(MTA) study, a large, six-site randomized clinical
trial designed to evaluate the long-term effects of
TREATMENT pharmacological and psychosocial interventions.
Since the 1930s ADHD has been treated with stimu- Over 500 children with ADHD aged 7–9 years
lant drugs. The first of these was amphetamine, were recruited from a variety of sources and ran-
but over the years this has been superseded by domly assigned to a treatment group for a period of
methylphenidate. Immediate-release formulations 14 months. In this study methylphenidate adminis-
of these drugs are short-acting and must be given tered three times a day was more effective than
two or three times a day. Newer sustained-release psychosocial treatment (intensive behavioral inter-
formulations based on ‘osmotic pump’ and ‘coated vention at home and school), and combinations of
bead’ delivery systems have been developed that these two therapies were little better than medica-
have long duration of action and avoid the mid-day tion alone. The success rates defined by a reduction
dose at school (which is often associated with of symptoms to a subthreshold level reflected this
embarrassment). The stimulant medications are ef- also: psychosocial 34%, pharmacological 56%, and
fective in reducing the symptoms of ADHD (about combination 68%. This study provides empirical
80% of children with this diagnosis show clinically evidence of the long-term effectiveness of these
meaningful benefits) and are safe (despite some two most common treatments for ADHD.
common side effects such as decreased appetite
and sleep). With the immediate-release formula-
tions, the therapeutic effects emerge within 1–2 h
ETIOLOGY
after each oral dose, but then dissipate within 3–6 h. The most prominent current theory about the cause
The sustained-release formulations have a duration of ADHD implicates dysfunction of brain dopa-
of action of 8–12 h. These stimulant medications mine (DA), a neurotransmitter involved in the
exert a profound cognitive effect, characterized by regulation of motoric, attentional and motivational
focused attention to tasks (even those with low circuits. One variant of this theory suggests that
intrinsic interest) and maintenance of attention ADHD is the result of a DA deficit at the neural
over time (even in the face of repetitive or boring level, which results in inattentiveness and dis-
tasks). The behavioral effects are also profound: tractibility at the cognitive level. This theory is
inappropriately high levels of activity and inatten- supported by the mechanism of action of methyl-
tion in the classroom setting are reduced and com- phenidate, which blocks DA transporters, the pri-
pliance with typical requests and rules is increased mary mechanism for removing DA from the
dramatically. Stimulants do not produce a para- synapse. Imaging studies in humans have demon-
doxical response in ADHD children: normal chil- strated that therapeutic doses of stimulants block
dren and adults respond in the same way on most more than half of the DA transporters, markedly
measures (e.g. by decreasing normal levels of activ- enhancing DA neurotransmission in the brain.
ity and increasing normal levels of attention). It is Similar findings have been obtained in animal
important to note that in individuals who do not studies, which have shown that stimulants given
have ADHD there is no impairment in these areas, at therapeutically relevant dosages increase extra-
so the response to stimulants does not alleviate cellular DA and activate DA-regulated circuits. In
impairment, which is the hallmark of clinical animals, gene ‘knockout’ studies have suggested
response. that the DA transporter gene (DAT) located on
In addition to pharmacotherapy, contingency chromosome 15 and the DA type 4 receptor gene
management programs have been developed (DRD4) located on chromosome 11 are involved in
based on the general principles of behavior modifi- basic underlying processes of activity and attention
cation (reinforcement, punishment, extinction, and that may contribute to ADHD.
stimulus control). Typically, these interventions What might produce a DA deficit? Acquired and
use token systems in the home and at school to inherited factors have been proposed. One sug-
prompt and shape appropriate target behavior gestion is that bouts of hypoxia and hypoten-
(e.g. getting started, staying on task, interacting sion during fetal development might selectively
appropriately with others, completing work, and damage striatal neurons, which are the main
shifting activities on schedule) and to extinguish target for DA cells. Inherited factors have also
4 Attention Deficit Hyperactivity Disorder

been implicated by molecular genetic studies of circuits regulate attention, executive function, mo-
ADHD. Initial investigations focused on two candi- tivation, response inhibition and motor activity,
date genes involved with DA regulation: the DAT research on ADHD has focused on how their dys-
and DRD4 genes. Several research groups have function could result in the cognitive deficits and
documented association of these two genes with behavioral symptoms of this disorder.
ADHD.
Further Reading

NEURAL CORRELATES OF ADHD American Psychiatric Association (1994) Diagnostic and

Statistical Manual of Mental Disorders, 4th edn.
In the early 1990s several teams of investigators Washington, DC: APA.
used imaging techniques to investigate brain Barkley RA (1997) Behavioral inhibition, sustained
anatomy in groups of children with ADHD com- attention, and executive functions: constructing a
pared with children free from this disorder. Abnor- unifying theory of ADHD. Psychological Bulletin 121:
malities in size of specific brain regions were 65–94.
Barkley RA, Fischer M, Edelbrock CS and Smallish L
observed across multiple studies. Even though
(1990) The adolescent outcome of hyperactive children
groups of children with ADHD were recruited diagnosed by research criteria 1. An 8-year prospective
from very different clinical settings by independent follow-up study. Journal of the American Academy of Child
research teams, research teams showed a moderate and Adolescent Psychiatry 29: 546–557.
reduction in size (about a 10% decrease compared Bradley C (1937) The behavior of children receiving
with a normal group) for measures of frontal lobes benzedrine. American Journal of Psychiatry 94: 577–585.
and basal ganglia (caudate nucleus and globus Bush G, Frazier JA, Rauch SL et al. (1999) Anterior
pallidus). Functional brain imaging studies have cingulate cortex dysfunction in attention-deficit/
provided converging information implicating hyperactivity disorder revealed by fMRI and the
basal ganglia and frontal lobe abnormalities in Counting Stroop. Biologicol Psychiatry 45: 1542–1552.
ADHD. Imaging studies based on single photon Castellanos FX (1997) Toward a pathophysiology of
attention-deficit/hyperactivity disorder. Clinical
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during baseline (resting) conditions documented a Castellanos FX, Giedd JN, Marsh WL et al. (1996)
reduction in blood flow and metabolism in striatal Quantitative brain magnetic resonance imaging in
and frontal brain regions. Studies using [18F]- attention-deficit hyperactivity disorder. Archives of
labeled dopa as a marker of DA synthesis in brain General Psychiatry 53(7): 607–616.
showed significant reductions in prefrontal cortex Collier D, Curran S and Asherson P (2000) Mission: not
in people with ADHD when compared with impossible? Candidate gene studies in child psychiatric
normal controls. Functional magnetic resonance disorders. Molecular Psychiatry 5: 457–460.
imaging has shown hypoactivity of frontal circuits Ernst M, Zametkin AJ, Matochik JA, Jons PH and Cohen
during activation by cognitive tasks, including RM (1998) DOPA decarboxylase activity in attention
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fluorodopa positron emission tomographic study.
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