Pearls in Clinical Neuroscience

Inattention and Hyperactivity-

Impulsivity: Psychobiological and
Evolutionary Underpinnings of
ADHD
By Dan J. Stein, MD, PhD, Jin Fan, PhD, John Fossella, PhD, and Vivienne Russell, PhD

ABSTRACT difficulties, but he had a good memory, spoke

Attention-deficit/hyperactivity disorder is a
prevalent and disabling disorder that is char-
acterized by inattention and/or hyperactivity-
impulsivity, impairment in executive functions,
structural and functional abnormalities in fron-
tal-striatal circuitry, associations with particular
catecholamine gene variants, and responsive-
ness to dopaminergic and noradrenergic agents.
There is a growing integration of findings from
basic and clinical studies, of data from differ-
ent methods (eg, genetics and imaging), and
of empirical data with hypotheses drawn from
evolutionary thinking. Here we briefly summa-
rize work on the cognitive-affective neurosci-
ence of attention-deficit/hyperactivity disorder.
CASE REPORT
Ned is an 18-year-old man who was referred
for assessment due to difficulties at college.
High-school assignments had caused him some
articulately, contributed to group work, and so
had managed to pull through. However, his col-
lege assignments required him to read more
broadly, to write more extensively, and to work
more independently. A closer history revealed
difficulties with attention and symptoms of
hyperactivity that dated back to childhood. Even
during the interview, he fidgeted a good deal and
often interrupted questions. There was no psychi-
atric comorbidity, and he was in good physical
health. Methylphenidate [AU: DOSAGE?] proved
helpful to him, allowing him to study in a more
disciplined way.
COGNITIVE-AFFECTIVE NEUROSCIENCE
Neuroanatomy/Neurochemistry
Attention-deficit/hyperactivity disorder (ADHD)
is characterized by impairments in executive func-
tions, such as self-regulation of affect-motiva-
tion-arousal, abnormalities in the frontal-striatal
circuits that mediate these functions, and associa-
tions with variants in genes that play an important
role in these circuits.1,2 Animal models3,4 demon-
strate elegantly that lesions in this neurocircuitry,
or targeted disruption of such genes, produce

Dr. Stein is professor and chair of the Department of Psychiatry and Mental Health at the University of Cape Town in South Africa, and is
also on faculty at the Mount Sinai School of Medicine in New York City. Drs. Fan and Fossella are assistant professors in the Department
of Psychiatry at the Mount Sinai School of Medicine. Dr. Russell is professor in the Department of Human Biology at the University of Cape
Town.
Disclosures: Dr. Stein receives grant support/honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck A/S, Orion, Pfizer, Pharmacia,
Roche, Servier, Solvay, Sumitomo, and Wyeth. [AU: PROVIDE DISCLOSURES FOR ALL CO-AUTHORS.]
Funding/Support: Dr. Stein receives support from the Medical Research Council of South Africa.
Authors’ note: This case is based on an amalgam of the authors’ experience.
CNS Spectr 12:3 19 March 2007

behavioral and cognitive deficits analogous to
those seen in the clinic.
These clinical and basic findings are consistent
with a view that ADHD is characterized by a defi-
cit in inhibitory control or less signaling to con-
trol systems.5-8 The prefrontal cortex (PFC) plays a
critical role in sustained attention and behavioral
inhibition, while more posterior cortical regions
are important for perception and the allocation of
attentional resources.4 Norepinephrine modulates
cortical and cerebellar processing, while dopa-
mine modulates cortical and striatal processing;
more specifically, norepinephrine α−2A receptor
stimulation enhances PFC “signal” and dopamine
(D)1 receptor stimulation helps reduce PFC “noise”
(optimizing sustained attention), while other cat-
echolamine conditions instead take the PFC “off-
line” and enhance posterior cortical or subcortical
processing (eg, during drowsiness or stress).4
Impairments in executive function in ADHD
are seen in tasks that require cognitive, or inhib-
itory control, such as no-go, stop- and Stroop
paradigms.9-11 Structural imaging studies show
smaller volumes in prefrontal cortex, caudate,
splenium of corpus callosum, and cerebellum,
as well as smaller total cerebral volume,12,13 and
there is some work correlating neuropsychologi-
cal and volumetric findings.14 Functional imaging
studies often show prefrontal hypofrontality15,16
(Figure 1), but also demonstrate compensatory
FIGURE 1.
Time-series plots of BOLD signal changes
in prefrontal cortex in children with ADHD
and controls during the Stop Signal task16
Children with
ADHD (n=17)
Healthy
Children (n=15)
1.50 Anterior cingulate cortex
1.00
0.50
% Signal Change
0.00
–0.50
1.50 Left ventrolateral
prefrontal cortex
1.00
0.50
0.00
–0.50
0 4 8 12 0 4 8 12
Time (seconds)
Pliszka SR, Glahn DC, Semrud-Clikeman M, et al. Neuroimaging of inhibi-
tory control areas in children with attention deficit hyperactivity disorder
who were treatment naive or in long-term treatment. Am J Psychiatry.
2006;163:1052-1060.
BOLD=blood-oxygen level dependent; ADHD=attention-deficit/hyperactivity
disorder.
Stein DJ, Fan J, Fossell J, Russell V. CNS Spectr. Vol 12, No 3. 2007.
CNS Spectr 12:3
Pearls in Clinical Neuroscience
activation, 17 involvement of other regions 18,19
(Figure 2), and increased saliency20 or functional
normalization21 (Figure 3) after pharmacotherapy.
Molecular imaging data have been somewhat
inconsistent to date,22 but electroencephalogram
and magnetic resonance spectrography studies
are consistent with delayed or impaired myelina-
tion of neuronal axons.23
Gene/Environment
Twin and adoption studies show high heritabil-
ity estimates for ADHD, but obstetric complica-
tions, such as maternal smoking, may also be
relevant.24 Associations have been found between
specific gene variants, particularly in the dopa-
minergic and noradrenergic systems and ADHD
in general,24-30 and impairment on attention tasks
in particular.31,32 Fan and colleagues33 found that
alleles of two genes related to dopamine signal-
ing (D4 receptor and monoamine oxidase A) were
associated with increased activation of anterior
cingulate gyrus. In subjects with ADHD, unaf-
fected siblings, and healthy controls, D4 recep-
tor (expressed predominantly in PFC) influences
prefrontal gray matter volume, while dopamine 1
transporter (expressed predominantly in the basal
ganglia) influences caudate volume.34 dopamine 1
transporter has also been linked with rCBF and
treatment outcome.35 Further work is, however,
needed to replicate and extend such findings.36
FIGURE 2.
Healthy subjects had significantly more
Successful Inhibition
activation than the ADHD group in bilat-
Unsuccessful Inhibition eral parietal association cortex, as well
as right precuneus/cuneus and thalamus/
mid-cingulate, during an fMRI of a visual
oddball task19
Tamm L, Menon V, Reiss AL. Parietal attentional system aberrations during
target detection in adolescents with attention deficity hyperactivity disorder:
event-related fMRI evidence. Am J Psychiatry. 2006;163:1033-1043.
ADHD=attention-deficit/hyperactivity disorder.
Stein DJ, Fan J, Fossell J, Russell V. CNS Spectr. Vol 12, No 3. 2007.
20 March 2007
 Pearls in Clinical Neuroscience
Evolutionary Approaches
Executive functions can be examined from
an evolutionary perspective, with one hypoth-
esis arguing that interpersonal competition
helped drive a shift from the control of behav-
ior by immediate context (overt) to self-regula-
tion (covert).37 Some authors38-43 have argued that
ADHD and impulsive symptoms can be under-
stood in adapative terms; for example, particular
environments favor “response-ready” individu-
FIGURE 3.
fMRI activation during response inhibition
for an ADHD child and a control child.
Yellow squares highlight the resonance of
MPH in the head of the caudate and puta-
men in the ADHD and control child21
Off–MPH On–MPH
ADHD
Control
P<.05 P<.001
Vaidya CJ, Austin G, Kirkorian G, et al. Selective effects of methylphenidate
in attention deficit/hyperactivity disorder: a functional magnetic resonance
study. Proc Natl Acad Sci U S A. 1998;95:14494-14499.
fMRI=functional magnetic resonace imaging; ADHD=attention-deficit/hyper-
activity disorder; MPH=methylphenidate.
Stein DJ, Fan J, Fossell J, Russell V. CNS Spectr. Vol 12, No 3
CNS Spectr 12:3
als (who are hypervigilant, rapid-scanning, quick
to pounce (or flee), and motorically hyperactive)
over “problem-solvers”.38 Other researchers44-46
have, however, argued that ADHD is best under-
stood as a maladaptation.
CLINICAL IMPLICATIONS
DSM-IV-TR Diagnosis
There is growing recognition of the prevalence
of ADHD in children and adults, and its associated
morbidity.47 In view of the evolutionary debate
described above, it is notable that ADHD symp-
toms do not necessarily imply impairment.48 There
are ongoing attempts to improve ADHD diagnostic
criteria and subtyping (eg the requirement that
ADHD have an onset prior to 7 years of age may
not be valid),49 and an improved understanding of
the cognitive-affective neuroscience of ADHD may
well contribute to this effort.
Assessment/Evaluation
Standardized scales for the assessment of
ADHD are readily available and useful for moni-
toring the effects of treatment. 50,51 Collateral
information is particularly useful. Although
symptoms of inattention and hyperactivity-
impulsivity may well have a genetic component,
and may well be due to general medical disor-
ders, in patients with a psychiatric diagnosis of
ADHD and normal intelligence, it is thought that
extensive genetic investigation (eg cytogenetics)
has a low yield.52
Pharmacotherapy/Psychotherapy
Although expert guidelines have emphasized
the value of pharmacotherapy and psychother-
apy in ADHD, pharmacotherapy plays a partic-
ularly crucial role. 53-57 Despite concerns about
the use of psychostimulants in children,58 meta-
analyses reinforce the enormously useful con-
tribution of psychostimulants, particularly in the
short-term.59 There is also a growing database
of studies of other agents53,60,61 and on genetic
predictors of treatment response. 30 The litera-
ture on the pharmacotherapy of adult ADHD is
smaller, 62,63 but consistent with findings from
children and adolescents.
CONCLUSION
A rich body of data informs the cognitive-affec-
tive neuroscience of ADHD. Work on the proximal
mechanisms underlying ADHD supports the cen-
21 March 2007
 Pearls in Clinical Neuroscience
trality of inhibitory dysfunction in ADHD, and the
neuronal and molecular basis of such dysfunction
is increasingly understood. Speculations on the
distal, evolutionary mechanisms underlying ADHD
have suggested that there are different ways-of-
being in the world (“response-ready” vs “problem-
solving”), the value of which changes depending
on environmental context. More careful character-
ization of ADHD heterogeneity and variability,23,64,65
as well as work on relevant endophenotypes,66,67 is
likely to lead to further advances. CNS
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