HISTORY OF NEUROLOGY: SEMINAL CITATIONS

SECTION EDITOR: CHRISTOPHER G. GOETZ, MD

Attention-Deficit/Hyperactivity Disorder
Thomas J. Spencer, MD

A
ttention-deficit/hyperactivity disorder (ADHD) is an early-onset clinically heterog-
eneous disorder of inattention, hyperactivity, and impulsivity. The nosology has changed
during the past century from minimal brain damage to hyperkinetic reaction of child-
hood and now to ADHD. These names reflect shifting causative theories, from an early
emphasis on subtle “minimal” brain injuries to motor hyperactivity and eventually to the primacy
of cognitive and attentional symptoms. Indeed, neuropsychological deficits reported in patients
with ADHD implicate executive dysfunctions and working memory deficits that are similar to those
in patients with acquired frontal lobe damage. In addition, neuroimaging studies1 implicate frontal-
subcortical pathways in patients with ADHD. While there is undoubtedly a complex interplay be-
tween genetic and environmental interactions, estimates of heritability from twin studies are high
(approximately 80%).1 Moreover, recently there has been a growing appreciation of the magni-
tude of impairment experienced by adults with continuing ADHD after childhood onset.

EARLY REPORTS apparent motive. In addition, there was

The first coherent description of ADHD
was by George Still2-4 in the Goulstonian
Lectures of 1902. He described an “ab-
normal defect in moral control in chil-
dren.”2(p1008) Moral control was defined
as “the control of action in conformity
with the idea of the good of all . . . [that]
can only exist when there is a cognitive
relationship to the environment.”2(p1008)
Thus, moral control required a “con-
sciousness” that informed the capacity of
“inhibitory volition.”2(p1008) Still dis-
cussed problems of inhibitory volition in
patients with intellectual retardation and
in those with an acquired physical ill-
ness, including brain tumors, epilepsy,
cerebral palsy, meningitis, and head in-
juries. In addition, he described prob-
lems of inhibitory volition in 20 nor-
mally intelligent children. His case
descriptions included children with dif-
ficulties despite psychosocial advan-
tages. In some, poor behavior, such as
stealing or lying, occurred without an
From the Pediatric Psychopharmacology Unit, Massachusetts General Hospital, and
the Department of Psychiatry, Harvard Medical School, Boston.
an “extraordinary failure of punishment
to have any deterrent effect.”3(p1079) In
these lectures, Still recorded a prescient
observation on the relationship between
poor inhibitory control and mental ca-
pacities: “I would point out that a no-
table feature in many of these cases of
moral deficit without general impair-
ment of intellect is a quite abnormal in-
capacity for sustained attention.”4(p1166)
Other early observations on the re-
lationship between behavioral disorders
and cerebral trauma or encephalitis
supported theories of a biological cause.
For example, Strecker and Ebaugh5 and
Ebaugh and Franklin6 noted behavior
disorders, including hyperactivity, explo-
sive behavior, fatigability, and attention
deficit, after acute epidemic encephalitis
and cerebral trauma in children. Blau7
also described characteristic posttrau-
matic chronic behavior disorders follow-
ing head injuries in children. In 5 of 12
cases, frontal skull fractures were noted
on an x-ray film.
The essential mental alteration in these chil-
dren is a change in personality and character.

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 The behavior becomes hyperkinetic, ir-
responsible, unrestrained, unmanage-
able and antisocial, but the change is ac-
companied by relative retention of the
formal intellectual faculties. . . . The
chronic syndrome of change in behav-
ior is found in psychiatric practice in
children mainly as a sequela of epi-
demic encephalitis.7(p757)
Levin8 described the relationship
of restlessness in children by an asso-
ciationwithcerebrallesions,especially
in the frontal lobe, and commented on
the consistency with earlier primate
literature.
Restless overactivity in monkeys with le-
sions of the frontal lobe was first de-
scribed by Ferrier in 1876.9 He noted
states of apathy alternating with rest-
less and purposeless wandering and
called attention to an inhibitory-motor
function of the frontal lobe.8(p764)
THE ORIGINS
OF PHARMACOTHERAPY
OF ADHD
In a letter to the editor, Gross10 re-
ported on the remarkable serendip-
ity involved in the discovery of
the use of stimulant medication. In
the 1930s, as part of the workup of
normally intelligent children with
neurologic and behavioral prob-
lems, Charles Bradley, MD, had per-
formed lumbar punctures. He had
speculated that the use of benzed-
rine (racemic amphetamine sul-
fate) to stimulate secretion in the
choroid plexus would diminish
post–lumbar puncture headaches.
The effect on the headaches was negli-
gible, but to his astonishment, the teach-
ers reported major improvements in
learning and behavior in a number of the
children that lasted until the benzed-
rine regimen was withdrawn.10(p299)
In a subsequent open trial, half of the
youth showed “dramatic improve-
ment in learning and behavior; they
were more interested in their work
and performed it more quickly and ac-
curately.”10(p299) In reporting these re-
sults, Bradley noted that the school
improvement was striking because the
children were normally intelligent and
already receiving care from a
capable staff in a most favorable set-
ting. . . . [who provided] adequate
attention for any personality dis-
order . . . [from] specially trained, sym-
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pathetic teachers [who] dealt with
their pupils either on an individual
basis or in very small groups. . . . To
see a single dose of benzedrine pro-
duce a greater improvement in school
performance than the combined efforts
of a capable staff working in a most
favorable setting would have been all
but demoralizing to the teachers, had
not the improvement been so gratify-
ing from a practical viewpoint.11(p582)
In addition to academic im-
provement, Bradley noticed behav-
ioral and social improvements with
apparent increased voluntary con-
trol.
However, “the use of medica-
tion in children was condemned
and was full of controversy, false re-
ports, and antagonism.”10(p299) Thus,
this revolutionary discovery of ben-
zedrine was largely ignored until the
1960s, when methylphenidate hy-
drochloride also was found to be ef-
fective in the treatment of attention
disorders.12 The use of medication
for the treatment of this condition
was acceptable “probably because
methylphenidate was less threaten-
ing to physicians and parents than
benzedrine.”10(p299)
DIRECTIONALITY OF
PARENTAL AND
CHILD BEHAVIOR
Barkley and Cunningham13 studied
the effects of methylphenidate on
the mother-child interactions of hy-
peractive boys. In a double-blind
placebo-controlled study, they re-
ported the following:
Methylphenidate produced a marked
improvement in the sustained compli-
ance of hyperactive boys to maternal
commands. In response, their mothers
became less directive and controlling
and more positive toward their sons.
Methylphenidate also resulted in
increased independent play in these
boys to which their mothers responded
with greater positive attention and less
control.13(p207)
THE PRIMACY OF
ATTENTIONAL DEFICITS
VS MOTOR OVERACTIVITY
Douglas14 reported on a series of in-
vestigations examining the relation-
ship of cognitive deficits and behav-
ioral manifestations.
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315
It appears that it may be just as impor-
tant to consider the quality of the hy-
peractive child’s behavior as its quan-
tity. Because of his short attention
span, he tends to flit from one goal to
another. As a result his behavior is of-
ten fragmented and disorganized and
these qualities may contribute to the
impression of excessive activity.14(p260)
Hyperactive children had more
variability from subtest to subtest on
the Wechsler Intelligence Scale for
Children and more errors on the con-
tinuous performance task, includ-
ing problems with vigilance, impul-
sivity, and sustained attention. “This
deterioration [over time] seemed to
be accompanied by increased motor
restlessness.”14(p265)
There is some suggestion that activity
level may not be the most critical as-
pect of the symptom picture. . . . The
youngsters are apparently unable to keep
their own impulses under control in or-
der to cope with situations in which care,
concentrated attention, or organized
planning are required. . . . [an] inabil-
ity to stop, look or listen.14(p275)
In a follow-up study on medi-
cation, Douglas noted the following:
On the CPT [continuous performance
task] on which the hyperactives have
shown their most serious impairment, the
numberofcorrectresponsesincreased,the
number of incorrect responses decreased,
and there was considerably less deterio-
ration over time when the children were
receiving the drug. . . . [These results
suggest] that methylphenidate exerts its
main effect by helping the hyperactive
child sustain attention, and control im-
pulsivity.14(pp270-271)
THE INDEPENDENCE
OF ADHD AND CONDUCT
DISORDERS
Consistent with evidence on the usual
early onset of conduct disorder (on-
set at ⬍10 years of age15), August et
al16 reportedthatchildhoodaggression
was associated with delinquency and
antisocial behaviors in adolescence,
but ADHD alone was not.
A four-year follow-up of clinically se-
lected hyperactive boys with and with-
out associated conduct disorder inves-
tigated their outcome during early
adolescence. . . . Boys originally diag-
nosed as “purely” hyperactive contin-
ued to be inattentive and impulsive at
 follow-up, but showed very few aggres-
sive and antisocial behaviors. Hyperac-
tive boys who had earlier been under-
socialized and aggressive continued to
have problems with attention and im-
pulsivity, [but also] were reported to be
aggressive, noncompliant, egocentric,
exhibiting antisocial behavior and us-
ing alcohol. These findings suggest that
antisocial and delinquent behavior of-
ten reported in follow-up studies of
hyperactive boys may be linked to child-
hood aggression and unsocialized be-
havior, rather than the syndrome of hy-
peractivity itself.16(p192)
FAMILY GENETICS AND ADHD
The transmission of ADHD seems to
be strongly influenced by genetic fac-
tors. In addition, ADHD either is a
risk factor of or shares common risk
factors with other comorbid psychi-
atric disorders. Initial evidence was
reported in a family study by Mor-
rison and Stewart:
Interviews with the parents of 59 hyper-
active and 41 control children revealed a
high prevalence of sociopathy, hysteria
and alcoholism in mothers and fathers of
the hyperactive children. Likewise, sig-
nificantly more of the parents of the hy-
peractive than control children had been
hyperactive as children. These familial as-
sociations of adult and childhood psychi-
atric disorders indicate that childhood hy-
peractivity may be etiologically related to
alcoholism, hysteria, and sociopathy and
that the hyperactive child syndrome is
transmitted genetically or socially from
parent to child.17(p189)
PERSISTENCE OF ADHD
Originally, it was thought that ADHD
was a childhood condition that was
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inevitably outgrown. There is a grow-
ing appreciation that a sizable pro-
portion of children with ADHD
endure persistent symptoms and
associated impairment. Borland
and Heckman18 studied 20 men who
had met the criteria for hyperactive
child syndrome 20 to 25 years ear-
lier and compared them with their
brothers.
Half of the men who had been hyper-
active continued to show a number of
major symptoms of hyperactivity. Nearly
half of the probands had problems
of a psychiatric nature, and despite
normal IQ scores and levels of educa-
tion, men who were hyperactive had
never achieved a socioeconomic status
equal their brothers . . . restlessness, ner-
vousness, and difficulty with temper
were present in half of the probands at
interview . . . these men worked more
hours each week and changed jobs sig-
nificantly more often than their broth-
ers . . . many seemed to tire of their jobs
easily and become impatient . . . [in
addition] each of these men also re-
garded his work as a means of avoiding
feelings of restlessness and nervous-
ness in periods of inactivity. . . . Our
findings suggest that emotional prob-
lems in everyday living may result from
the persistence of symptoms of hyper-
activity.18(p669)
Accepted for publication July 28, 2000.
This study was supported by
grant R29MH57511 from the Na-
tional Institute of Mental Health,
Rockville, Md.
Corresponding author and re-
prints: Thomas J. Spencer, MD, Pedi-
atric Psychopharmacology Unit, Room
WACC-725, Massachusetts General
Hospital, 15 Parkman St, Boston, MA
02114.
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316
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2. Still G. The Goulstonian Lectures on some abnor-
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3. Still G. The Goulstonian Lectures on some
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9. Ferrier D. The Functions of the Brain. New York,
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