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Journal of the History of the Neurosciences
Basic and Clinical Perspectives
ISSN: 0964-704X (Print) 1744-5213 (Online) Journal homepage: http://www.tandfonline.com/loi/njhn20
The Early History of the Neuroscience of Attention-
Alan A. Baumeister , Kristopher Henderson , Joni Lee Pow & Claire Advokat
To cite this article: Alan A. Baumeister , Kristopher Henderson , Joni Lee Pow &
Claire Advokat (2012) The Early History of the Neuroscience of Attention-Deficit/
Hyperactivity Disorder, Journal of the History of the Neurosciences, 21:3, 263-279, DOI:
To link to this article: http://dx.doi.org/10.1080/0964704X.2011.595649
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264 Alan A. Baumeister et al.
Chronology of Important Events in the Early Neuroscience of ADHD
1798 Crichton provides the ﬁrst clinical description of attention disorder linking it
to disturbances of the nerves.
1902 Still proposes disorders of brain cell metabolism as the cause of attention
1920s Encephalitis pandemics and their association with ADHD conﬁrm organicity.
1926 Bond and Partridge describe post-encephalitic hyperkinetic syndrome linking
ADHD to the basal ganglia.
1929 Hans Berger introduces the electroencephalography.
1931 Von Economo reports the brain stem is damaged in encephalitis patients.
1934 Kahn and Cohen propose concept of “Organic Drivenness” and link it to a
lesion of the brain stem.
1937 Bradley observes EEG abnormalities in behavior-disordered children.
1937 Bradley reports the therapeutic effect of stimulants and proposes that they
activate inhibitory cortical systems.
1939 Cutts and Jasper report amphetamine reduces behavior problems without
reducing EEG abnormality.
1954 Methylphenidate is discovered.
1957 Lauffer, Denhoff, and Solomon propose a dysfunction of the diencephalon
based on photo-metrazol EEG studies.
1957 Sigg and Schneider report that methylphenidate and reticular formation
stimulation suppresses reserpine-induced rhinenchephalitic seizures in cats.
1958 Zimmerman and Burgemeister use methylphenidate in behaviorally
1958 Bradley and Key report that amphetamine and methylphenidate act on the
reticular activating system.
1959 Knobel et al. propose a “syndromic” approach using neuropsychological tests
to establish organicity.
1960s Various researchers, based on neuropsychological tests, propose that ADHD
is caused by deﬁcient cortical inhibition of subcortical structures.
1970 Kornetsky proposes the “Catecholamine Hypothesis” of ADHD.
These early neurobiologic theories anticipated some core concepts of modern theory.
Table 1 contains a chronology of major developments in the early history of ADHD.
ADHD was ﬁrst formally recognized by psychiatry when it appeared in the second
edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-II) published
by the American Psychiatric Association in 1968. The DSM-II referred to the condition
as “Hyperkinetic reaction of childhood.” It lists attention disorder and hyperactivity but
not impulsivity as characteristics of hyperkinetic reaction. The name of the syndrome was
changed to “Attention Deﬁcit Disorder” in 1980 with the publication of the DSM-III. This
revision did not consider hyperactivity to be an essential aspect of the disorder. Thus, the
criteria that deﬁne the syndrome have changed with time. Mainly, this article deals with
the period before the syndrome was formally recognized in its present form. Because the
deﬁnition of ADHD has changed with time, to avoid confusion, much of the following
discussion refers to speciﬁc signs and symptoms associated with ADHD rather than ADHD
The Early History of the Neuroscience of ADHD 265
Evolution of the Concept of Organic Behavior
Many authorities today consider ADHD to be a neurobiological disorder. This is not a
new idea. A book by Scottish physician Sir Alexander Crichton, titled An Inquiry into the
Nature and Origins of Mental Derangement (Crichton, 1798/1976), contains the earliest
known clinical description of attention disorders. In this book, Crichton devotes an entire
chapter to “Attention, and its Diseases” (p. 254). He notes that these diseases make people
“incapable of attending with constancy to any one object of education” (p. 271), that they
cause “mental restlessness,” “walking up and down,” and the “ﬁdgets” (p. 272). Crichton
mentions all of the core features of ADHD except impulsivity. Palmer and Finger (2001)
have argued that the disorder described by Crichton (1798) is the inattentive subtype of
ADHD. Crichton recognized that attention disorders can have multiple etiologies including
“debility, arising from neglecting to exercise the faculty [attention] sufﬁciently” (p. 275),
but he emphasized neurobiologic causes:
The incapacity of attending with a necessary degree of constancy to any one
object, almost always arises from an unnatural or morbid sensibility of the
nerves. . . . It may be either born with a person, or it may be the effect of
accidental diseases. (p. 271)
Although Crichton clearly described attention disorders, George Still, a British pediatri-
cian, is often credited with being the ﬁrst person to describe ADHD (Schachar, 1986;
Walters & Barrett, 1993). In 1902, Still gave a series of lectures on Some Abnormal
Psychical Conditions in Children (Still, 1902a, 1902b, 1902c). He focused his discussion
on defective moral control in children. By moral control, Still meant “the control of action
in conformity with the idea of the good of all” (Still, 1902a, p. 1008).
Still’s case materials, upon which the lectures were based, came from his many years
of pediatric practice. The children described in the three lectures were extremely diverse.
They included mentally retarded children, children who had suffered brain damage from
various insults (e.g., tumors, encephalitis), as well as a small subset of children with normal
intelligence and with no clear physical defects. Many of Still’s subjects, especially those
with normal intelligence, would be considered to have conduct disorder today.
The idea that Still described ADHD comes from passing statements about children
with normal intelligence, such as “lack of attention which is very noticeable in many of
these cases . . . no doubt accounts to a considerable extent for backwardness in school
acquirements” (Still, 1902b, p. 1081), and “a notable feature in many of these cases of
moral defect without general impairment of intellect is a quite abnormal incapacity for sus-
tained attention” (Still, 1902c, p. 1166). Still is describing a group of children that would
probably be labeled ADHD today. However, the subtype of ADHD that Still describes
is unclear. He mentions children with attention disorders but does not describe this sub-
set as hyperactive or impulsive. On the other hand, Still emphasizes the importance of
impaired “inhibitory volition” in these children, which implies impulsivity. Thus, he may
be describing either the inattentive or mixed subtypes.
Although Still recognized the importance of the social environment in establishing
inhibitory volition, he clearly placed emphasis on biological determinants of defective
moral control and attention: “there is not only a perversion of function in the higher ner-
vous centres but an actual physical abnormality underlying the moral defect,” and “the fact
that a similar moral change occurs after more general diseases, particularly the speciﬁc
fevers, and is followed sometimes by complete recovery, suggests that cell-modiﬁcation
266 Alan A. Baumeister et al.
dependent upon interference with cell-nutrition, may be the physical basis for the moral
defect” (Still, 1902c, p. 1166). This is one of earliest suggestions that childhood behavior
disorders can have a biochemical basis.
The occurrence of encephalitis pandemics between 1917 and 1926 ﬁrmly established
the association of behavioral disorders characteristic of ADHD with infectious disease.
Encephalitis lethargica (or von Economo’s encephalitis), as the disease was called, was
a sequelae of the Spanish ﬂu (Ravenholt, 1993), which began during World War I and
killed some 40 million people worldwide (Kolata, 2001). Encephalitis lethargica often
occurred months after acute inﬂuenza and was characterized by lethargy, fever, and oculo-
gryic crisis. The disease was fatal in about one third of cases. Among the survivors, fully
80% developed Parkinson’s disease (Post-encephalic Parkinsonism) during the ensuing
The encephalitis epidemics led to the recognition that behavioral sequelae could be a
manifestation of brain damage in children who otherwise appear normal. The medical lit-
erature of the 1920s is replete with descriptions of behavior disorders among children who
survived acute encephalitis (e.g., Happ & Blackfan, 1920; Happ & Mason, 1921; Hohman,
1921, 1922; Leahy & Sands, 1921; Auden, 1922; Ebaugh, 1923; Strecker & Ebaugh, 1924;
Bond & Partridge, 1926). The characteristics of these children and the range of behav-
ior problems attributed to encephalitis were as varied as those described by Still (1902a,
1902b, 1902c). But it was documented and became accepted that “The behavior changes in
children . . . are mainly associated with some degree of hyperkinesis” (Bond & Partridge,
1926, p. 34). This post-encephalitic hyperkinetic syndrome included all the cardinal fea-
tures associated with ADHD, including overactivity, attention deﬁcits, impulsivity, conduct
disorders, and poor school performance. Thus, with the encephalitis epidemic we have the
ﬁrst clear descriptions of the combined form of ADHD.
The motor disturbances (akinetic, dystonic, and hyperkinetic) seen in post-encephalitic
children suggested a disorder of extrapyramidal function. In the early 1900s, experimental
studies in animals showed that lesions of the basal ganglia produce motor disturbances,
suggesting a motor function for these structures (Percheron et al., 1994). Thus, Bond and
Partridge (1926), in a review of the literature on the sequelae of encephalitis, concluded
that “The most purely neurological theory of the behavior reactions would account for
these changes as due not to some general effect upon personality, but to deﬁnite physical
changes, localized most probably in the basal ganglia” (p. 40). This is among the earliest
statements linking ADHD signs and symptoms to a disorder in a particular brain region.
The next step in the evolution of the concept of ADHD as a neurobiologic disorder
occurred in 1934 with the proposed existence of a syndrome called “Organic Drivenness”
by Kahn and Cohen (1934). A “surplus of inner impulsion” characterized the disorder.
This was manifest in “general hyperkinesis,” “inability in maintaining quiet attitudes,”
“explosive motor release of all voluntarily inhibited activity” (p. 750), as well as “extreme
ﬂuctuation of attention or lack of continued concentration” (p. 752). Kahn and Cohen pro-
posed that Organic Drivenness resulted from a lesion of the brain stem, based on the
ﬁndings of von Economo (1931) that “it is the brain-stem above all which encephalitis
lethargica selects as a favorite target” (von Economo, 1931, p. 87). They also argued
that any insult that damages the brain stem, including encephalitis, can produce Organic
Drivenness. Thus, signiﬁcantly, the authors proposed that Organic Drivenness was not
solely the result of a single disease (e.g., encephalitis), but, rather, it had a multitude of
potential etiologies. The work of Kahn and Cohen is important in that it extended organic
behavior beyond encephalitis and subsumed all of the core features of ADHD under a
The Early History of the Neuroscience of ADHD 267
The Origin of Stimulant Therapy for Childhood Behavior Disorders
The discovery that stimulant medications are useful in treating behavior disorders in chil-
dren was critical to further development of neurobiological theories of ADHD, because
early and modern theories are based, in part, on the mechanism of action of stimulants
(see below). The practice of treating behavior-disordered children with stimulants began
at the Bradley Hospital in Rhode Island in the 1930s (Bradley, 1936). Charles Bradley,
the Medical Director of the Bradley Hospital, was the ﬁrst to report that stimulants have
useful therapeutic effects in behavior-disordered children. The ubiquitous modern use
of stimulants for this purpose is directly traceable to experiments conducted by Charles
Bradley in the 1930s (Figure 1).
There are two different accounts about the impetus for Bradley’s original trial of
amphetamine. According to one, the discovery was purely serendipitous (Baumeister,
Hawkins, & L´opez-Muñoz, 2010). The account comes from a friend and colleague of
Bradley’s, Dr. Maurice Laufer, who verbally passed it along to Dr. Mortimer Gross
(1995). According to Gross, children at the Bradley home were given routine spinal
taps in preparation for pneumoenchephalography. The loss of spinal ﬂuid gave the chil-
dren severe headaches. According to Laufer (as recounted by Gross), Bradley gave the
children amphetamine with the hope that it would stimulate spinal ﬂuid production and
reduce the headaches. To Bradley’s surprise, teachers at the school reported that the drug
seemed to improve behavior and academic performance. In the second account, given by
Bradley in the seminal report on the subject, amphetamine was given to children because
of reports “describing its effect upon the mood and other psychological reactions of adults”
(Bradley, 1937, p. 577). Among these effects were a decrease in fatigue, increase in mood,
Figure 1. Charles Bradley. The ﬁrst medical director of the Bradley Hospital and discoverer of
stimulant treatment of behavior disorders in children. Used by permission of the Bradley Hospital.
268 Alan A. Baumeister et al.
alleviation of depression, neuroses, and catatonic stupor, increased capacity for work, and
increased intelligence test scores in adults and children (Davidoff, 1936; Myerson, 1936;
Sargant, 1936; Carlisle, 1937; Molitch & Sullivan, 1937; Nathanson, 1937; Wilbur, 1937).
Bradley’s account diminishes the role of serendipity.
The original clinical trial of amphetamine was conducted on 30 children (21 boys
and 9 girls) ranging in age from 5 to 14 years. The children had diverse behavior problems
and medical conditions. They included children with school-related behavior problems and
speciﬁc learning disabilities, a withdrawn “schizoid” child, and an “aggressive, egocentric
epileptic.” All children had intelligence in the normal range. The study had a pretest-
posttest design. Teachers and nurses observed the children’s behavior one week prior to
medication, one week on medication, and one week off medication. “The most striking
change in behavior during the week on Benzedrine [amphetamine] therapy occurred in the
school activities. . . . Fourteen children responded in spectacular fashion” (Bradley, 1937,
p. 578). Increased interest in school work, increased drive to work, and increased speed
of comprehension and accuracy, particularly in math, were among the reported school-
related beneﬁts. School staff started referring to amphetamine as math pills (Gross, 1995;
Brown, 1998). Fifteen children responded with “subdued” emotional responses includ-
ing decreased mood swings, decreased motor activity, and decreased “noisy, aggressive,
domineering behavior” (Bradley, 1937, p. 579).
Published reports on the new therapy came primarily from the Bradley Hospital dur-
ing the 15 years after its introduction. During this time Bradley and colleagues continued
to add subjects and to reﬁne their analysis. They reported, for example, that, although
amphetamine improved scholastic performance, it did not increase IQ, as measured by the
Stanford-Binet test (Bradley & Green, 1940), and that amphetamine and Dexedrine (the
d isomer of amphetamine) were equal in efﬁcacy (Bradley, 1950). However, nothing fun-
damentally new regarding the therapeutic use of amphetamine was reported during this
period despite numerous publications on this subject (Cutts & Jasper, 1939; Bradley &
Bowen, 1940, 1941; Bradley & Green, 1940; Bradley, 1942, 1950).
Only a few studies before circa 1950 not originating in the Bradley Hospital
were found. One was by Bender and Cottington (1942). These authors reported that
amphetamine was “a useful adjunct to the treatment of the neurotic child, in that it
gives him a feeling of well-being, and temporarily allows him to feel secure and loved”
(p. 120). They also reported that it decreased aggression in psychopathic children but
did not decrease the overactivity of two boys with evidence of brain anomalies. Bakwin
(1948), using wording similar to Bender and Cottington (1942) but based on independent
studies, reported that amphetamine “gives the neurotic child a feeling of well-being
and temporarily allows him to feel secure” (p. 216). Pasamanick (1951) reported that
anticonvulsant and sedative drugs were “uniformly disappointing” in treating behavior
disorders in children. In contrast, of 10 children treated with amphetamine, 4 showed
marked or obvious improvement.
The discovery of methylphenidate in 1954 by Ciba laboratories in Switzerland
(Meier, Gross, & Tripod, 1954) advanced signiﬁcantly stimulant therapy for ADHD.
Methylphenidate is a structural analogue of amphetamine (Figure 2). The chief advantage
of methylphenidate is that it is a milder stimulant. It has a shorter half-life (about 2 hours)
than amphetamine (7 to 30 hours) and is less likely to produce psychosis and other side
effects. However, the clinical effects of methylphenidate and amphetamine are qualita-
tively similar. Both drugs are thought to stimulate the release of catecholamines and block
catecholamine reuptake. But, methylphenidate is thought to enhance vesicular exocytosis,
whereas amphetamine stimulates the release of newly synthesized catecholamines from a
nonvesicular site by causing catecholamine transporters in the presynaptic membrane to
The Early History of the Neuroscience of ADHD 269
Figure 2. The structures of amphetamine (Top) and methylphenidate (Ritalin; Bottom). Retrieved
pump catecholamines out of the cell rather than in, a phenomenon known as exchange
diffusion (García-García et al., 2009).
Although methylphenidate was introduced to the United States in 1955, the ﬁrst men-
tion of its use to treat childhood behavior disorders was found in a paper by Laufer and
Denhoff published in 1957. The focus of this paper is on the treatment of behavior disor-
ders with amphetamine. However, in a brief section on “Other Medications” the authors
write: “A variety of other medications have been advocated, such as Benadryl, Phenergan,
Ritalin, desoxyn, Miltown, Meratran, Dramamine and Bonamine, and Atarax” (p. 473).
The earliest published empirical clinical study of methylphenidate found was
by Zimmerman and Burgemeister (1958). These investigators were prompted to try
methylphenidate in children because they were looking for a stimulant that had fewer side
effects than amphetamine:
The rather excessive and well-known side reaction of Benzedrine . . . appeared
. . . in such a high percentage of cases that it was necessary to search
for a drug . . . on a physiological scale halfway between caffeine . . . and
Benzedrine. Methyl-phenidylacetate hydrochloride (Ritalin) appears to be that
drug. (p. 323)
The subjects in this study were 108 children and adults with “emotional problems” includ-
ing hyperactivity. Half of the subjects were given methylphenidate and the other half,
matched for numerous variables (e.g., age, sex, and diagnosis), were given reserpine1
control. The average age of the methylphenidate groups was 15 years. Eighty percent of the
methylphenidate subjects had no discernible neurological abnormalities. Various outcome
measures were taken before and after drug treatment. With respect to hyperactivity specif-
ically, 50% and 66% improved on methylphenidate and reserpine, respectively. Although
reserpine appeared to be superior in reducing activity, methylphenidate had less pro-
nounced side effects. The efﬁcacy of methylphenidate in treating behavior disorders in
children was subsequently conﬁrmed (Knobel, Wolman, & Mason, 1959; Lytton & Knobel,
1959). In 1961, it was approved by the FDA for the treatment of childhood behavior
disorders (Mayes, Bagwell, & Erkulwater, 2008). It quickly supplanted amphetamine as
the ﬁrst-line medication for ADHD.
Reserpine is an antipsychotic and antihypertensive agent. It blocks the transport of newly syn-
thesized monoamines into synaptic vesicles. This makes the monoamines accessible to monoamine
oxidase for catabolism. Sufﬁcient doses cause depletion of monoamine stores throughout the body
(Baumeister, Hawkins, & Uzelac, 2003).
270 Alan A. Baumeister et al.
Electroencephalography and Childhood Behavior Disorders
Research on the neuropathology of ADHD took a new tack in the 1930s. Hans Berger, a
German psychiatrist, introduced the electroencephalographic (EEG) method into clinical
medicine in 1929 (Swartz & Goldensohn, 1998; Niedermeyer, 2005). Charles Bradley was
the ﬁrst to employ the new technology in behavior-disordered children. The EEGs of 11 of
Bradley’s original subjects showed a “spike and slow wave” form that was characteristic
of petit mal seizures. He proposed that this EEG abnormality was indicative of impaired
cortical function. He also reported that in 10 subjects, amphetamine reduced the “seizure
waves.” Bradley noted that subdued behavior in hyperactive children seemed like a “para-
doxical” effect of a stimulant. Signiﬁcantly (see below), he suggested that this could be
explained by stimulant-induced activation of inhibitory cortical systems (Bradley, 1937,
Jasper, Solomon, and Bradley (1938) conducted a more thorough analysis of EEG
abnormalities in 71 diverse behavior-disordered children. They reported that 74% of
patients with histories suggestive of central nervous system (CNS) disorder have abnormal
EEGs. However, approximately 50% of behavior-disordered children with hyperactivity
have no history suggestive of insult to the nervous system (Childers, 1935; Levin,
1938). Bradley reported that 38% of such children had abnormal EEGs. He concluded
that “The electroencephalogram has succeeded in revealing a deﬁnite abnormality of
brain function in over one half of a group of child behavior disorders which had
been previously considered as largely psychogenic” (Jasper, Solomon, & Bradley, 1938,
A follow-up study conducted at the Bradley Hospital by Cutts and Jasper (1939)
examined the relationship between EEG abnormalities, behavior disorders, and response
to stimulant treatment. All the 12 children in this study exhibited erratic and asocial behav-
ior. All were characterized as “epileptoid” based on EEG and clinical ﬁndings. Seven of
the subjects had favorable behavioral responses to amphetamine, becoming less active,
less impulsive, and more cooperative. All subjects who had a positive behavioral response
exhibited the EEG abnormality. However, in contrast to Bradley’s original report (Bradley,
1937; see above), amphetamine had no effect on EEG abnormalities, even in children
with behavioral improvements. The authors concluded that “The changes in personality
with Benzedrine are probably due to an alteration in the patient’s emotional reactions to
the type of brain disorder revealed in the electroencephalogram without any fundamental
change in the disorder itself” (Cutts & Jasper, 1939, p. 1145). In numerous later stud-
ies, Bradley and colleagues conﬁrmed that about 50% of behavior-disordered children
have abnormal EEGs that are unaffected by stimulants (Bradley & Bowen, 1940, 1941;
Bradley & Green, 1940; Bradley, 1942, 1950; Lindsley & Henry, 1942; Laufer & Denhoff,
1957). Nevertheless, Bradley proposed that EEG abnormalities in a child characterized as
“irritable, hyperactive, and aggressive, who has a short attention span” were sufﬁcient to
classify the child as having an organic behavior problem and “indicate a need for deﬁnite
pharmacologic treatment” (Bradley, 1942, p. 774).
At about this time other researchers reported that amphetamine controls petit mal
seizures (Lennox, 1945; Livingston, Kajdi, & Bridge, 1948). But in contrast to stimu-
lants, standard anticonvulsant drugs (e.g., diphenylhydantoin and phenobarbital) either had
no effect or worsened behavior disorders in children (Pasamanick, 1951). The failure of
amphetamine to eliminate EEG abnormalities and the exacerbation of behavior disorders
by sedative anticonvulsants suggested the behavioral therapeutic effect of amphetamine
was unrelated to its anticonvulsant action. This led Pasamanick to proposed the stimulant
The Early History of the Neuroscience of ADHD 271
effect on behavior was caused by “inhibition of some of the random, circular and poorly
integrated stimuli tracks, secondary to minor or major lesions” (p. 765).
As the neuroscience of EEG evolved, techniques were developed to assess the func-
tion of subcortical brain regions. One such technique was the photo-metrazol activation
test developed by Gastaut (1950). This technique involves determination of the threshold
doses of pentylenetetrazol (Metrazol) needed to obtain a particular EEG and myoclonic
response in subjects exposed to a stroboscopic light. Abnormality (i.e., a lowered thresh-
old) was thought to be associated with thalamic function (Gastaut & Hunter, 1950).
Laufer, Denhoff, and Solomons (1957) used the photo-metrazol technique to evaluate brain
function in behavior-disordered children. They reported lower thresholds in hyperactive
children than in normal children. Also, thresholds were lower in both hyperactive children
with a history of brain disease and those with no such history. Moreover, administration
of amphetamine raised the threshold in hyperactive children. Based on the photo-metrazol
ﬁndings, the authors postulated that in hyperactive children “dysfunction of diencephalon
would alter resistance at synapses. This would allow incoming impulses to spread out of
usual pathways and irradiate large cortical areas” (p. 45).
Other studies suggested that the effects of stimulants on behavior disorders were medi-
ated through an action on the reticular formation. Sigg and Schneider (1957) showed that
reserpine produced rhinencephalic seizures in cats with “encephale isole” preparations.
This effect was suppressed by electrical stimulation of the brainstem reticular forma-
tion and by administration of methylphenidate. Bradley and Key (1958) showed that
amphetamine lowered thresholds for cortical activation by electrical stimulation of the
reticular formation. They concluded that amphetamine and methylphenidate have a direct
action on the reticular activating system.
A Neuropsychological Approach to Deﬁning Organicity
In about 1950, efforts to link the signs and symptoms of ADHD to neurobiologic lesions
began to take more of a neuropsychological approach. That is, in addition to EEG and
other neurologic indicators, investigators began using psychological tests that presumably
evaluate speciﬁc brain functions. Lauretta Bender (1949), an American psychiatrist who
is best known for the development of the Bender-Gestalt Visual Motor Test, advocated
neuropsychological testing as a way to diagnose organic brain disorders. She reported
that post-encephalitic children, whose motor disturbance “was mostly extrapyramidal,”
are unable to “copy a diamond or even a square . . . [and have] poor memory for digits
especially backwards, inability to reproduce designs from memory, and failure often to
distinguish weights” (p. 409). Most signiﬁcant, she wrote, was poor performance on the
Goodenough Draw-A-Man test. This test was developed in the 1920s by American psy-
chologist Florence Goodenough as a projective test of intellectual maturity. According
to Bender, this test, in particular, showed that post-encephalitic children are unable to
organize perceptions into meaningful wholes. “This, in turn, leads to an increase in drive
to contact [the external world] and to experience contacts and in itself accounts for the
hyperkinesis” (p. 409).
Knobel, Wolman, and Mason (1959) used neuropsychological testing combined with
EEG and neurological examination to identify organic behavior disorders. Psychiatric
evaluation of 40 behavior-disordered children showed 23 were hyperactive, 8 had mixed
symptomatology, and 9 were hypokinetic. All subjects were given EEGs, neurological
evaluations, and a battery of psychological tests. None of the three measures reliably dif-
ferentiated hyperactive and nonhyperactive children. However, all hyperactive children
272 Alan A. Baumeister et al.
who had positive psychological ﬁndings also displayed either EEG abnormalities or
neurological signs. The authors concluded that “Though EEG and psychological tests
may yield false-positives when considered singly, if they are combined with positive
neurological signs, one can expect some abnormal occurrence in the nervous system”
In a review of his “syndromic” approach, Knobel (1959) clearly described all the
core behavioral and psychological features of ADHD, including “impulsivity, aggressiv-
ity, distorted perception and hyperactivity” (p. 85). He argued that a purely diencephalic
dysfunction was unlikely to be the cause of the behavior disorder, because such dys-
function would produce “a more complicated symptomatology and more expressive
psycho-neurologic and endocrine-metabolic sequelae” (p. 81). Instead, he was “inclined
to think that the disorder may be cortical or more probably in the cortical-subcortical path-
ways” (p. 81). More speciﬁcally, he implicated cortical areas of the frontal and temporal
lobes. He based this hypothesis on the evidence that the frontal lobes are a control area and
that dysfunction is associated with inhibitory releases (Jacobsen, 1931; Bricker, 1936).
The temporal lobes were implicated by behavioral disturbances associated with tempo-
ral lobe epilepsy (Gibbs, Gibbs, & Fuster, 1948; Bailey & Gibbs, 1951). Interestingly,
Knobel (1959) concluded that in calling “acting out” behavior organic this “doesn’t nec-
essarily mean anatomical or structural lesions; it could refer to an encephalic dysfunction
for reasons presently not known, or a dysfunction due to a change in the enzymatic par-
ticipation in brain metabolism” (p. 81). This is one of the earliest statements of a possible
neurochemical basis for hyperactivity.
Conners, Eisenberg, and Sharpe (1964) supported the idea that ADHD children have
deﬁcient inhibitory mechanisms. These investigators used neuropsychological tests to eval-
uate the effect of methylphenidate in “emotionally disturbed” children who were not
psychotic, brain damaged, or mentally retarded. The main ﬁnding was the drug had min-
imal effects on a paired-associate learning task but improved performance on the Porteus
Maze Test, a nonverbal test of intelligence developed by the Australian psychologist
Stanley Porteus. It consists of paper forms on which the subject is required to trace
paths through a series of drawn mazes. No time limit is placed on the test. However,
subjects are penalized if they back-track or trace down blind alleys. The test is thought
to place a premium on planning and impulse inhibition. The researchers interpreted the
results of the Porteus Maze Test as indicating that methylphenidate inhibits “impulsive
discharge.” Based on the proposition that behaviorally disordered children “lacked central
cortical inhibitory capacity over their internal drives and the external stimuli impinging
upon them,” they attributed the improvement in impulsivity to “some form of heightened
cortical activity” (p. 15).
Another early study by Connors (1966) showed that d-amphetamine improved per-
formance on a visual discrimination test in hyperactive children (who had no evidence of
brain damage) and that this effect was greatest under conditions of stress. Connors sug-
gested “the drug may produce more organized perceptual response under stress . . . with
effects being more dramatically noticeable in children with diencephalic lesions or other
forms of imbalance between cortical and sub-cortical mechanisms” (p. 432).
During the ensuing decades, a huge number of studies were conducted using a vast
array of neuropsychological tests to try to identify the underlying neuropathology, the spe-
ciﬁc psychological defects, and the effects of stimulants in ADHD. Beyond the general
conclusion that ADHD children differ from normal controls in their attention and inhibitory
capacities and that stimulants improve these capacities, modern neuropsychological testing
has not yielded much new knowledge about the neuropathology of ADHD. Indeed, after
The Early History of the Neuroscience of ADHD 273
reviewing the literature on this subject, Rapport and Kelly (1993) concluded that “There
appears to be an inverse relationship between the number of studies investigating MPH
[Ritalin] effects on children’s cognitive performance and our understanding of these
effects” (p. 116). Nevertheless, neuropsychological theories have achieved considerable
prominence in recent years. These theories focus on deﬁcits in executive functions (e.g.,
planning and working memory) and inhibition of ongoing activity (Barkley, 1997). The
latter, of course, is an idea that goes back at least to George Still in 1902 and was sup-
ported by neuropsychological research in the 1950s and 1960s. Current neuropsychological
research supports deﬁcits in both areas of function, particularly in the combined type of
the disorder. However, children under the generic label of ADHD display considerable
neuropsychological heterogeneity, suggesting the possible existence of distinct disorders
with distinct etiologies (Baumgaertel, Blaskey, & Antia, 2008).
The First Neurotransmitter Theory of ADHD
Speciﬁc neurochemical postulates about the brain pathology in ADHD are a relatively
recent development. Apparently, Kornetsky (1970) was the ﬁrst person to offer such a
theory. Kornetsky proposed the action of amphetamine was to inhibit norepinephrine
synthesis, turnover, or release. As mentioned above, it is now known that stimulants actu-
ally increase catecholamine release and block catecholamine reuptake. But, based on his
assumption that these drugs have the opposite effect, Kornetsky proposed, “there would
simply be an increase in norepinephrine turnover causing increased hyperkinetic activity”
(p. 130). This idea was called the “Catecholamine Hypothesis” of ADHD (Zametkin &
Kornetsky also proposed that
Since many of the drugs that are useful in treating behavior problems in
children have marked effects upon catecholamine levels in the brain, studies
comparing urine catecholamine levels in various types of behavior disor-
dered children after the administration of sympathomimetic amines might give
speciﬁc direction to further research. (1970, p. 105)
Kornetsky’s conjecture stimulated a massive amount of research trying to document vari-
ous indices of catecholamine disturbances in hyperkinetic children. About 15 years later,
Zametkin and Rapoport (1987) summarized this research. Scores of biochemical stud-
ies were conducted looking for indices of monoamine function that distinguish between
ADHD children and normal controls. These indices included urine MHPG (the principal
metabolite of norepinephrine), peripheral autonomic functions, platelet monoamine oxi-
dase activity, and cerebrospinal ﬂuid monoamine metabolites. They concluded that “no
consistent differences in any peripheral measure of monoamine or metabolites has been
found between hyperactive and control children” (p. 678). They found that drug-induced
biochemical changes correlated with clinical improvement in some studies but not in oth-
ers. Nevertheless, based on the fact that stimulants affect catecholamines, they concluded
that these transmitters are probably involved in the pathogenesis of ADHD.
This idea still holds sway. A recent review of the topic concludes:
The dominant hypothesis for the pathophysiology of ADHD is that of
prefrontal cortical dysfunction, which is mediated by abnormalities of
274 Alan A. Baumeister et al.
catecholaminergic neurotransmission in the catecholamine-rich fronto-striatal-
cerebellar networks. The hypothesis is supported by the treatment effectiveness
of stimulants, which increase the availability of extracellular catecholamines.
(Baumgaertel, Blaskey, & Antia, 2008, p. 311)
With the exception of the reference to catecholamines, which were not known to be brain
neurotransmitters until about 1950, this hypothesis is entirely consistent with ideas that
were put forward by researchers as early as the 1930s.
From the time that attention disorders and hyperactivity were ﬁst recognized to be a dis-
tinct syndrome, it was proposed that they have an organic basis. Crichton (1798/1976), the
ﬁrst person to describe attention disorders, argued that they were caused by disturbances of
the nerves. Still (1902a, 1902b, 1902c) thought that disorders of attention were caused by
disorders of brain cell metabolism. The association of attention and other behavior disor-
ders (e.g., hyperactivity) with encephalitis in the 1920s conﬁrmed organicity. The salience
of motor problems in these children led to the suggestion that the basal ganglia are the seat
of these disorders. Subsequently, based on histopathologic studies of encephalitic children,
the brain stem was blamed. Between the 1930s and 1950s, many studies showed that about
50% of children with behavior disorders have EEG abnormalities. EEG studies were used
to link these disorders to hypothesized disturbances in many brain regions including the
diencephalon, the reticular formation, the frontal and temporal lobes, and the cortex. The
frequent occurrence of hyperactivity among children with normal EEGs led to efforts to
combine EEG, neurological examination, and neuropsychological tests as a means to dis-
tinguish between organic and nonorganic hyperactivity. Studies using combined metrics
led to the widely held belief that childhood behavior disorders are mainly organic in nature.
The early neuroscience of childhood behavior disorders anticipated aspects of modern
ADHD theory. Based on EEG ﬁndings and neuropsychological tests, early investigators
proposed that inhibitory functions of the frontal lobes are impaired in ADHD. Prominent
current theories of ADHD (e.g., Barkley, 1997) attribute the disorder to impaired “exec-
utive functions,” which are thought to reside in the frontal lobes. Furthermore, these
impaired executive functions are thought to lead to a deﬁcit in behavioral inhibition. This
idea that higher brain functions inhibit lower brain functions and that a decrease in such
inhibition is responsible for signs and symptoms of ADHD dates back to the 1930s.
The advent of the EEG in 1929 was signiﬁcant in that it represented a noninvasive
diagnostic tool for assessing brain function and identifying focal lesions. EEG studies
dominated the early research on the neuroscience of ADHD. In recent years, the use of
EEG, outside of diagnosis of epilepsy, has declined substantially (Benbadis & Rielo, 2010;
Boro & Haut, 2010). Nevertheless, EEG studies of ADHD children continue to the present.
More recent studies have contributed little new knowledge. They have conﬁrmed the main
ﬁndings of earlier studies that (a) approximately 50% of ADHD children have abnormal
EEGs, (b) the principal abnormality is a nonspeciﬁc slowing of brain wave activity, and
(c) there is a poor relationship between EEG abnormalities and response to stimulant med-
ication (Melo & Niedermeyer, 2005; Small, 2005). The results of modern EEGs studies
are interpreted as showing that ADHD children have decreased cortical inhibitory control
over lower brain centers, as was suggested by Bradley in the 1930s. In recent years, the use
of the EEG as a method to study brain disturbances in ADHD has been largely replaced
The Early History of the Neuroscience of ADHD 275
by new sophisticated neuroimaging techniques. Ironically, use of the more sophisticated
neuroimaging technology has failed to reveal reliable differences between ADHD and
non-ADHD children (Baumeister & Hawkins, 2001).
The ﬁrst neurochemical theory of ADHD (the Catecholamine Hypothesis) was
proposed in 1970. It is interesting that this proposal was somewhat belated. The “psy-
chopharmacology revolution” in psychiatry had been underway since the middle of the
1950s. One result of this revolution was the rise of theories about the underlying neuro-
chemical pathology of mental disorders based on drug mechanisms of actions. Thus, in
1958 Everett and Toman (1959) proposed a monoamine theory of depression based on
the observations that monoamine oxidase inhibitors, which increase monoamine levels,
and reserpine, which decreases monoamine levels, are antidepressant and depressogenic,
respectively. In 1962, Van Rossum proposed the dopamine hypothesis of schizophrenia
(Baumeister & Francis, 2002). Again, the hypothesis was based on drug mechanisms of
action. Drugs that stimulate dopamine function (e.g., amphetamine) worsen schizophrenic
symptoms, whereas drugs that block dopamine function are antipsychotic. Like other the-
ories of mental disorders of the time, the ﬁrst neurochemical theory of ADHD was based
on drug mechanism of action. Stimulants such as amphetamine were suspected of alter-
ing catecholamine function as early as the 1930s (Nathanson, 1937). Therefore, it was
proposed that disordered catecholamine function is responsible for ADHD.
Although it is rarely acknowledged, amphetamine was the ﬁrst modern psychiatric
medication used for any clinical disorder. This is not well known because later devel-
opments overshadow the discovery of stimulant drugs to treat ADHD. The introduction
of antipsychotics in the 1950s played a role in one of the most important develop-
ments in modern psychiatry: deinstitutionalization of the mentally ill (Johnson, 1990).
In addition, the antipsychotics were the impetus for the psychopharmacology revolution.
Nevertheless, neurobiologic theories of ADHD and stimulant treatment of the disorder
have had a profound social impact too. Between 2 and 3 million children in the United
States alone take stimulants for ADHD (Mayes, Bagwell, & Erkulwater, 2008; Denchev
et al., 2010). Another interesting point is that the clinical beneﬁts of stimulants were
discovered before the advent of the randomized double-blind experimental design, the
gold standard of today’s clinical science. This is also true of other major discoveries in
psychopharmacology, including the antipsychotics and antidepressants developed in the
In conclusion, neuroscientists before 1970 anticipated the basic tenets of our current
theories of the neuroanatomical and neurochemical substrates of ADHD. This is not to say
that there have been no advances in our understanding of ADHD since that time. Complex
neurocognitive models have been proposed (e.g., Barkley, 1997; Bush, 2010), but they
remain highly speculative. Probably the most reliable recent ﬁnding relating to the patho-
genesis of ADHD is its high heritability (60% to 90%) (Curatolo, D’Agati, & Moavero,
2010). However, whole genome linkage studies have not provided compelling evidence
for regions of the genome that contain ADHD-susceptibility genes. Several speciﬁc genes,
particularly those involved in dopamine metabolism, have been associated with ADHD
in some studies, but results across studies are highly variable (Stergiakouli & Thapar,
2010). It is generally accepted today, as it was in the 1930s, that ADHD is not a uni-
tary disorder with a single etiologic pathway. Rather, it is current consensus that ADHD
is polygenetic, that environmental factors contribute to the disorder, and that genes and
environment interact in complex ways producing variable ADHD phenotypes (Curatolo,
D’Agati, & Moavero, 2010).
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