Neurotoxicology and Teratology 22 (2000) 631 ± 651

Symposium overview
Attention deficit/hyperactivity disorder: characteristics,
interventions, and models
Merle G. Paulea,*, Andrew S. Rowlandb, Sherry A. Fergusona, John J. Chelonisc,
Rosemary Tannockd, James M. Swansone, F. Xavier Castellanosf
a
Behavioral Toxicology Laboratory, Division of Neurotoxicology, HFT- 132, National Center for Toxicological Research, 3900 NCTR Road, Jefferson,
AR 72079 - 9502, USA
b
Epidemiology Branch, NIEHS, A3 - 05, P.O. Box 12233, Research Triangle Park, NC 27709 - 2233, USA
c
Department of Psychology, University of Arkansas at Little Rock, 2801 South University Avenue, Little Rock, AR 72204, USA
d
Brain and Behaviour Research Programme (Psychiatry Research), The Research Institute of the Hospital for Sick Children, University of Toronto,
555 University Avenue, Toronto, Ontario, Canada M5G 1X8
e
Child Development Center, University of California at Irvine, 19722 MacArthur Boulevard, Irvine, CA 92612, USA
f
Child Psychiatry Branch, National Institute of Mental Health, Room 3B - 19, 10 Center Drive, Bethesda, MD 20892 - 1251, USA
Received 28 April 2000; accepted 30 May 2000

Abstract

An epidemiological study of Attention Deficit / Hyperactivity Disorder (ADHD) suggests that the prevalence may be two to three times
higher than the figure of 3 ± 5% often cited. In addition, the data suggest that both underdiagnosis and overdiagnosis occur frequently. Rodent
animal models of ADHD, like the Spontaneously Hypertensive Rat (SHR) and other rat models such as those with chemical and radiation -
induced brain lesions and cerebellar stunting, and the Coloboma mouse model exhibit clear similarities with several aspects of the human
disorder and should prove useful in studying specific traits. Operant behavioral tasks that model learning, short - term memory and simple
discriminations are sensitive to ADHD and methylphenidate has been shown to normalize ADHD performance in a short - term memory task.
Recent findings challenge not only the current postulate that response inhibition is a unique deficit in ADHD, but also the concepts of ADHD
and its treatment, which presume intact perceptual abilities. Time perception deficits may account, in part, for the excessive variability in
motor response times on speeded reaction time tasks, motor control problems and motor clumsiness associated with ADHD. The
Multimodality Treatment Study of ADHD (MTA) provided data suggesting that pharmacological interventions that included systematic and
frequent follow - up with parents and teachers, with or without psychosocial interventions, are superior to psychosocial interventions or
standard community care alone. Additionally, the MTA was one of the first studies to demonstrate benefits of multimodal and
pharmacological interventions lasting longer than 1 year. Imaging studies have demonstrated differences in brain areas in children with
ADHD: anterior corpus callosum, right anterior white matter, and cerebellar volumes are all decreased in children with ADHD and there is
less brain asymmetry in ADHD subjects. Additionally, functional imaging studies, coupled with pharmacological manipulations, suggest
decreased blood flow and energy utilization in prefrontal cortex and striatum, and the dysregulation of catecholamine systems in persons with
ADHD. D 2000 Elsevier Science Inc. All rights reserved.

Keywords: Attention deficit disorder; Epidemiology; Prevalence; Rodent models; Cerebellar stunting; Short - term memory; Cognitive markers; Treatment;
Stimulant medication; Multimodal interventions; Neuroimaging; Prefrontal cortex; Dopaminergic dysfunction

1. Introduction presentations that focused on Attention Deficit /Hyperac-

At the 1999 Annual Meeting of the Neurobehavioral
Teratology Society held in Keystone, CO, a series of
* Corresponding author. Tel.: + 1 - 870 - 543 - 7147 / 7203; fax: + 1 -
870 - 543 - 7720.
E-mail address: mpaule@nctr.fda.gov (M.G. Paule).
tivity Disorder (ADHD) were presented. The following text
summarizes these six presentations and includes a biblio-
graphy that should serve as an important resource for all of
those interested in this topic. Dr. Andy Rowland from the
National Institute of Environmental Health Sciences
opened the symposium with an overview of the epidemio-
logy of ADHD.

0892-0362/00/$ ± see front matter D 2000 Elsevier Science Inc. All rights reserved.
PII: S 0 8 9 2 - 0 3 6 2 ( 0 0 ) 0 0 0 9 5 - 7
632 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
2. Studying the epidemiology of ADHD: problems
and prospects
ADHD is one of the most common childhood disabilities
[198], yet there are enormous gaps in the epidemiologic
literature on ADHD. There is tremendous variability in
prevalence estimates and little available data concerning
how prevalence varies by age, race, gender, or socio -
economic status. Data on diagnosis and treatment patterns
in community settings are scarce, as are data on the long -
term effectiveness of treatment. Our understanding of the
developmental course of ADHD is heavily based on in-
formation collected in a few key longitudinal studies
[14,70,115,116]. However, most of these studies were based
on relatively small (about 100 ADHD children) clinical
samples. Data on etiologic risk factors are also limited.
Here, some of the barriers to conducting epidemiologic
studies on ADHD are described, some of the approaches we
are taking to address those barriers in an ongoing study in
North Carolina are summarized and some future directions
for research are suggested.
2.1. Clinical and epidemiologic case definition of ADHD
The clinical diagnosis of ADHD is based on the criteria
established by the diagnostic and statistical manual of the
American Psychiatric Association (DSM -IV) [4]. The clin-
ical criteria are based on collecting a history of nine
symptoms of hyperactivity /impulsivity or nine symptoms
of inattention that have been present for 6 months or more
and evidence of impairment in at least two settings (for
example, at school and at home). There also has to be
evidence of ``clinically significant impairment'' in social,
academic or occupational functioning. The DSM - IV criteria
for ADHD establish three subtypes: a predominately hyper-
active ± impulsive subtype; a predominately inattentive sub-
type; and a combined subtype where an individual displays
both types of symptoms. According to DSM -IV, there are
no laboratory tests that have been established as diagnostic
in clinical assessment [4]. The criteria require that some
hyperactive ± impulsive symptoms or inattentive symptoms
that caused impairment were present before age 7 years.
There are a number of problems applying these criteria in
a clinical setting or in an epidemiologic study. The difficul-
ties of establishing the diagnosis in the clinical setting are
summarized in several excellent reviews [25,237]. For
example, children with ADHD often do not display symp-
toms in novel settings (like the doctor's office) and the
differential diagnosis can be tricky when a child has other
co -morbid conditions.
Difficulties in the measurement of ADHD are substantial
and have hindered progress in understanding or conducting
research on the condition. In epidemiologic studies, there
are several key issues in defining cases that need to be
addressed. These include: (1) how to combine the reports of
different respondents; (2) how to define impairment; (3)
how to rule out other explanations for ADHD -like symp-
toms that could produce similar symptom profiles; (4) how
to identify co -morbid or co -occurring conditions; and (5)
how to handle the age at onset criteria.
Reports from different respondents often disagree and
epidemiologists need to establish rules for combining
symptoms. The rules they apply can have dramatic effects
on which children they identify as cases, and consequently,
on prevalence [18,66]. As noted above, the DSM - IV
criteria for ADHD require evidence of clinically significant
impairment. This is meant to distinguish between a child
who is showing symptoms but is still functioning well.
However, for epidemiologists, the challenge lies in reliably
defining impairment even though the underlying construct
of impairment is complex and there are no universally
accepted methods for measuring it [5,21,37]. For example,
several lines of research suggest that the risk of accidental
injuries is increased among ADHD children [43]. Should
information about accidental injuries be used in the defini-
tion of impairment? Much of the debate about whether
ADHD is a ``real'' condition occurs because ADHD is
heterogeneous [40]. That is, ADHD includes children who
present with a wide range of symptom profiles and is often
accompanied by other cognitive or psychological conditions
such as learning disabilities, anxiety disorders, or depres-
sion [25,63]. Epidemiologists and clinicians are faced with
the difficult challenge of distinguishing cases from non-
cases who may be displaying ADHD - like symptoms. There
are many reasons a child without ADHD could display
symptoms of inattention or hyperactivity / impulsivity that
mimic ADHD. For example, he or she might be living in a
dysfunctional family situation, have an underlying condi-
tion like anxiety, depression or absence seizures, or be
experiencing an adverse response to medication [25,148].
Separating non- cases from cases who also have other co-
morbid conditions is both challenging and important. The
DSM - IV criteria require that some symptoms that caused
impairment were present before age 7. However, in the
DSM - IV field trials, many children who otherwise met all
other case criteria did not meet the age -of -onset criteria [6].
This was particularly true for children with the inattentive
subtype of ADHD. Based on these data, several leading
researchers have suggested that these criteria be ignored or
revised [6,13].
2.2. The Johnston County ADHD study
The problems in creating an epidemiologic case defini-
tion for ADHD are substantial and many epidemiologists
have been reluctant to study ADHD as an endpoint. This
means that our understanding of ADHD and its taxonomy
have too often been based on data collected from small,
clinic -based samples rather than on data collected from
large population - based samples. The Johnston County
ADHD study was started in 1997 at NIEHS and our goal
was to try to learn as much as possible about the prevalence
 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
of ADHD in one North Carolina County. We also sought to
determine how that prevalence varies by age, race, gender,
and social class, how treatment patterns vary, and to try to
identify familial, reproductive, and environmental risk fac-
tors for the disorder.
The approach we took in designing the study was to
recognize that whatever case definition we used would be
experimental and potentially flawed. On the other hand, we
concluded that substantial progress had been made in
defining the taxonomy of ADHD for DSM -IV [99 ± 102]
and in the development of instruments like the NIMH
Diagnostic Interview Schedule for Children (DISC)
[189,195] and that the time was right to try to operationalize
the DSM - IV criteria into a case definition that would make
an epidemiologic study possible.
The overall design is a population -based case control
study. We are screening all 8000 elementary school children
in this semi -rural North Carolina County. The only exclu-
sions are children in self -contained classrooms for autism
and mental handicap. We are using a two- stage screening
process. In Stage 1, parents give us information about
whether the child has ever been diagnosed with ADHD
and whether they are being treated with medication. Tea-
chers then complete a DSM -IV symptom checklist on each
child, which contains items about symptoms for ADHD,
oppositional defiant disorder, and some conduct disorder
symptoms. The checklist also contains questions about
academic performance and impairment in social or aca-
demic functioning. In Stage 2, parents complete an hour-
long telephone interview that includes a modified version of
the ADHD module from the NIMH DISC [195] and
complete a mail questionnaire that includes modified ver-
sions of the Child Behavior Checklist that contains items
from all subscales [1] and the Columbia Impairment Scale
[22]. Our goal is to identify 650 cases and 650 randomly
selected controls over 2 years.
To be classified as a potential case, a child had to show at
least three symptoms of inattention or hyperactivity / impul-
sivity and impairment at school. They also had to show at
least three symptoms of inattention or hyperactivity / impul-
sivity and impairment at home. When the symptoms re-
ported by the teacher and the parent are combined, the child
has to show at least six unique symptoms of inattention or
hyperactivity / impulsivity and evidence of impairment in
both settings. Some studies have used the ``or'' rule, which
combines symptoms from different respondents in any
combination. The difficult part comes if the reports conflict,
for example, if a teacher reports five symptoms and a parent
only reports one. In a clinical setting, it might be possible to
sort out what is going on. However, in our study, we decided
that this situation was one in which we were most likely to
misclassify children, so we required that teachers and
parents each had to show moderate agreement and report
at least three symptoms. This represents a conservative
approach compared to using the ``or'' method and will
mean that we will classify fewer children as ADHD.
633
However, it is a more liberal approach than some research-
ers have employed where they have required that parents
and teachers report six symptoms of inattention or hyper-
activity /impulsivity in both settings. This latter approach is
a very strict interpretation of the DSM -IV guidelines and is
rarely applied this way in clinical practice.
If children are taking ADHD medication, the symptom
data from the teachers cannot be used to evaluate ``case-
ness.'' We considered children taking ADHD medication to
be cases unless their parents told us that during the year
before they began taking medication, they did not meet
symptom and impairment criteria at home. For reasons
stated above, we decided to collect information on age-
of -onset but will not use it to define cases.
One of the advantages of our sampling approach is that
we can still analyze the data from children who would have
been excluded if we had included the age- of- onset criteria
and see what difference that would have made. Similarly, we
can analyze our data with several stricter definitions of
caseness and see what impact that would have on our results.
There are, however, important limitations to the approach
we are taking. Our study is limited to one county, so it is not
clear how generalizable our results will be to other geo-
graphic areas (even though the study - county is diverse and
closely resembles the overall urban ±rural, racial, and socio -
economic makeup of North Carolina). We have only limited
data on co -morbidity; teacher data on diagnosed reading
disability, parent data on other medical conditions, and
parent -reported data from the Child Behavior Checklist.
We would have liked to collect more information about co-
morbidity, but could only collect a limited amount of this
type of information given time and financial constraints.
Instead, we opted to spend a significant portion of the
interview collecting information on potential biological,
familial, and social risk factors. Finally, our case definition
is only a screening diagnosis, not a clinical diagnosis, so
there may be a significant proportion of false - positives
among our ``cases.'' We plan to collect detailed information
(including a semi -structured clinical interview, psychologi-
cal testing data, school and medical history data) on a sub -
sample of our cases to estimate the proportion of children
who might have been classified with a different disorder if
we had been able to give each child in our study an
extensive clinical evaluation.
The power of the approach we are taking is suggested by
some of the preliminary findings from a large pretest we
conducted before beginning the study. In that pretest, we
screened 424 children from 18 classrooms in four schools.
Eighty -six percent of the parents gave us permission to
have their child screened by their teacher. The most im-
portant finding from this initial survey was that the ADHD
prevalence in this population was between two and three
times the 3± 5% prevalence estimate that is cited in the
DSM - IV [4,172]. We also found that history of previous
diagnosis of ADHD was only marginally different between
black students and white students, that about 40% of our
634 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
cases had never been identified before (underdiagnosis) and
that about 20% of the children who had been previously
diagnosed did not meet the criteria after the two - stage
screening (overdiagnosis) [172].
2.3. Future directions for epidemiologic research on ADHD
Because ADHD is so common, we need more informa-
tion about its prevalence and how it varies, about the
prevalence of medication treatment, community treatment
patterns and barriers to treatment. We need information
about the long - term safety and effectiveness of treatment
[134,173]. We need more information about the natural
history of ADHD and about possible risk factors, particu-
larly preventable risk factors. We have pointed out the many
problems and potential stumbling blocks associated with
collecting solid epidemiologic data. On the other hand, it is
possible to collect epidemiologic data on ADHD from large
population -based samples and this type of data may pro-
vide important new insights into our current understanding
of ADHD.
Dr. Sherry Ferguson of the Food and Drug Adminis-
tration's National Center for Toxicological Research fol-
lowed with a presentation on aspects of animal models that
should prove useful in furthering our understanding of the
brain areas and mechanisms associated with certain beha-
vioral manifestation of the syndrome.
3. Overview of rodent models of ADHD
Studies using animal models of ADHD provide some
inherent advantages over human studies. For example,
socio - economic status, parental behavior, and school en-
vironment are potential confounds in many human studies
of ADHD. As noted by Smith [199], over- or undercontrol-
ling for these variables in human neurotoxicological studies
can diminish or magnify effects. The development of sub-
jects in longitudinal studies of humans cannot be hastened
and thus, such studies proceed slowly. There may be
interactions of ADHD with aging during the geriatric
period, and these would be extremely difficult to assess
longitudinally. Finally, in correlational studies, establish-
ment of causal relationships is impossible and such relation-
ships are important in investigating the etiology of ADHD.
Animal models, on the other hand, can causally establish
effects resulting from documented exposure or treatment. In
addition, they permit more invasive manipulations in order
to investigate underlying neurochemical or neuropathologi-
cal alterations. More specific to ADHD, animal models
allow assessment of potential new pharmacological thera-
peutics or behavioral interventions. The most thoroughly
studied animal model of ADHD is the Spontaneously
Hypertensive Rat (SHR). Other models include the colobo-
ma strain of mouse, use of chemical lesions or irradiation,
and a proposed model of developmental cerebellar stunting.
3.1. Spontaneously hypertensive rat
Used in studies of hypertension, the SHR was developed
in Kyoto, Japan by selectively inbreeding rats of the Wistar ±
Kyoto strain that exhibited high systolic blood pressure.
During the course of such inbreeding, the SHR was noted to
be significantly more active in open - field tests than its
normotensive strain, the Wistar ± Kyoto [72,224,234].
Much of the work examining the use of the SHR as a
model of ADHD has been done by Sagvolden et al. at the
University of Oslo and many of the findings do seem to
parallel ADHD - related behaviors. For example, when sub-
jects are reinforced for remaining immobile in a specific
area of an operant chamber, SHRs perform as well as
Wistar ±Kyoto rats when the required duration of immobi-
lity is relatively short (< 8 s) [233]. However, when the
required duration is increased (e.g., 8± 10 s), SHRs make
more movements, seemingly unable to remain immobile for
the target duration. Such findings suggest that the behaviors
of the SHRs closely resemble the ``fidgety'' movements of
ADHD children. SHRs are more active in operant tests,
pressing the levers more frequently even when reinforce-
ment is not contingent on frequent pressing [177]. Detailed
analyses of operant performance indicate that the SHRs
appear to be more sensitive to immediate and less sensitive
to delayed reinforcement [178]. This finding parallels that in
ADHD children, in which a smaller, but immediate reward
is chosen over a larger, but delayed reward [201]. Finally,
differences in response rates are noted only during times of
infrequent reinforcement, indicating the SHRs are more
sensitive to reward processes [179].
Results from learning assessments of the SHR appear to
parallel those of ADHD children as well. For example,
when the learning task requires varying sequences of
responses, SHRs are as accurate as Wistar ± Kyoto rats.
However, when the task requires repetitive responses, SHRs
perform poorly [80,112,126,127]. Similar findings have also
been described for children with ADHD [82].
Such findings as described above suggest that the beha-
vioral alterations exhibited by the SHR are similar to those
of the ADHD child. However, it is unclear whether the
alterations result from the hypertension or the hyperactivity.
For example, the SHRs make more errors in acquisition and
performance of an eight - arm radial maze, a task specifically
designed to measure learning and memory [132]. Similarly,
hypertensive humans often exhibit learning and memory
problems [48,65]. However, no study has consistently
demonstrated such deficits in ADHD children (although
some ADHD children do have learning disabilities). The
SHRs exhibit greater than normal decrements in learning
and memory that occur with aging than either Wistar ±
Kyoto or Sprague ±Dawley rats [124,235]. If the SHRs are
treated with anti - hypertensive drugs, those deficits are
attenuated, indicating that the hypertension appears to be
responsible for the exaggerated learning and memory de-
ficits [235].
 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
Several researchers have questioned the use of the Wis-
tar ± Kyoto strain as the ``control'' for the SHR. For example,
evidence of sufficient genetic polymorphism [90] has caused
some to suggest that continued use of the Wistar ± Kyoto as a
control strain for the SHR is no longer useful in studies of
hypertension [202]. Others, however, note that such genetic
polymorphism is typical for inbred disease strains relative to
their control strains [104]. Thus, when the SHRs are de-
scribed as exhibiting behavioral alterations, one pertinent
question is ``relative to what control.''
The hyperactivity commonly described in the SHR is
environment -specific. In activity tests, the SHRs were more
active than Wistar ± Kyotos only when the open field is of
the ``free -exploration'' type [179]. For example, when the
home cage is accessible (i.e., the rat can move from its home
cage to the open field and return to the home cage during the
test), the SHR is more active than the Wistar ± Kyotos.
However, in that same open - field paradigm (``free -explora-
tion''), Sprague ± Dawley rats were more active than either
the SHR or Wistar ± Kyoto. When the test is of the more
common ``forced -exploration'' type (i.e., the rat is placed
into the open field and cannot leave or escape the appara-
tus), then the SHR and Sprague ±Dawley rats are equivalent
in activity. Thus, when compared with other common
laboratory rat strains in typical laboratory tests, the SHR
is not a particularly hyperactive strain.
The SHR offspring exhibit a unique response to their
maternal environment. Specifically, if the SHR offspring are
cross - fostered to normotensive dams (Sprague± Dawley or
Wistar ± Kyoto dams), they exhibit lower blood pressures as
adults than if reared by their natural SHR dams [34,42,121].
More detailed investigations determined that the SHR dams
behave differently with their natural offspring, licking /
grooming the pups, and assuming a nursing position more
often than Wistar ± Kyoto dams [131,180]. Thus, some of
the described behavioral alterations may be related to
alterations in maternal behavior.
While some of the behaviors exhibited by the SHR
resemble those of ADHD, others do not (e.g., learning
deficits) and it is unclear which alterations are more directly
associated with the hypertension. Thus, some have exam-
ined these potential confounds using different approaches.
Hendley et al. [71,73] at the University of Vermont have
selectively bred hypertensive only and hyperactive only rats
by crossbreeding the SHRs with Wistar ±Kyoto rats. Beha-
vioral profiles of the resulting WKHA (hyperactive without
hypertension) and WKHT (hypertensive without hyperac-
tivity) show that the original SHR is different from either of
the two new strains [176], but additional work is needed to
validate the WKHA as a potential animal model of ADHD.
3.2. Chemical lesions
When combined with desmethylimipramine treatment (to
prevent norepinephrine depletion), intracerebroventricular
or intracisternal injection of the catecholamine neurotoxin,
635
6 - hydroxydopamine (6 - OHDA), in neonatal rats causes
selective and permanent dopamine depletion. Such rats later
exhibit hyperactivity and that activity decreases with admin-
istration of amphetamine [95,113]. However, the lesioned
rats also exhibit severe learning deficits [113], which limit
their use as a model of ADHD. The learning deficits are
apparent as early as 48 h after treatment and are unrelated to
sensory or motor deficits [232].
3.3. Hippocampal irradiation
Focal X -irradiation of the hippocampus in young rats
(PND 2 ± 15) results in ADHD -like behaviors in the adult
(e.g., hyperactivity) [41]; however, such treatment induces
severe learning deficits [38]. Again, those learning deficits
limit the usefulness of this particular model.
3.4. Coloboma strain of mouse
In 1966, a new mutant strain of mouse resulting from
neutron irradiation was described [190]. The coloboma
strain is a pigmented mouse with severe ophthalmic dys-
morphology, making it essentially blind. The mutation
results from deletion of the SNAP - 25 gene, a neuron -
specific plasma membrane protein thought to facilitate
synaptic vesicle fusion at the presynaptic membrane [74].
The Coloboma mouse is extremely hyperactive in open -
field tests [75,76] and delayed in achieving certain devel-
opmental milestones such as the righting reflex and bar
holding [78]. In addition, it exhibits the particularly promi-
nent stereotyped behavior of near-constant head bobbing
[76,78]. Because the exact genetic mutation is known in this
strain, the human analog of the SNAP -25 gene was in-
vestigated in five families in which a genetic inheritance of
ADHD was suspected [77]. However, there was no signifi-
cant linkage detected between the human SNAP - 25 and
coloboma mouse loci. Further research with this prospective
model will determine its usefulness.
3.5. Developmental cerebellar stunting
A recent review described an apparent age- dependent
principle of cerebellar disruption in that there is develop-
mental stage specificity in the severity and type of cerebellar
structural and functional effects [54]. Specifically, insults in
the developing rat produce neuroanatomical and functional
consequences that are strikingly different depending on
when the insult is produced. In general, early neonatal insults
(birth ± postnatal day 4) produce more severe cerebellar
neuropathology accompanied behaviorally by what is typi-
cally thought of as the classic cerebellar syndrome: ataxia,
motor incoordination, hypoactivity, tremors, and learning
deficits. However, insults produced later in the neonate
(postnatal day 4 through postnatal days 10 or 12) result in
much less severe neuropathology (e.g., normal cerebellar
foliation and appropriate orientation of Purkinje cells) but the
636 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
granule cell population is drastically depleted. The behavior-
al alteration most often associated with these later insults was
hyperactivity with few or no learning deficits.
Several compounds have been shown to reduce cerebel-
lar weight and increase activity levels with postnatal treat-
ment, suggesting the association between developmental
cerebellar stunting and hyperactivity. For example, treat-
ment with the antimitotic methylazoxymethanol acetate (4
mg / kg on postnatal days 5± 8) caused a permanent 8%
reduction in cerebellar weight, leaving other brain regions
relatively unaffected (as assessed by gross wet weight) [56].
Concurrent with this, a mild hyperactivity was apparent in
several assessments (e.g., open - field and running wheel
tests) and this hyperactivity was more prominent in males
than females. Gross measures of learning indicated no
deficits in these rats. Treatment with the synthetic gluco-
corticoid dexamethasone (DEX) (1.5 mg / kg on postnatal
day 7) caused a permanent 9± 14% reduction in cerebellar
weight concurrent with mild hyperactivity, again particu-
larly prominent in males [53]. Again, gross measures of
learning indicated no deficits.
Those recent studies are reminiscent of the results of
many years of study in the laboratory of Joseph Altman
using focal irradiation of the cerebellum during the second
postnatal week in which open field and running wheel
hyperactivity were evident; however, learning deficits were
few (reviewed in Ref. [54]). Such results indicate that use of
developmental cerebellar stunting in the rat may provide a
useful model of ADHD.
It is important to relate how such effects might resemble
the behaviors and neuropathology exhibited by children
with ADHD. While the cerebellum is rarely the focus of
studies investigating ADHD, a careful review of the litera-
ture indicates that there is sufficient evidence to suggest its
involvement in the disorder [31]. Scanning studies indicated
mild cerebellar atrophy in adults diagnosed with ADHD as
children [133]. In ADHD boys, the cerebellum was approxi-
mately 7% smaller even after correcting for differences in
total cerebral volume [32] and this size decrease was
particularly apparent in the vermal area [20]. Finally, some
studies have suggested deficits in fine motor control, sug-
gestive of cerebellar dysfunction [69,204,222,229].
Dr. Merle G. Paule from the FDA's National Center for
Toxicological Research then presented data Ðobtained in
collaboration with Dr. John J. Chelonis from Arkansas
Children's Hospital Ð on the performance of several tasks
by ADHD children.
4. Operant behavior in children with ADHD and effects
of methylphenidate (Ritalin1)
4.1. Use of an operant test battery in behavioral assessments
For several years, we have employed operant behavioral
techniques to examine complex behaviors in nonhuman
primates [151,153,188], rodents [55,119,160], and children
[149,152,154]. Often, identical or very similar tasks are
used in all species, providing for unique interspecies com-
parisons. Several tasks are often used in concert as the
National Center for Toxicological Research (NCTR) Oper-
ant Test Battery (OTB) and have been described in detail
elsewhere (e.g., Refs. [150,188]). The tasks in the NCTR
OTB and the brain functions that they are thought to model
include: incremental repeated acquisition (learning), delayed
matching - to - sample (short - term memory), temporal re-
sponse differentiation (time estimation), conditioned posi-
tion responding (color and position discrimination), and
progressive ratio (motivation). Briefly, the learning task
requires subjects to learn a specific sequence of lever
presses to obtain reinforcement (food pellets for monkeys
and rats, money in the form of nickels for children). The
short - term memory task requires subjects to view a sample
stimulus (geometric shape) and, after some delay (six
different delays ranging from 2 ± 32 s), choose a matching
stimulus from among three choices. The time estimation
task requires subjects to depress a response lever and hold it
in the depressed position for at least 10 s but no more than
14 s. The color and position discrimination task requires
subjects to view one of four colors (red, yellow, blue, or
green) and subsequently respond to a specific position (left
or right) depending upon the color presented; left for red and
yellow, right for blue and green. The motivation task
requires subjects to increase their work output (number of
lever presses) to continue to obtain reinforcement: e.g., the
first reinforcer might `cost' 10 presses, the second 20, the
third 30, etc.
4.2. Operant task performance correlates with IQ and is
selectively sensitive to psychoactive drugs
Recently, we have demonstrated that many aspects of
OTB performance in children (with the exception of the
motivation task) are significantly correlated with traditional
IQ measures [154]. We have also repeatedly demonstrated
in both the rat and monkey models that psychotropic drugs
can selectively affect OTB behaviors and that the effects of
individual drugs are characterized by specific behavioral
profiles [150]. Thus, delta - 9 - tetrahydrocannabinol, the
active ingredient in marijuana smoke, produces a profile
of effect characterized as follows: time estimation >lear-
ning =short - term memory = color and position discrimina-
tion > motivation [188]. Here, the tasks are organized from
the most sensitive (affected by lowest doses) to the least
sensitive (affected only by the highest doses). The antic-
holinergic compound atropine, on the other hand, produces
a completely different profile: learning = color and position
discrimination > time estimation = motivation = short - term
memory [187].
The observations that the chemical (drug) manipulation
of OTB behaviors in our animal models results in specific
profiles of behavioral effect, support our hypothesis that
 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
different neural substrates (e.g., neurochemicals) are in-
volved to varying degrees in the expression of specific
OTB behaviors. Given the hypothesis that some aspects of
neural function are different in ADHD children vs. non -
ADHD children, we further hypothesized that such differ-
ences would manifest as differences in the performance of
OTB tasks.
4.3. Operant behaviors are sensitive to ADHD
In pilot studies of 19 hyperactive children and 24 non -
hyperactive children, it was observed that motivation and
timing task performance did not differ between the two
groups, whereas response latencies (particularly those asso-
ciated with trial initiation) in the color and position dis-
crimination and short -term memory tasks were longer for
hyperactive children. Color and position discrimination
accuracies, while tending to be lower for the hyperactive
children, were not statistically significantly different from
those of non -hyperactive children, yet accuracies for hyper-
active subjects in the short -term memory task were sig-
nificantly less than those for non- hyperactive subjects. In
addition, accuracy of performance in the learning task was
significantly less for hyperactive subjects. Thus, in several
OTB tasks, the performance of hyperactive subjects does,
indeed, differ from that of non -hyperactive subjects.
A more detailed analysis of data for the short - term visual
recognition memory task indicated that the accuracy of
subjects declined much more rapidly in hyperactive than
in nonhyperactive subjects: over `recall delays' from 2 to 16
s, accuracy decreased over 12% (from about 96.5% to about
84%) in hyperactive subjects but only by about 4% (from
about 99% to about 95%) in nonhyperactives. For the longer
delay of 32 s, the decreases in accuracy were comparable
between the two groups. These data were striking in that
they seemed to indicate that about as much information was
being correctly discriminated and encoded in both groups
(accuracies at short delays were not significantly different
between groups), but that either retrieval and/or retention
mechanisms were less efficient in hyperactive subjects, at
least for delays out to 16 s.
4.4. Methylphenidate normalizes operant behavior of
ADHD children
In order to replicate these findings and to explore the
effects of methylphenidate on performance in this kind of
task, we incorporated into a subsequent study 10 (rather
than six) different recall delays and extended the longest
delay out to 54 s. The subjects were 35 children aged 7 ±10
years. Children were excluded if they met criteria for
schizophrenia, major depressive disorder, or pervasive
developmental disorder based on the Child Symptom In-
ventory (CSI; [60]). Children were also excluded if their
full -scale IQ as measured by the Kaufman Brief Intelli-
gence Test (KBIT; [93]) was less than 70. Control children
637
(n =24) were also excluded if they had a score of less than
6 on either the inattentive or hyperactive scales of the
parent version of the Attention Deficit Disorder Evaluation
Scale (ADDES; [120]), four or more symptoms on the CSI
for either the hyperactivity subscale of ADHD or the
inattention subscale of ADHD, or a score of greater than
65 on any subscale of the Child Behavior Checklist
(CBCL; [1]). Children diagnosed with ADHD (n= 11) were
excluded if they did not have a score of 5 or below on at
least one subscale of the ADDES, and if they did not have
at least six symptoms on the inattention or hyperactive
scales of the CSI.
The short -term memory task was administered to each
child on two separate occasions separated between 80 and
180 days. ADHD subjects completed one session 1 to 2 h
after taking their previous dose of methylphenidate and the
other, at least 16 h after their previous dose. Eight ADHD
children participated in their first session on medication and
the other three participated in their first session off of
medication. As in our earlier work, each trial of the short -
term memory task began with the presentation of a single,
simple geometric shape (sample) projected onto the central
of three press -plates, horizontally aligned. This shape was
extinguished after it was pressed and a random delay of 2 to
54 s followed (all press - plates dark) after which three
geometric shapes were presented, one on each of the three
press - plates (randomly located) and one of which matched
the original sample. A reinforcer (nickel) was delivered if the
child pressed the shape that matched the sample for that trial.
At the beginning of each session, the experimenter told
the child that he /she would play one game (task) and that
he /she should watch the videotaped instructions for the
game on the nearby monitor. The recorded instructions
explained how to earn reinforcers (nickels) for the game
prior to the commencement of the game and were the same
for each child. The use of videotaped instructions allowed
for the standardization of instructions across subjects and
eliminated the need to expend large amounts of time
training subjects on the task. After the child finished watch-
ing the instructions, the short -term memory task began with
one of the seven stimuli appearing randomly on the center
press -plate (the sample). The stimulus remained on the
center press - plate until the child pressed it. Afterwards,
the press -plate went dark and a delay was initiated. The
delay could take on one of 10 values (2, 4, 6, 8, 12, 16, 20,
28, 40, or 54 s) and was randomly selected. Following each
delay, each press -plate was illuminated with a different
symbol, one of which was the same symbol that initially
appeared on the center press - plate (sample). If the child
pressed the stimulus that matched the sample, he / she
received a nickel and the next trial began immediately.
However, if the child pressed a stimulus that did not match
the sample, the press -plates were darkened, and there was a
10 -s timeout after which the next trial began. The short -
term memory task lasted up to 40 min or until 100 nickels
were earned.
638 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
ADHD children were significantly less accurate on this
task and earned fewer nickels than children who were not
identified as ADHD. These results are consistent with the
findings that children with ADHD perform worse on tasks
of working memory than children without this disorder
[23,109,147]. Further, an analysis of the data by delay
indicated that this deficit appeared to be mostly a result of
an inability to retain information and not due to an inability
to encode information; accuracies at short delays did not
differ between groups and consistent deficits in accuracy for
hyperactive children were not noted for delays of less than 8
s. The finding that accuracy decreases as delay increases
suggests that greater attentional resources are required to
maintain attention to the stimulus over time, and that ADHD
children have much more difficulty allocating these re-
sources to this task than do normal children.
Methylphenidate normalized the performance of the
ADHD children on this task as measured by overall accu-
racy, percent task completed, and accuracy at longer delays,
a finding consistent with those noted for free recall tasks
[23,109,147]. It should be noted that the short - term memory
task used here was designed to enhance the encoding of
information, which might account for the noted lack of
deficits at short delays. Specifically, for a trial to continue,
the subject had to make a response indicating that he/ she
saw the initial stimulus. Therefore, the subject had to attend
to the stimulus to continue with a trial. A procedure that
simply presents the target stimulus for a brief period of time
without requiring that subjects make an observing response
to it would likely increase the potential of the task to detect
differences in encoding.
ADHD children took longer to make observing responses,
correct responses, and incorrect responses than control chil-
dren. These findings suggest that either ADHD children were
not attending to the task as well as control children or that
ADHD children require a greater amount of time to process
the information to be remembered. The significant increase in
choice response latency for ADHD children compared to
controls suggests that once a trial was initiated, ADHD
children had more difficulty in attending to the task, espe-
cially, if there was a long delay. Methylphenidate decreased
each of these measures of response latency and increased
accuracy to values more similar to those of controls.
4.5. Summary
ADHD children exhibit deficits in their performance of
learning, color and position discrimination and short -term
memory tasks. In the short - term memory task, ADHD
children had more difficulty making correct choices at
longer delays than control children did and methylphenidate
normalized performance of this task by decreasing response
latencies and increasing accuracy of responding at longer
delays. Additional studies will be needed to determine
whether methylphenidate also normalizes performance of
the learning and color and position discrimination tasks.
Dr. Rosemary Tannock from the University of Toronto's
Research Institute of The Hospital for Sick Children fol-
lowed with a presentation on other specific cognitive
deficits associated with ADHD.
5. In search of primary cognitive deficits in ADHD
As mentioned earlier, ADHD is currently defined solely
in terms of developmentally inappropriate levels of inatten-
tion or hyperactivity /impulsivity, or both clusters of beha-
vioral symptoms [4]. ADHD is one of the most intensively
studied syndromes in child psychiatry, but remains contro-
versial because of its prevalence, heterogeneity, high rates of
co - morbidity (e.g., see Ref. [182]), reliance on clinical
evaluation rather than a specific diagnostic test or marker,
and the increasing prescription rates of psychostimulant
medication for its treatment [134].
The preceding concerns, along with a growing conviction
that the behavioral phenomenology of ADHD reflects
underlying impairments in cognitive functioning, have sti-
mulated empirical investigations into the cognitive corre-
lates of ADHD [215]. Cognitive correlates provide a useful
set of criteria for examining the validity of ADHD because
they do not share method variance with the clinical mea-
sures used to assess the behavioral symptomatology (e.g.,
reports of parents and teachers). However, establishing that
specific cognitive deficits are primary and unique to ADHD
requires evidence that the deficits occur in most individuals
with ADHD, persist across the lifespan (albeit with altered
expression), are not shared with other disorders, and cannot
be attributed to co - morbid problems (e.g., conduct disorder,
oppositional disorder, reading disorder (RD)).
Three domains of interest are discernible in empirical
investigations designed to isolate specific psychological
dysfunctions that might underlie ADHD: (1) higher -order
cognitive control processes, termed executive functions, that
include working memory, a system for temporary storage
and simultaneous on -line processing of information [9±
11,46,92,159,165,210]; (2) visual ± spatial orienting
[27,122,141,155,209]; and (3) energetic state, particularly
activation [193,225]. By contrast, the basic sensory, percep-
tual, and short - and long -term memory abilities are pre-
sumed to be intact [11,44,45]. Among the postulated
deficits, executive functions, particularly response inhibi-
tion, have garnered the most attention among researchers
[12,207,215] since current theory proposes that the failure to
inhibit or delay behavioral responses may be the funda-
mental deficit in ADHD [11,12,165,183,184].
5.1. Response inhibition
The general concept of inhibition appears in many guises
and is measured in a variety of ways [39,98,181]. In the
research literature on ADHD, two major approaches are
discernible in the study of executive function and response
 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
inhibition: (1) neuropsychological, using standardized tasks
which involve a wide range of processes (e.g., Matching
Familiar Figures Test, Continuous Performance Test, Stroop
test), but cannot determine which of the component pro-
cesses may be impaired; and (2) experimental tasks that use
a controlled, process - oriented approach, which permits
separation and measurement of component processes.
5.2. Stop -signal inhibition
Many of the studies on inhibition in ADHD have focused
on the type of inhibition that is manifest in the stop -signal
procedure [103,106,107,143,145,146,227]. This type of in-
hibition is conceptualized as one of several internally
generated acts of control in a higher- order executive system
that regulates the operations of information processing in
humans [64,105,106,196]. It is defined as the ability to stop
(suddenly and completely) a planned or ongoing thought
and action [106]. This central act of control is required in
many daily situations in which an individual's planned or
ongoing actions are suddenly rendered inappropriate by
anticipated events or changes in the immediate environment
(e.g., you are driving along a main road when a child darts
out into the road in front of your car). The stop -signal
procedure has several advantages over neuropsychological
measures of inhibition [106,231]. One clear advantage is
that the underlying model provides a way of measuring the
latency of the internally generated act of control (stop -
signal reaction time; SSRT), even though successful inhibi-
tion produces no overt behaviour. In the stop - signal task,
SSRT is the primary dependent variable and indicates the
speed of the inhibitory process. SSRT does not provide all
the information yielded by the stop -signal procedure, but it
is highly informative because differences in SSRT reflect
important differences between groups of individuals (e.g.,
impulsive adults have slower SSRTs than non- impulsive
adults [108]) and in individuals tested under different
conditions (e.g., stimulant medication speeds SSRT com-
pared to placebo [220,221]).
5.3. Deficient inhibition in ADHD
There is substantial evidence of mild deficits in compo-
nent executive functions in ADHD, particularly those asso-
ciated with control of motor responses (planning,
preparation, execution, inhibition) and working memory,
which is believed to be one of the key components under-
lying executive functions [46,216]. Motor planning deficits
are indicated by the fairly consistent evidence of poor
performance on neuropsychological tasks such as the Tower
of Hanoi, Porteus Mazes or WISC - Mazes, and Rey - Oster-
reith Complex Figure Drawing Test (e.g., Refs. [2,94,140,
191]). Motor inhibition deficits are indicated by more errors
of commission on tests such as the Go /No - Go and con-
tinuous performance test, decreased accuracy and /or shorter
latency to first response on Match -to -Sample tests; and
639
greater interference effects from conflicting stimuli on tasks
such as the Stroop Color ±Word Test [36,110,159]. Set -
shifting difficulties are indicated by more perseverative
errors on the Wisconsin Card Sorting Task and fewer items
on Trails -b test, although findings are somewhat inconsis-
tent [159,169,191]. Working memory deficits are reflected
by poor performance on tests such as the backwards digit
span, self - ordered pointing, paced auditory serial addition,
Simon Tone /Color Game and the Dot Test of Visuospatial
Working Memory [16,92,159,230]. Also, recent findings
indicate that some executive function deficits (e.g., plan-
ning) are attributable to ADHD (or one of its subtypes) rather
than to various co- morbid disorders [94,139,191,230].
Deficits in response inhibition are also indicated by the
findings from studies based on the stop - signal procedure.
For example, the recent meta - analysis of international
studies based on the stop -signal procedure generally con-
firms differences in response inhibition between ADHD and
normal peers, with an effect size of 0.6 [144]. However, the
meta- analysis did not confirm specificity of this response
inhibition deficit to ADHD; deficits were not impaired in
anxiety disorder, but there was some evidence of response
inhibition deficits in conduct disorder, oppositional defiant
disorder and aggression, suggesting that the deficits were
not a unique correlate of ADHD [144]. Moreover, recent
findings of response inhibition deficits in ADHD are not
independent of concurrent reading problems [139,164,218].
5.4. Extreme variability in response time
One of the most robust findings from studies based on
information processing theory, is of extremely variable
response latencies, which are found across a variety of tasks
[46,219]. For example, studies based on the stop -signal
procedure consistently find greater variability in response
times and slower response times to the go- task as well as
longer SSRTs [144]. Not only are these findings inconsistent
with the notion of an impulsive response style, but they also
raise the question of whether ADHD may be associated with
impairments in the precise representation of temporal in-
formation that is integral with all speeded response time
tasks. The precise representation of temporal information is
required for the ability to predict precisely the point in time
when an impending stimulus event requires a fast response.
Moreover, time perception is predicted to be impaired in
ADHD according to current models of ADHD and impul-
sivity [11,12,17,61,203]. Specifically, one model of ADHD
proposes that the fundamental impairment in ADHD is
behavioral inhibition, which in turn impairs four executive
neuropsychological functions that are dependent upon in-
hibition for their efficient functioning. One of these execu-
tive functions is working memory, which plays a central role
in time perception (e.g., Ref. [114]). Also, time perception
impairments in ADHD are predicted independently by
recent models of impulsivity, which is a core feature of
ADHD (e.g., Refs. [17,203]). Moreover, neuroimaging
640 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
studies indicate anomalies in brain morphology in ADHD in
those brain regions that subserve time perception, as well as
executive functioning (e.g., Refs. [8,20,28,32,58,215]).
5.5. Time perception
Accurate perception of time is an important determinant
of behavior: it facilitates the ability to predict and anticipate
events, to organize and plan sequences of action, and
prepare fast responses. Research in the neuropsychology
of time has applied psychophysical and neuroimaging
techniques with adults who have sustained focal or diffuse
brain lesions in order to associate particular timing functions
with particular brain structures or networks [29,68,86 ±
88,91,114,135]. The perception of duration and estimation
of duration has been differentiated on the basis of the type
of cognitive processing involved. For example, recent
models suggest that timing in the millisecond and second
range may be dissociated behaviorally and neurally
[59,123,167]. Behaviorally, timing in the millisecond range
may be achieved relatively automatically via an internal
timing system, whereas processing of longer durations
implicate other processes, such as memory and strategy
use (counting). A large body of evidence has implicated the
cerebellum, particularly the lateral cerebellum and vermis,
in the perception of durations in the range of milliseconds
and in cognitive timing of motor output; perception of
longer durations is supported by a network involving the
basal ganglia and frontal cortex [29,87,91,114,123,135].
More recently, the suprachiasmatic nucleus (SCN) of the
hypothalamus has been implicated in the perception and
production of brief durations in the hundreds of millisecond
range, using methods similar to those employed by Ivry [87]
to explore timing functions of the cerebellum [35]. The SCN
mediates circadian rhythmicity of sleep ±wake and endo-
crine cycles in humans and other primates. Importantly,
these brain regions have been identified as the possible
neural substrate for both ADHD [57,128,215] and RD
[136,163,166,186].
Impairments in time perception may have negative im-
pact on motor control processes, particularly response
preparation [24,125,174,175]. The preparation of a fast
response benefits from predicting precisely the point in
time when an impending event would require a response.
Thus, processing of temporal information can be considered
an important part of response preparation. Specifically,
evidence from reaction time paradigms indicate that re-
sponses to an imperative stimulus can be considerably faster
when the imperative stimulus is preceded by a warning
stimulus. This benefit is accrued from the accurate timing of
response preparation enabled by the warning stimulus and
by estimation of the interstimulus interval. The processes
that facilitate behaviour during this foreperiod anticipating
the onset of the imperative stimulus have been considered
to be part of the alertness component of attention [161].
Thus, the more precise the timing, the faster the response
can be performed, particularly if the interval between the
warning and imperative stimulus is constant (i.e., predict-
able) and less than about 3 s [47,138]. Individuals who are
impaired in time perception would likely have more vari-
able response times.
5.6. Impairments in time perception in ADHD
Clinical phenomenology is consistent with the hypothe-
sized time perception deficits in ADHD. For example,
clinical descriptions indicate that individuals with ADHD
have marked difficulties in conforming to directions
containing time parameters, meeting deadlines for work
assignments, and in adjusting the timing of their behavior
to the pacing of the immediate context (e.g., calling out
in class, interrupting an ongoing conversation, difficulty
waiting turn). Also, a diverse array of empirical findings
from studies of cognitive processes involved in motor
response control support the hypothesis of impaired time
perception in ADHD. For example, deficits are evident in
working memory that is believed to play a major role in
time perception [92,117]. Task performance is impaired
by the presence of certain temporal characteristics, such
as very brief or long delays between stimuli and of
temporal uncertainty [15,33,194,226]. A high rate of
premature responses is evident in experimenter - paced
tasks [200,236].
Empirical investigations of time perception in ADHD
indicate deficient abilities, although the data are limited and
not always consistent [13,26,175]. One problem is that the
few available studies differ in sampling procedures (school
vs. clinic sample), diagnostic criteria (clinical diagnosis of
ADHD vs. ratings of hyperactivity or inattention), methods
of assessing time perception (duration discrimination vs.
time production or time reproduction), and in the range of
intervals used (typically in the range 7 to 60 s). This makes
it difficult to integrate findings across the different studies.
Furthermore, none of the existing studies considered the
possible impact of co - morbidity. In particular, the failure to
control for co -morbid RD is potentially problematic given
the evidence of impairment in duration discrimination in
children with RD [137]. However, a recent study conducted
by Tannock et al. [217] provided more robust evidence of
time perception impairments in children with ADHD with
and without co -morbid RD. Specifically, the study used
psychophysical tasks to measure the children's perception
of duration in the range of 400 ms (as well as the perception
of tone frequency, as a control condition) and the estimation
of duration, using a method of reproduction of presented
intervals of 400, 2000, and 6000 ms. Results indicated that
both ADHD groups were impaired in the perception of brief
durations in the range of 400 ms, but not in the perception
of tone frequency, compared to normal peers. Also, both
ADHD groups were impaired in the precision and reliability
with which they reproduced the presented intervals of all
three durations (400, 2000, 6000 ms). Moreover, prelimi-
 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
nary findings from small -sample studies (n = 16) suggested
that stimulant medication may not have any impact on these
components of time perception [13,217].
5.7. Limitations
Many of the neuropsychological studies of executive
function in ADHD and most of the international studies on
stop - signal inhibition, have relied almost exclusively on
male samples of school - aged children, did not include
adolescents, nor consider the impact of co -morbid disor-
ders, particularly RD on task performance. These limita-
tions are germane in view of questions about the nature
and severity of cognitive mechanisms, neural substrates,
and genetic factors underlying ADHD in males and fe-
males [50,140,170], the stability of deficits across the life
span, and the role of RD in cognitive deficits currently
attributed to ADHD (e.g., Refs. [140,158]) or vice versa
(e.g., Ref. [216]).
5.8. Significance
Recent findings challenge the current postulate that re-
sponse inhibition is a primary (i.e., unique) deficit in ADHD.
Also, the preliminary findings of specific time perception
deficits in ADHD that were not ameliorated by stimulant
medication, challenge the current concepts of ADHD and its
treatment, which presume intact perceptual abilities. Time
perception deficits may reflect an underlying dysfunction of
the cerebellar ± thalamic± prefrontal networks and account in
part for the excessive variability in motor response times on
speeded reaction time tasks, motor control problems, and
motor clumsiness associated with ADHD.
Dr. Jim Swanson followed with a presentation on
medication, behavioral intervention, and both in children
with ADHD.
6. Multimodality treatment of ADHD: initial findings of
the multimodality treatment of ADHD (MTA) study
6.1. Short -term benefits of pharmacological and
psychosocial interventions
The disorder now called ADHD in DSM -IV [4] and
Hyperkinetic Disorder (HKD) in ICD -10 [85] has been the
topic of many articles over the years, and different sets of
symptoms and labels have been used to describe this
condition. One of the first descriptions was by Still in the
Lancet [205]. Almost 100 years later, the Lancet commis-
sioned an article to summarize the literature on ADHD
[207], which provides a good background for the topic of
multimodality treatment. That article outlined the two pri-
mary modalities of treatment: pharmacological (with stimu-
lant medications) and behavioral (with a variety of
psychosocial interventions). In the USA, treatment is usual-
641
ly initiated with a trial on stimulant medication such as
methylphenidate (Ritalin1) or amphetamine (Dexedrine1
or Adderall1), while in Europe, treatment is usually in-
itiated with a trial on psychosocial interventions such as
behavior modification, family therapy, and teacher consulta-
tion. Extensive research [208] has documented that low
doses of stimulants have beneficial short - term effects of
reducing the symptoms of ADHD in about 80% of the
diagnosed cases, and considerable research (see Ref. [157])
has documented the short - term effectiveness of two psy-
chosocial treatments (behavioral parent training and beha-
vioral token systems in the classroom).
6.2. Long -term benefits of pharmacological and
psychosocial interventions: the multi -site MTA study
Little controlled research has been conducted to evaluate
the long - term effectiveness of these two modalities of
treatment [134,142]. In the early 1990s, the National In-
stitute of Mental Health issued a Request for Applications
for a multi -site prospective study to address this important
issue [171]. After review, six sites were chosen, each with a
Principal Investigator and Co -Investigator (UC Irvine, J.
Swanson and D. Cantwell; UC Berkeley, S. Hinshaw and G.
Elliott; Columbia University, L. Greenhill and J. Newcorn;
U Pittsburgh, W. Pelham and B. Hoza; Duke U, K. Conners
and K. Wells; Long Island Jewish Medical Center / Montreal
Children's Hospital, H. Abikoff and L. Hetchman). Groups
at NIH (led by P. Jensen and G. Arnold) and the US
Department of Education (led by E. Shiller) monitored the
implementation of the project. The assigned tasks were to
design a large randomized clinical trial to evaluate the long -
term effects of pharmacological and psychosocial interven-
tions for children with ADHD. The investigation that
emerged from this initiative is called the Multimodality
Treatment Study of ADHD (MTA) (see Ref. [7]).
6.2.1. Treatment strategies
The MTA was designed as a multi - site randomized
clinical trial comparing four treatment strategies: medication
management (MedMgt); behavior modification (Beh); the
combination of these two modalities (Comb); and an active
control condition based on usual treatment available in the
community (CC). A large sample of children between the
ages of 7 and 9 years were recruited from a variety of
sources. A broad assessment battery (see Ref. [79]) was
used to identify about 96 cases at each site with symptoms
of inattention and hyperactivity / impulsivity (i.e., with
ADHD -Combined Type). Treatment manuals were devel-
oped for pharmacological [67], psychosocial [225], and
combined [212] interventions. Trained and monitored
MTA staff followed these manuals to provide intensive
treatment for about 144 subjects randomly assigned to each
of the MedMgt, Beh, and Comb groups. Another 144
subjects were randomly assigned to the CC group. The
recruited sample of 579 ADHD children was typical of
642 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
clinical samples described in the literature. Most of these
cases had at least one co -morbid disorder. The primary co -
morbidities were Oppositional Defiant Disorder, Conduct
Disorder (in about 54% of the cases) and Anxiety Disorder
(in about 35% of the cases). Only 30% of the sample had
pure ADHD.
6.2.2. Long -term treatment
Intensive treatment was provided over a period of 14
months. The MedMgt treatment was based on a double
blind, dose ± response titration trial to evaluate response to
methylphenidate. If a favorable response was not manifested
in the titration trial, which happened for about 20% of the
cases, then an open clinical trial was conducted to evaluate
response to other stimulant (e.g., amphetamine) and non -
stimulant (e.g., imipramine) medications. After titration,
there were monthly office visits with a physician to evaluate
response to medication. The monthly medication checks
included a meeting with the family and a telephone call to
the teacher, and these sources were used to monitor the
child's status and to make adjustments in medication. The
Beh treatment was based on psychosocial provisions that
included 35 parent training sessions spread across 14
months, school consultations with teachers in the spring of
one school year and the fall and winter of the next school
year, an 8- week summer treatment program that focused on
direct intervention with the child in the playground or in a
camp - like setting, and a paraprofessional program with an
extra part - time classroom aide in the child's regular class-
room for up to 12 weeks [228]. This treatment was staged to
be intensive at the beginning, and then gradually faded so
that direct contact was finished by the end of the 14 months.
The Comb treatment was based on multimodality provisions
specified by both the MedMgt and Beh treatments, with
some modifications to co -ordinate implementation. The CC
treatment was not provided by the MTA staff but instead
consisted of whatever treatments were sought and obtained
by participants in the various communities. The actual
treatments of all subjects were monitored by interviewing
the parent about MTA and other interventions that were
implemented during the study.
6.2.3. Assessment battery
The broad MTA assessment battery was designed to
cover multiple domains and sources of information, and it
included so many instruments that the clinical use of the full
battery is impractical [212]. Data reduction methods on
baseline assessments identified 19 key outcome variables
to cover the theoretically important combinations of three
sources (parent, teacher, and child) and six domains (ADHD
symptoms, Oppositional Defiant Disorder (ODD)- aggres-
sion symptoms, internalizing symptoms, social skills, par-
ent ± child relations, and academic achievement). The 19
outcome measures mentioned above were evaluated in a
randomized clinical trail framework, using random effects
regression (RR) in which regression equations for each
individual subject was obtained and used to evaluate change
over the four assessment points and to estimate missing data
[97]. In this intent - to - treat (ITT) analysis (i.e., ``once
randomized always analyze''), scores (e.g., slopes of the
individual regression equations) for all subjects assigned to
a treatment group were included in the group average,
whether or not they complied with or responded to the
treatments that were offered.
The primary analyses revealed a statistically significant
omnibus (overall) effect of Treatment for 10 of these marker
variables. Six of the 10 were derived from the SNAP rating
scale [206], on which parents (P) and teachers (T) assessed
the symptoms for DSM - IV disruptive behavior disorders
(DBD)Ð ADHD and ODD. The other significant outcome
measures were based on three different instruments and
covered non - DBD domains: P -Internalizing and T-Social
Skills (from the Social Skills Rating System), P - Power
Assertion (from the Parent ± Child Relationship question-
naire), and Reading Achievement (from the Weschler Indivi-
dual Achievement Test for children). For these significant
outcome variables, multiple comparisons were performed to
address the primary questions of the study. The general
pattern of effects on the manifestation of symptoms of
ADHD and ODD were clear.
What was the relative effectiveness of the two modalities
of treatment? MedMgt was superior to Beh. Was multi-
modality treatment superior to unimodal treatment? Comb
was not significantly better than MedMgt, but it was super-
ior to Beh. Were the systematic MTA treatments better than
treatment as usual? Comb and MedMgt were better than
CC, but Beh and CC did not differ.
The general pattern for the order and difference for
the treatment groups was expressed as Comb  MedMgt
>Beh  CC, where the ``> '' symbol denotes the paired-
comparisons of group means (of the individual slopes) that
were statistically significant, and the `` '' symbol denotes
the paired - comparisons of group means that were not
statistically different in the primary analyses. On non -
ADHD symptom domains, a slightly different pattern was
manifested. On some of these outcome measures, only the
Comb treatment was superior to the CC conditions:
Comb > MedMgt Beh  CC.
6.2.4. Findings
In the primary analyses [129], some of the statistically
non -significant group differences (e.g., Comb ±MedMgt)
are controversial and may be misunderstood [156]. For
example, the non - significant difference between the
Comb and MedMgt groups may be misinterpreted as
evidence for the absence of multimodality superiority.
However, the ``absence of evidence is not evidence of
absence,'' and the statistically non -significant difference
may be due to lack of precision of measurement, not to
lack of practical or clinical significance [96]. Also, the
lack of a difference between Beh and CC may be
misinterpreted as evidence that the psychosocial treatment
 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
was not effective. However, both of these groups im-
proved over the 14 months, and monitoring of the CC
group revealed that most families (about 2 /3) sought and
received pharmacological treatment in the community. The
Beh treatment provided about the same degree of im-
provement as the usual community treatment, which for
2 /3 involved stimulant medication.
Moderator analyses were performed to evaluate the
impact of pre - existing conditions at randomization [130].
These analyses revealed that co -morbid Anxiety Disorder
moderated the treatment effects. The general pattern held for
the subgroup of subjects without a diagnosis of anxiety
(about 70%), but in the subgroup with anxiety, the Comb
treatment was superior to the MedMgt, and the Beh treat-
ment was superior to the CC treatment. Also, families
receiving public assistance (poor or single parent family)
moderated treatment effects, so that Comb was superior to
MedMgt in families receiving public assistance.
Mediator analyses were performed to evaluate accep-
tance / attendance with the intended treatments. Acceptance /
attendance in the MedMgt conditions did mediate treatment
effects (good attendance was associated with better out-
come), but acceptance /attendance in the Beh treatment had
no impact on outcome.
Statistical significance of group comparisons may be
misleading, too, since a difference of any magnitude can be
made significance by increasing sample size. To avoid this
problem, Kraemer [96] recommended the use of ``effect
size''. For the primary analyses, effect size is expressed as
the standardized mean difference between groups (Cohen's
delta, or d). As a general guideline for conveying magnitude
of effect, d = 0.3 is considered a small effect, d = 0.6 is
considered a moderate effect, and d = 0.9 is considered a
large effect. Even though six paired -comparisons are pos-
sible, basic statistical principles dictate that only three
independent (non -redundant) contrasts are possible. Effect
size estimates for orthogonal comparisons can be used to
clarify the general pattern of group outcomes reported in
the primary analyses for the impact of treatment on symp-
toms of ADHD and ODD (Comb  MedMgt > Beh  CC).
The difference between the average outcome for the two
treatments that included the MTA medication [(Comb + -
MedMgt) /2] and the average of the other two groups that
did not [(Beh +CC) / 2] can be used to evaluate the impact
of the MTA ``Medication Algorithm.'' The effect size for
this comparison was large (about 1.0 for symptoms of
ADHD and ODD). A comparison of [CombÿMedMgt]
can be used to address the issue of ``Multimodality Super-
iority.'' This effect size was small (about 0.3 for symptoms
of ADHD and ODD). The remaining contrast [BehÿCC]
addresses the critical question about the relative efficacy of
intensive psychosocial treatment alone vs. the usual treat-
ments for ADHD provided during the time when the MTA
study was conducted, which in a majority of the cases
included stimulant medication. Since intensive psychosocial
treatment is rare and treatment with stimulants is common,
643
this represents ``Psychosocial Substitution.'' This effect size
was negligible.
6.2.5. Summary and future directions
As should be expected for the largest clinical trial yet
conducted to address treatment of childhood psychopathol-
ogy, the interpretation of the primary and secondary
findings will be complex and controversial. One of the
major advances is that the MTA study provides an evalua-
tion of long -term effectiveness that has been lacking in the
literature. The demonstration of long - term benefits of
multimodality treatment and pharmacological intervention
is the primary finding of this study. To supplement the
primary analyses, the investigators of the MTA are pre-
paring papers to describe the results using different meth-
ods of analysis (i.e., analysis of a qualitative outcome
measures such as ``success'' or analysis of composite
measures to summarize the impact across all outcome
domains) and the results for different subgroups (i.e.,
presence or absence of parental psychopathology such as
depression or substance abuse). So far, only the results at
the 14 - month outcome point have been presented and
discussed. The MTA group is now addressing the long-
er-term effects at 24- and 36 -month assessment points.
The full clinical and practical significance of the MTA
study must await these analyses and long -term follow - up
of this group of children with ADHD.
Some additional information has been derived from the
MTA study. For example, the ``disconnection'' between
medical and educational components of intervention was a
topic of the NIMH Consensus Conference on ADHD, and
this was addressed in a description of experiences in the
MTA that included monthly contact of physicians with
teachers in the monitoring of medication [212]. There has
also been a study concerning the molecular genetics of
ADHD and the involvement of candidate dopamine genes
[213], including the dopamine receptor D4 genes, in the
disorder [211]. A subset of the MTA sample (just cases from
UC Irvine) were evaluated by a neuropsychological test
battery designed to evaluate Posner's neuroanatomical net-
work theory of attention [162], and DRD4 genotypes were
used to define subgroups. In a speculative article, Swanson
et al. [214] reported that the subgroup defined by the
presence of the presumed ``risk allele'' of the DRD4 gene
manifested only behavioral deficits (as documented by
parent and teacher ratings of symptoms of ADHD), com-
pared to the remainder of the cases (a subgroup with perhaps
a higher percentage of cases with non -genetic etiologies)
that manifested cognitive (slow and variable responding on
neuropsychological tests) as well as behavioral deficits.
Based on this, a recommendation was made to evaluate
the full MTA sample to investigate subgroups based on
genotypes defined by candidate dopamine genes.
Dr. F. Xavier Castellanos of the National Institute of
Mental Health closed the symposium with a review of data
from a variety of imaging studies in children with ADHD.
644 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
7. Neuroanatomy of ADHD
The present review focuses on recent advances in neu-
roimaging studies of ADHD. The neuroimaging field has
evolved rapidly over the past decade, but until recently,
most studies took a piece -meal approach more appropri-
ately characterized as hypothesis formation rather than
hypothesis testing. However, investigators increasingly are
able to make explicit their hypotheses and design studies to
test them. The goal of this presentation is to take stock of
where the field is, and where it is likely headed.
7.1. Magnetic resonance imaging (MRI)
7.1.1. Corpus callosum
Although total corpus callosum area in ADHD patients
has not differed from controls in any of the studies using
MRI, smaller anterior regions have been found [19,62,84]
with one study reporting a smaller posterior area [192].
The corpus callosum is the primary connecting structure
for the cerebral hemispheres and smaller anterior corpus
callosal areas are consistent with involvement of prefron-
tal cortical regions in ADHD. In healthy subjects, the
right anterior brain is slightly but consistently larger than
the left. Significant decreases in this asymmetry in
ADHD have been reported using computed tomography
[197], and MRI [32,58,83]. Volumetric measures have
also detected smaller right -sided prefrontal brain regions
``en bloc'' [32,58] in boys with ADHD. In the only
published study to date to report gray ± white segmenta-
tion, right anterior white matter was also reduced in
ADHD boys [58].
7.1.2. Caudate nucleus
Abnormalities of caudate nucleus volume [32,58], or
asymmetry [32,81,118] have been reported, although the
studies differ in whether the normal caudate is asymmetric,
and whether this asymmetry normally favors the right [32]
or the left caudate [58,81,118].
7.1.3. Putamen
Neither of the anatomic MRI studies that reported puta-
men volumes detected significant diagnostic group differ-
ences [8,32] although statistical power was insufficient in
one study to rule out type II error [8].
7.1.4. Basal ganglia
The output nuclei of the basal ganglia are the internal
segment of the globus pallidus (GPi) and the substantia
nigra pars reticulata, but the latter cannot generally be
measured with MRI, and the globus pallidus can only be
measured as a unit (lateral and medial segments together),
and then only with difficulty. Still, this small region has
been found to be significantly smaller in ADHD [8,32],
although these two studies again differed in finding the
larger difference on the left and right sides, respectively.
7.1.5. Cerebellum
In a sizable quantitative study, the volumes of the cere-
bellar hemispheres were found to be significantly smaller in
ADHD boys [32]. In a follow - up study, the cerebellar vermis
as a whole, and particularly the posterior ± inferior lobules
(lobules VIII ± X) were found to be significantly smaller in
ADHD [20]. Another group recently confirmed this finding
in ADHD [128]. However, a similar observation was also
made in childhood- onset schizophrenia [89], demonstrating
once again the non -specificity of most anatomic deviations.
Despite the caveats, there is increasing interest in under-
standing the role of the cerebellum in non -motor domains
such as cognition and modulation of emotion [185].
7.2. Functional brain imaging studies of ADHD
Positron emission tomography (PET) with [18F] -fluoro-
2 -deoxy - D -glucose (FDG) was used to demonstrate de-
creased frontal cerebral metabolism in adults with ADHD
[239] although inconsistent results in adolescents [49,50,
238] led the authors to explore other techniques in ADHD
[51]. Other investigators of brain function have measured
local cerebral blood flow, which is closely linked to neuro-
nal activity, with a variety of techniques including 133Xenon
inhalation and single photon emission tomography. De-
creased blood flow has been found in ADHD subjects in
the striatum [111] and in prefrontal regions [3]. However,
these results remain tentative because ethical constraints
make it difficult to obtain truly independent observations
from normal controls. A more promising technique is blood
oxygenation level dependent (BOLD) functional magnetic
resonance imaging (fMRI) which obviates the need to use
ionizing radiation.
The BOLD fMRI technique was used in a study of 10
boys with ADHD and six controls, all of whom were scanned
on and off methylphenidate while they performed Go /No -
Go tasks [223]. The authors extended to methylphenidate the
observation that stimulants improve performance in patients,
as well as controls [168]. In caudate and putamen, Vaidya et
al. [223] found a striking group difference. In the more
difficult task (of two), methylphenidate increased the number
of activated pixels in caudate and putamen in ADHD sub-
jects, but it had the opposite effect in the controls. In both
caudate and putamen, controls activated significantly fewer
pixels when scanned while on methylphenidate compared to
drug -free scans. Perhaps equally interesting was the finding
that patients as well as controls activated significantly larger
numbers of pixels in prefrontal cortex.
Utilizing a sample of seven adolescent boys with ADHD
who were unmedicated or medication free for 1 week before
scanning and nine controls, hypothesized differences in
frontal striatal circuitry have again been detected with fMRI
[175]. Rubia et al. [175] scanned subjects while they
performed the stop task [183] and a ``delay'' task that
required synchronization of a motor response to an inter-
mittently appearing visual stimulus. They found that the
 M.G. Paule et al. / Neurotoxicology and Teratology 22 (2000) 631±651
hyperactive subjects showed less brain activity, predomi-
nantly in the right mesial frontal cortex during both tasks,
and in the right inferior prefrontal cortex and left caudate
nucleus during the stop task.
7.3. Positron emission tomography
Before concluding, it is worth noting that despite the
natural advantages of magnetic scanning for ADHD, PET
still offers the only practical way of assaying the neuro-
chemistry of the human brain in vivo. Ernst et al. [51] have
used [fluorine -18] fluorodopa ([18F]F -DOPA) to label do-
pamine terminals in 17 unmedicated adults with ADHD.
They found [18F]F - DOPA uptake was significantly dimin-
ished in the left and medial prefrontal cortex of the ADHD
adults compared to the 23 controls, with no differences in
the striatum or midbrain regions. By contrast, in 10 adoles-
cents with ADHD, they found significantly elevated [18F]F -
DOPA uptake in the right midbrain compared to 10 controls
( p =0.04, uncorrected for multiple comparisons) [52]. Taken
together, these preliminary results further support the notion
that dysregulation of catecholamines is central to the patho-
physiology of ADHD, and not just to its treatment. They
also highlight the fact that dopaminergic and noradrenergic
systems cannot be understood without taking developmental
effects into account [30].
8. Conclusions
It seems clear that there are large gaps in the under-
standing of the epidemiology of ADHD. If strict adherence
to the DSM - IV criteria for ADHD is applied, then the
incidence of cases may very well be two to three - fold
greater than the 3± 5% often cited in the recent literature.
In addition, there is little information on risk factors asso-
ciated with specific demographic variables such as race,
gender, socio - economic status, age, co - morbidities, etc.
The DSM - IV requirement for onset prior to age 7 likely
needs to be revisited and the definition of `impairment'
should, perhaps, be refined. There is currently no objective
laboratory test that is diagnostic for ADHD.
Acknowledgments
We would like to acknowledge the support of the
Neurobehavioral Teratology Society and the Burroughs
Wellcome Fund for partial financial support of the
symposium from which this manuscript is derived.
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