> **Precis**

Attention Deficit hyperactivity disorder (ADHD) is the most common
behavioral disorder of childhood, affecting an estimated 5-10% of the
general population (Solanto et al., 2001). ADHD is characterized by
difficulty paying attention and by inappropriate hyperactivity and
impulsive behavior (Kaplan et al 1995). The exact cause of ADHD is
unknown, but genetic influence is high with estimates of up to 85% (Levy
et al., 1997). Dopamine pathways in the brain are thought to play a
vital role in the etiology of this disorder, and psychostimulants,
agents known to affect the dopaminergic pathway, are the treatment of
choice. There is considerable public controversy about the validity of
this diagnosis and its treatment.

Both healthy children and children with ADHD have the same behavioral
response to psychostimulants (Rapoport et al., 1980, 1981; Rapoport and
Germain, 2003) which had seemingly put to rest the notion of
"paradoxical" response to stimulants in ADHD. With the advent of brain
imaging techniques, a better understanding of the underlying mechanisms
of ADHD has emerged, most consistently implicating frontostriatal
systems. Two recent brain imaging studies have again raised the question
of whether brain response to stimulants is "paradoxical" for ADHD
(Langleben et al., 2002; Vaidya et al., 1998). In these studies, the
ADHD and healthy groups had different brain activation patterns at
baseline and different patterns of response to stimulant medication.
However, these studies were small, and did not attempt to discriminate
between the influence of state and trait. Moreover, confounding factors
in these studies (such as differences in performance) might have
spuriously led to the appearance of a paradoxical effect.

To address the important issue of a unique central response to
stimulants in ADHD, this study includes a double blind,
placebo-controlled challenge with a single, low oral dose of 0.10 mg of
amphetamine. Subjects include 14 healthy control children and 14
children with ADHD matched for age and sex, and 12 pairs of monozygotic
twins discordant for ADHD and 12 pairs of same sex dizygotic twins
discordant for ADHD. Following a practice session using the "stop task",
a motor inhibition task widely used in ADHD research (Logan, 1994;
Oosterlaan, 1998), counterbalanced placebo or amphetamine will precede
functional MRI scanning using the stop task and the attentional task of
Casey (1997) used in Vaidya et al (1998).

Radiation involved in most neuroimaging techniques precludes application
to children, but functional MRI represents an important exception in
this regard, as the procedure relies on magnetic fields rather than
radioisotopes. Previous experience with single dose challenge in healthy
children and studies of treated ADHD and learning disabled children did
not indicate any long-term adverse effects, or an increased risk of
abuse.

If children with ADHD or their siblings exhibit differential activation
of the fronto-striatal regions of the brain than do control children, at
baseline and/or after stimulant treatment, these response patterns will
be examined in relation to clinical severity and to genetic relatedness
to the ADHD patient.

> **II. Introduction**

A.  **Type of Protocol:** This protocol examines the neural effects of a
    single dose of stimulant on children who have ADHD and on healthy
    children. As such, this protocol is designed to study the neural
    mechanisms of therapeutic psychostimulant medication.

B.  **Background:** This section reviews four issues relevant to the
    current proposal: 1.Imaging studies delineating the functional brain
    differences between normal individuals and those with ADHD. 2.
    Studies combining psychostimulant medication and brain imaging. 3.
    Informative functional MRI tasks in ADHD. 4.The rationale for twin
    populations.

**1. Brain Imaging Studies:** Several studies have concluded that the
brains of children with ADHD have subtle anatomical and functional
differences from the brains of healthy children (relevant imaging
studies are summarized in Appendix I).

> **a. Anatomical MRI studies**: Using magnetic resonance imaging (MRI),
> over fifteen anatomical studies have shown that ADHD children have
> subtle reductions in volume in the prefrontal cortex, caudate nucleus,
> globus pallidus, and a sub-region of the cerebellar vermis (Solanto et
> al., 2001).
>
> **b. SPECT and PET studies**: (See Appendix Ia.) Two (of three) SPECT
> studies in children show decreased frontal activation in ADHD. Two (of
> two) PET studies with adults and teenagers also indicate that subjects
> with ADHD show decreased frontal activation. Further, hypoperfusion in
> parietal and temporal regions was noted using SPECT (1/3 studies) with
> children with ADHD as compared to controls.
>
> **c. Functional MRI (fMRI) studies**: (See Appendix Ib.) Of three fMRI
> studies, one has shown decreased activation in the anterior cingulate,
> one has shown a decrease in prefrontal activation, and one has shown
> decreased activation in the caudate nucleus. Taken together, the above
> studies provide evidence for brain differences between healthy
> volunteers and patients with ADHD. However, to date, none of the tasks
> utilized during fMRI have controlled for performance differences
> between individuals with ADHD and healthy controls.
>
> **d. Dopamine and ADHD:** (See Appendix Ic &Id.) Genetic studies have
> shown ADHD to be associated with the dopamine transporter gene DAT1
> (Swanson et al., 2000). Four (of six) SPECT studies and one (of three)
> PET study have concluded that ADHD is characterized by an
> overexpression of the dopamine transporter (DAT) in the striatum or
> basal ganglia, presumably lowering dopamine concentration in the
> synaptic cleft. One (of six) SPECT study has found no difference in
> DAT between ADHD and controls, and one found lower DAT levels in
> adults with ADHD. Three (of three) PET studies have concluded that
> there is dopaminergic dysfunction at the level of the dopaminergic
> nuclei in ADHD.

**2. Medication Effects:**

**SPECT and PET studies: (See Appendix Id.)** Three (of four) SPECT
studies and one (of one) PET study have shown that following
Methylphenidate (MPH) administration, either DAT density in the caudate,
putamen, and/or striatum decreased or dopamine levels in the striatum
increased. It is believed that target medications such as
psychostimulants increase exogenous dopamine by blocking the DAT (Volkow
et al., 1998). Amphetamine and MPH both raise extracellular dopamine
levels by blocking DAT; in addition, amphetamine directly releases
dopamine (Seeman and Madras, 1998). Volkow and colleagues (1999, 2001)
predict that there is a certain optimal range for dopaminergic D2
receptors. By studying the responses of healthy subjects to MPH, while
at the same time measuring D2 receptor levels, the following was
hypothesized: too few receptors may not allow individuals to respond
effectively to a salient stimulus, while too many receptors may be
aversive. Since stimulants affect the behavior of children with ADHD and
of healthy children in a similar manner (Rapoport et al., 1980; Rapoport
and Germain, 2002), it may be that the same brain regions are involved
in response to stimulants, but the baseline physiology and activation
patterns of these regions may differ between the groups.

**Brain Imaging With Psychostimulant Administration to Children:** To
date, two studies have combined imaging, psychostimulants, and a
pediatric control population.

**Langleben et al**.: Using SPECT, Langleben et al. (2002) examined the
effects of MPH discontinuation on cerebral blood flow in 22 boys with
ADHD and 7 healthy controls. The researchers used a stimulus-controlled
version of the go/ no-go task as in Vaidya et al (1998), discussed
below. Unfortunately, task performance data were not reported, and
therefore it is unknown whether performance differed between the on- and
off-MPH conditions. However, because abnormal performance on go/no-go
tasks is among the most consistent findings in ADHD, one might expect
such differences in this study. The investigators found that when
children with ADHD were not taking MPH, their regional cerebral blood
(rCBF) flow was higher in the motor, premotor, and anterior cingulate
cortices compared to the on-MPH condition. Surprisingly, there were no
significant differences in blood flow in any region between patients
with ADHD and healthy controls either in the on-MPH or in the off-MPH
state. Also, there were no differences between controls in the off-MPH
or on-MPH state. Exact results were not provided, and hence it is
unknown how the rCBF of the controls and ADHD subjects compared. Perhaps
the small number of control subjects (n=7) limited any conclusions.

**Vaidya et al**.: This is the only fMRI study to image both healthy and
ADHD children during a go/no go task with and without MPH (Vaidya et
al., 1998). Both children with ADHD and healthy controls performed a
stimulus-controlled and a response-controlled version of the go/no-go
task (Casey et al 1997). At baseline, children with ADHD showed
decreased striatal activation compared to controls. Both groups showed
improved performance on MPH on the stimulus-controlled task, but only
the children with ADHD showed improvement with MPH on the
response-controlled task. By examining fMRI data during the
stimulus-controlled task, this study concluded that although the
behavioral response to MPH is identical across all subjects, the brain's
response was not; MPH increased striatal activation in children with
ADHD but reduced striatal activation in controls. The findings were
interpreted as highly novel, and no neurophysiological model was
presented in an effort to explain this result. This study used a
block-design, and performance differed between the ADHD and comparison
subjects. Hence, the study could not determine whether between-group
differences in activation patterns were confounded by between-group
differences in performance. An event-related design would address this
confound.

**3**. **Informative functional MRI tasks**: An fMRI task must be
well-characterized and effective at engaging circumscribed brain regions
and systems, produce robust signals in every individual, and show
variance across individuals (Hariri and Weinberger, 2003). Vaidya's
imaging paradigm does not allow researchers to control for performance
or to examine the degree to which neural structures are engaged by
specific types of events. If performance differed between ADHD patients
and controls, any differences in activation could either be attributed
to deficits in performance (e.g. neural responses to more errors in
affected subjects) or to deficits in the degree to which one or another
brain region (e.g. striatum) is engaged. 

Alternatively, we have used the stop task and an event-related design to
study motor inhibition in the fMRI environment (Protocol 02-M-0036). The
stop task controls for performance and the event-related design allows
investigators to contrast activations between trials involving
successful inhibition and those involving unsuccessful inhibition. In
the stop task, the subject is asked to perform a fast reaction time
task, denoted as the primary task. Occasionally, a stop signal is
presented, which requires the child to inhibit response to the primary
task. In a sense, then, the stop task is a variant of the go/no go task.
However, in the stop task, a "go" appears on every trial, and subjects
are instructed to respond unless a stop signal also appears; the timing
of the stop signal varies depending on the individual's performance on
the previous stop trial. Thus, the stop task adjusts for
inter-individual differences in motor execution. Since the timing of the
stop signal is tailored to individual motor performance, inhibitory and
motor execution processes are effectively dissociated and error rates
are equated across different groups of subjects. The estimated speed of
the inhibitory process, termed SSRT or stop signal reaction time, is
calculated. Performance on this task differs between children with ADHD
and healthy controls; seven of eight studies show that children with
ADHD have, on average, a 103 ms longer SSRT than healthy controls,
indicating that children with ADHD are slower to inhibit a response
(Oosterlaan et al, 1998). Results from this meta-analysis suggest that
this is a moderate-to-large effect. Moreover, children with a familial
form of ADHD are more likely to have a prolonged SSRT than children with
non-familial ADHD (Crosbie and Schachar, 2001). Studies in both healthy
individuals and individuals with ADHD have found that SSRT is
significantly shorter on MPH treatment than on placebo (Uftring et al.,
2001, Tannock et al., 1989, 1995, Bedard et al., 2002). Hence, like the
go/no-go task, the stop task is sensitive to stimulant effects in both
impaired and healthy individuals. However, unlike the go/no-go task, the
stop task produces similar rates of "incorrect" responses in impaired
and healthy subjects. Therefore, the task eliminates confounds
associated with differing error rates, and their associated neural
concomitants, across impaired and healthy subjects.

The stop task can be used to identify brain regions involved in motor
inhibition. As noted above, a contrast of particular relevance to
psychopathology compares brain activation during stop trials in which
subjects inhibit successfully ("stop correct") to activation during stop
trials in which they do not ("stop incorrect"). Preliminary work from
our group indicates that, in healthy adults, successful inhibition is
referentially associated with activation of left inferior and bilateral
medial prefrontal areas (Leibenluft et al., submitted). In other
analyses, attempted inhibitions, whether or not they are successful, are
associated with broader areas of activation, encompassing aspects of the
basal ganglia, parietal, and prefrontal cortices. Rubia et al. (1999)
found that when executing a similar stop task, children with ADHD,
compared to controls, had lower power of response in the right mesial
prefrontal cortex, right inferior prefrontal cortex, and left caudate
than did controls. However, this study, like the Vaidya et al. (1998)
study, used a block design, which does not allow for contrasts based on
task performance.

In the present study, Vaidya's stimulus response task (developed by
Casey et al 1997) and the stop task will be given. The two tasks will be
used to examine which neural systems distinguish children with and
without ADHD during the process of motor inhibition. Functional MRI,
which uses no ionizing radiation, is ideal for testing children. It is
essential to be able to study children because the deficits observed in
adults with ADHD may not be the primary pathological defect but may
rather result from an interaction of the primary neural deficit with
maturation and aging processes. If time permits, the Durston (2003)
Go-No-Go task will also be attempted, which has a parametric design.
Even if the Durston task can not be incorporated however, there is a
parametric component to the stop task (the stop signal delay) which will
be examined.

**4. Benefits of using twins**: If ADHD subjects differ from controls in
their pattern of response to stimulants, the basis for this difference
is not clear as stimulants almost invariably improve performance, and
placebo response is rare. Twin designs can, with certain assumptions,
reveal the extent to which diagnostic differences can be attributed to
genetic and non-genetic "state" factors. For most purposes, monozygotic
(MZ) twins can be taken to be genetically identical whereas dizygotic
(DZ) twins share 50% of their genes, on average. By using both MZ and DZ
twins discordant for ADHD, the question of state versus trait influence
on stimulant-related brain activation can be addressed. Statistical
techniques on anatomic brain mapping have shown the usefulness of twin
design in mapping genetic disease-related brain patterns (Thompson et
al., 2002). These have already been adapted for analyses of functional
activation patterns (Paul Thompson, personal communication).

**C.** **The research question for the current protocol:** Although
healthy and ADHD children react in the same behavioral manner to
psychostimulants, there may be differences between healthy children and
those with ADHD in the brain circuits that mediate the behavioral
response to medication. Imaging studies suggest that the difference lies
in the frontal-striatal brain regions important for inhibitory control
and in the striatal response to psychostimulants. However, no studies
have examined the activation differences between healthy and ADHD
children with a task that accurately controls for error rates in task
execution and that allows for separate analyses of trials with
successful and unsuccessful inhibition. Also, by using subjects at
different degrees of genetic risk for the disorder, this study aims to
untangle state and trait measures. The overall goal of this study will
be to better understand the pathophysiology of ADHD while focusing on
three specific aims: 1.To study brain activation patterns during
response inhibition tasks in children with ADHD and in healthy controls.
2. To simultaneously examine the central and behavioral effects of a
single-dose of amphetamine versus placebo in the two groups. 3. To
examine (using monozygotic and dizygotic twins) brain activation
patterns in relation to both clinical state and to the degree of genetic
relatedness. Based on the data reviewed above, this protocol tests three
hypotheses concerning the relationship between brain region activation,
genetic relatedness, and ADHD diagnosis.

> **Hypothesis 1a:** At baseline, children with ADHD will exhibit poorer
> performance on cognitive tasks compared to controls: specifically,
> those with ADHD will make more errors of commission on the go/no-go
> task and they will have a longer SSRT on the stop task.
>
> **Hypothesis 1b:** On placebo, prefrontal cortex and striatal
> activation will be higher in controls than in children with ADHD
> during both tasks. On placebo, activation in three prefrontal ROIs
> (namely: medial, inferior, and dorsal) will be lower in children with
> ADHD than in controls, again, during both tasks.

**Hypothesis 2a:** After the amphetamine dose, both healthy controls and
children with ADHD will show improved performance on the cognitive
tasks, as evidenced by fewer errors of commission on the go/no-go task
and a faster SSRT on the stop task.

**Hypothesis** **2b:** On the stop task, both healthy children and those
with ADHD will show increased striatal activation following the
amphetamine dose. In contrast, as in Vaidya et al. (1998), on the
go-no-go task, striatal activation will increase in children with ADHD
and decrease in healthy controls following the amphetamine dose.

> **Hypothesis 3:** Brain region activation response pattern will be
> related to ADHD symptom level rather than to degree of genetic
> relatedness.

**D. Background of Approach:** It is assumed that psychostimulants
affect the behavior of healthy children and those with ADHD in the same
manner (Rapoport et al., 1980; Rapoport and Germain, 2002). As a result,
it was assumed that brain activation in response to amphetamine was
likely to be identical as well. Two recent controlled imaging studies
with stimulants given to healthy and ADHD children have cast doubt on
this (see section IIB). Langleben et al. (2002) found that
psychostimulants lower cerebral blood flow in the anterior cingulate
cortex and motor cortex in children with ADHD but have no such effect in
healthy children. These results may explain why MPH helps relieve the
symptom of locomotor hyperactivity. Vaidya et al. (1998) conducted the
only fMRI controlled study in which MPH was administered both to
children with ADHD and to healthy controls. Without MPH, striatal
activation was greater in controls than in ADHD subjects. Both controls
and children with ADHD improved significantly in the stimulus-controlled
task while on MPH. During the stimulus-controlled task, MPH increased
striatal activation in ADHD children but reduced it in healthy controls.
Studies in animal models show that striatal engagement relates to
appropriate execution of a planned motor response (Hikosaka et al.,
2002). In Vaidya et al. (1998), between group differences in task
performance show that children with ADHD and healthy children did not
perform equally well: children with ADHD make more inappropriate motor
responses. Therefore, one could argue that observed differences in
activation patterns are secondary to observed differences in
performance. However, the two studies (Langleben et al., 2002 and Vaidya
et al., 1998) do raise the strong possibility that brain activation in
response to psychostimulants is different in ADHD children than in
controls. Both studies had small sample sizes and used less-than-optimal
tasks, generating higher rates of inappropriate motor responding in
patients than comparisons. Neither addressed the question of state
versus trait. By using twin samples discordant for ADHD, unrelated
children with ADHD, and unrelated controls, a larger sample size, and a
more revealing task, differences in brain activation in response to
psychostimulants can be examined. The study can not be carried out with
adults as there is evidence for change in brain anatomy in ADHD late in
adolescence (Castellanos), and adult ADHD samples differ significantly
from childhood ADHD with respect to gender, co-morbidity and symptom
pattern (Shaffer, 1994).

**E. Qualifications of the Investigators**: Three aspects of the
investigators' extensive previous research are relevant to the current
protocol. These include studies of: a) behavioral effects of amphetamine
in ADHD and healthy children; b) stop tasks and other cognitive tasks in
children; and c) fMRI in healthy and psychiatrically disordered
children.

## III. Study Design and Methods

**A. Study Design Descriptive Statement:** Following initial assessment
for eligibility, the study will use a double-blind placebo-controlled
crossover design, wherein all subjects undergo two drug challenges: a
single dose of dextroamphetamine sulfate and of a placebo. Procedures
for randomization will be implemented with the NIH pharmacy. All
subjects will undergo fMRI one hour after each dose. Subjects with ADHD
already receiving psychostimulant medication will withhold medication
for 36 hours prior to each drug challenge.

**B. Overview Summary:** This study examines the behavioral and neural
response to dextroamphetamine sulfate in four groups of children, namely
unrelated children with ADHD; unrelated, healthy controls; monozygotic
twins discordant for ADHD; and dizygotic twins discordant for ADHD. The
twins will be selected in part from an already existing sample used
previously for examination of clinical characteristics (Sharp et al.,
2002). The healthy controls and children with ADHD will be recruited
from nearby communities. Following telephone and mail screening, all
groups will undergo three days of study, one involving a trial practice
of the fMRI tasks, one involving placebo, and the third involving
dextroamphetamine sulfate. Procedures will be implemented using a
double-blind, placebo-controlled crossover design with the
placebo/dextroamphetamine order determined randomly. During both the
placebo and dextroamphetamine days, subjects will undergo fMRI scanning,
during which time two cognitive tasks will be administered. We
considered randomizing task order, but we elected to administer the stop
task second in all children. This allows us to more directly attempt to
replicate prior results in Vaidya et al. (1998). Thus, the first task
will be a stimulus-controlled go/no-go task as in Vaidya et al. (1998).
The second task will be the stop task (Logan et al, 1994). Both tasks
will test response inhibition, a cognitive process that is disrupted in
children with ADHD. fMRI scans will be performed approximately one hour
after placebo or psychostimulant is administered. Both tasks are needed
to be relevant to the literature (Vaidya) and to better control for
performance (stop task).

**C. Study Phases:** This study will have two phases. During phase I,
all subjects will be screened for inclusion and exclusion criteria using
procedures outlined below and will practice the cognitive fMRI tasks.
During phase II, all subjects will receive both a single dose of
dextroamphetamine and a dose of placebo in random order, using a
double-blind cross-over design.

**D. Sample Stratification:** The sample will be stratified into four
groups, based on genetic relatedness and on ADHD diagnosis. This will
include a group of twin pairs: discordant (for ADHD) monozygotic twins,
discordant dizygotic twins, unrelated healthy children, and unrelated
children with ADHD. The inclusion of a genetically-unrelated healthy
control group is required because, as shown in a previous study,
unaffected siblings of children with ADHD may be genetically predisposed
to exhibit the same abnormalities in brain activation patterns that are
observed in children with ADHD (Vaidya et al., 1998).

**E. Sample Size Justification:** FMRI studies examining the effects of
dopaminergic manipulations on the BOLD signal have noted large effect
sizes (standardized differences \[Cohen's d\] of 1.0-1.2) (Rubia et al.,
1999; Bush et al., 1999). Therefore, with sample sizes as small as n=14
per cell, assuming alpha = .05 two-tailed, we would have power of \>.80
to detect between-group differences. We note that in Vaidya et al.,
1998, the only other study that examined activation differences after
stimulant administration in patients with ADHD and controls, significant
between-group differences were found with a sample size of 10 patients
and 6 controls. Our study will have more than twice as many healthy
controls.

**F. Data Analysis:**

**1. Cognitive Response to stimulants:** Relative to placebo treatment,
dextroamphetamine treatment is hypothesized to produce improvements in
performance on the go-no-go and stop tasks (i.e. fewer errors of
commission on the go/no-go task and shorter SSRT on the stop task). To
test this hypothesis, we will contrast study groups using ANOVA/random
effects regression models, one for each of the two tasks. Each of these
analyses will have one between subject factor (ADHD vs. control) and one
within-subject factor (stimulant vs. placebo). In each analysis, the
continuous dependent measure from a given task (Y~jkl~) is predicted by
the following model: Y~jkl~= *β~0k~* + *β~1j\ ~*+ *β~2l~* + *β~3lj~* +
*ε~jkl~*, where j indexes group (ADHD vs. control), k indexes person,
and l indexes treatment (stimulant vs. placebo). As shown in the model,
*β~0k~* indexes the person-specific mean (random effect),
*β~1j\ ~*indexes the overall mean difference for the dependent measure
between ADHD vs. comparison subjects (fixed effect), *β~2l~* indexes the
overall mean difference across the two treatment conditions (fixed
effect), *β~3lj~* indexes the interaction between the two previous
effects (*β~1j\ ~* & *β~2l~*), and ε~jkl~ is a random effect for error.
We will assess significance of β~3~ (group-by-treatment interaction) to
evaluate the differential effects of stimulant treatment on task
performance across our two study groups.

**2. fMRI Response to stimulants:** Because we enter this study with
regionally-specified a priori hypotheses, fMRI analyses will examine
changes in BOLD signal within pre-specified regions-of-interest (ROIs).
Identification of ROI's will use established methods for cortical and
subcortical parcellation on high resolution T1 weighted images. ROIs
will comprise subcomponents of the striatum and PFC, as defined in our
prior studies (Castellanos et al., 2002; Castellanos et al., 1996;
Castellanos et al., 2001; Szeszko et al., 1999a; Szeszko et al., 1999b;
Szeszko et al., 2001). Two methods will be used to analyze fMRI data.
For the components of the striatum, including the caudate nucleus and
globus pallidus, average BOLD intensity in the entire structure will be
used as the dependent measure. This method will be used due to the small
size of these structures. Moreover, similar methods have been used in
Vaidya et al. (1998) and other recent fMRI studies of striatal
activations during inhibitory tasks. For larger ROIs within the PFC,
voxel-based methods with small volume correction will be used.

As in prior publications from our group (Monk et al., 2003; Nelson et
al., 2003; Pine et al., 2002), analyses will begin with realignment and
motion correction. Data from any subject with movement greater than 2 mm
in any direction will be discarded. Stereotactic normalization,
resampling, and spatial smoothing will use methods in SPM '99 (8 mm
smoothing kernal). Smoothing will not be employed for the analysis of
striatal activity. Results are co-registered on either individual
subject scans or averaged, spatially/stereotactically normalized images
for presentation of group results.

**Striatum:** Single values will be generated for each subject in each
striatal subregion to quantify the magnitude of response in these ROIs,
both during the placebo-day scan and during the stimulant-day scan. To
examine between group differences in stimulant response, these sets of
values will be submitted to the same type of random regression/ANOVA
analysis, as noted above, used to examine stimulant-induced changes in
cognition. To examine baseline differences, values will be used only
from the placebo scan, and terms for a treatment effect and
group-by-treatment interaction will be excluded from the model.

**Larger ROIs:** Hypotheses on task-associated changes in larger PFC
ROIs will be tested using random effects regression models in SPM '99 to
analyze task effects on the hemodynamic response. As in prior studies,
procedures will draw on the expertise of Eric Zarahn, Ph.D. to model
effects on BOLD activity of specific events occurring within larger
blocks of events. Full details of the application of these approaches to
our work appear in recent publications (Monk et al., 2003; Nelson et
al., 2003; Pine et al., 2002).

In brief, these analyses will test secondary hypotheses concerning
response to stimulants within three PFC sub-regions, comprising medial,
inferior, and superior components. These regions will be defined based
on anatomical criteria (Szeszko et al., 1999a; Szeszko et al., 1999b;
Szeszko et al., 2001), as in our prior fMRI studies (Monk et al., 2003).
Cerebellar regions will also be examined bilaterally (Indovina and
Sanes, 2001).

We provide further details for one specific contrast in the go/no-go
task (parallel models test hypotheses for other contrasts).
Specifically, for the go/no-go task, we will first compute for each
subject the interaction of a task factor (e.g. "no-go" vs. "go") and a
"medication" factor (stimulant vs. placebo), yielding a "double
difference" ("no-go" during stimulants -- "go" during stimulants) --
("no-go" during placebo -- "go" during placebo). Selection of the
specific "task factor" contrasts is based on prior data documenting
task-related activation in the contrast, either from Vaidya et al.
(1998) for the current contrast or from data in our group for the stop
task. These individual-subject data will then be submitted to a second,
group-level "random effects" analysis in SPM '99, where we will use the
small volume correction to determine a ROI-wise α=.05 threshold for each
of the specific ROIs. This provides a group level significance map for
precise PFC regions where activations during stimulants vs. placebo are
hypothesized to differ in ADHD vs. comparison subjects.

**G. Justification for use of medication washout:** As outlined in
Section II, compelling scientific data point to the importance of
studying the neurophysiological effects of amphetamine versus placebo in
children with ADHD and healthy controls. As such, it will be necessary
for children with ADHD currently on stimulant medication to temporarily
withhold it. Since drug holidays are often recommended for patients with
ADHD and since temporarily withholding stimulant medication is standard
practice in over 100 outpatient studies of ADHD, it is unlikely that
this will present a problem. If the family finds this unacceptable, the
children will not be entered.

IV\. Subject Enrollment

A.  Recruitment -- sample composition and characteristics:

The sample will consist of: 14 healthy children and adolescents, 14
subjects with ADHD, 12 pairs of dizygotic twins (n=24) discordant for
ADHD and 12 pairs of monozygotic twins (n=24) discordant for ADHD.

ADHD subjects: Determination of ADHD phenotype will be made based upon
the Structured Interview and Rating Scales (with a parent and separately
with the patient if the patient is older than 9), Conners Teacher Rating
Scale, and the Teacher Report Form (Conners, 1997).

Healthy controls: Subjects will be assessed for inclusion and exclusion
criteria. Screening will include a telephone interview, parent and
teacher rating scales and an in-person assessment that will include
physical and neurological examinations, structured psychiatric interview
using the K-SADS (Kaufman et al., 1997), and Child Behavior Checklist.
History of ADHD in all 1^st^ degree relatives will be investigated using
the Family Interview of Genetic Studies. Individuals who meet inclusion
criteria will be contacted to schedule the necessary imaging sessions.

Discordant twins: Each individual will be assessed for inclusion and
exclusion criteria. Healthy twins will undergo the same screening as
healthy control subjects and twins with ADHD will complete identical
screening as other subjects with ADHD.

B.  Inclusion criteria:

ADHD subjects: a) hyperactive, inattentive, and impulsive behaviors that
were impairing in at least 2 settings (home, school, or during testing
and/or interviews), b) a Conners' Teacher Hyperactivity rating greater
than 2 SDs above age mean, c) a DSM-IV diagnosis of ADHD based upon the
K-SADS, the Conners Teacher Rating Scale, and the Teacher Report Form.

Healthy controls: Subjects will be included as healthy controls using
the following criteria: no current psychiatric or medical conditions
revealed during screening and with the K-SADS with exceptions listed
below. Mild past anxiety disorder or depressive episodes will not be
exclusionary.

All subjects must be between 9 and 18 years of age, be able to give
consent, and have a minimum IQ of 80.

C.  Exclusion criteria:

ADHD subjects: Any DSM-IV psychiatric diagnosis with the exception of
Oppositional Defiant Disorder or mild learning disabilities that are
often comorbid with ADHD. Any subject who has a history of substance
abuse or smoking (based on parent report or K-SADS interview) will be
excluded. Any subjects who may not tolerate a drug holiday during
testing will be excluded. Past history of mood or anxiety disorders will
not be exclusionary. Subjects will be excluded with a full-scale
WISC-III IQ score less than 80.

Healthy controls: Any medical or neurological disorders on exam or by
history, any developmental disorders or ADHD in a first-degree family
member.

Any subject who is taking medication will be excluded as well as any
subject who meets general MRI exclusion criteria. Any subjects with a
body weight below 25 kg will be excluded.

D.  Study initiation and screening methods:

    1.  Sample: Preliminarily, 10 healthy subjects will be piloted on
        the two tasks. For the protocol: ADHD subjects age 9-18 will be
        recruited locally and may also include ADHD subjects who have
        participated in previous studies. Healthy controls will be
        recruited locally. Discordant twins have been and will be
        recruited nationally through patient advocacy groups, mothers of
        twins groups and from pools of available subjects from previous
        studies (Castellanos et al., in press; Sharp et al., 2003).

    2.  Screening methods: Subjects will be assessed using three sets of
        procedures. These procedures will be completed over two visits,
        though there will be some flexibility in this schedule to
        accommodate families.

        a.  Psychiatric History: All subjects will be screened for
            lifetime history of psychiatric disorders using the K-SADS
            Interview administered by a trained clinician. This measure
            requires one-to-two hours to complete. Families will also be
            assessed for family history of psychopathology, through an
            interview with at least one parent.

        b.  Physical Exam: All subjects will receive a medical history
            and physical examination from a licensed physician. The exam
            will assess all relevant inclusion/exclusion criteria. This
            measure requires 30 minutes to complete.

        c.  Neuropsychological Assessment: Subjects will undergo full
            WISC-III testing by a trained clinician during a
            medication-free period. Diagnostic interviews with parents
            require two hours to complete.

**V.** **Procedures**

A.  **Details of method:** A general overview of the procedures and
    description of data analytic methods appear in Section III. This
    section summarizes methods for assessments, the drug challenge, and
    fMRI portions of the study.

B.  **Details of assessment by study phase:**

    1.  **Schedule of visits:** Children and parents are seen as shown
        below by psychiatrists or psychologists for 30-40 minutes. A
        list of procedures at each visit appears below.

> Schedule

  ---------------------- ----------- -------- ------------- ----------- ----- ----- -----
  Form                   Informant   Time     Interviewer   Screening   Day 1 Day 3 Day 8
                                     (min)                                          

  KSADS                  C, P        120      Therap        X                       

  Neuropsych Testing     C           60-120   RA            X                       

  FMRI Assessment        \--         60-90    \--                             X     X

  Physical Exam          C           20       MD            X                       

  Amphetamine/Placebo    C           60       MD                              X     X

  Cognitive Tasks        C           25       RA                        X     X     X
  (stimulus-controlled                                                              
  go/no-go task & stop                                                              
  task)                                                                             

  Cheek swab for DNA     C, (twins   2        MD            X                       
                         only)                                                      

  Post-task survey       P           5        RA                        X     X     X
  ---------------------- ----------- -------- ------------- ----------- ----- ----- -----

> Key for abbreviations in table appearing above: "KSADS" full =
> Complete Kiddie SADS; Therap = trained, non-medical researcher or
> social worker, RA = research assistant, MD = child psychiatrist or
> pediatrician, P = parent, C = child.

**2. Drug Challenge Procedure:**

Subjects are enrolled into a double-blind, placebo-controlled crossover
drug challenge study and are randomly assigned to either an amphetamine
drug challenge first and placebo second or placebo first and amphetamine
second. To avoid carryover effects, a period of at least 2 days between
each drug challenge will be established. We will use a single dose of
dextroamphetamine sulfate at therapeutic levels; all children will
0.10mg p.o. of dextroamphetamine. A single dose is chosen because
amphetamine response is related more to rate of absorption and
relatively less to blood level. The dose/per kg would be expected to
vary therefore from .4 to .12 mg/kg across our age range.

The effects of dextroamphetamine versus placebo on performance will be
evaluated by administering the two cognitive tasks one hour after the
subjects receive a placebo dose and one hour after an amphetamine dose.

**3. fMRI Paradigms:**

**a. Stimulus-controlled go/no go task**: Subjects will perform a
stimulus-controlled version of the go/no-go task. The task will last for
5 min and consist of six alternating go and no-go blocks, each 25 s
long. Each block will begin with the presentation of the task
instruction ("press for all letters" for go blocks and "do not press for
X" for no-go blocks) followed by a consonant letter on each trial. For
go blocks, subjects will press a button for every letter. "X" will not
be presented and "C" will occur in 50% of the trials; no other letter
will be repeated within each block. For no-go blocks, subjects will
press the button for every letter except "X"; "X" will occur in 50% of
the trials and no other letter will be repeated within each block. Go
and no-go blocks will be equated for the rate of presentation (exposure
duration = 500 ms, inter-trial interval = 1.4 s) and number of trials
but differ in the number of key presses (12 in go blocks, six in no-go
blocks) (adapted from Vaidya et al., 1998 and Casey et al 1997.)

**b. Stop task:** The stop task, developed to measure response
inhibition, has been used extensively in behavioral and in fMRI studies.
The task is based on previous published work (Logan et al., 1994).
Subjects are trained to proficiency prior to entering the scanner. In
the scanner, subjects complete four blocks, each with 64 trials (32 go,
16 stop, and 16 blank trials). As in prior fMRI studies, blank trials
provide an implicit background against which to contrast other events.
The three trial types are distributed randomly throughout each block.

During go and stop trials, a white fixation cross appears on a black
background for 500 ms; it is replaced by an "X" or "O" for 1000 ms
(Fig.1). Trials are separated by 750 ms. During stop trials, the stop
signal is indicated by a change of the black background to red after the
"X" or "O" appears. Using a button box, subjects indicate "1" for "X"
and "2" for "O", but are told to not respond if the background color
changes to red. Subjects are told that they must respond before the "X"
or "O" disappears from the screen (i.e. within 1000 ms).

On the first "stop" trial, the stop signal appears 250 ms after the "X"
or "O". Subsequent stop signal timing is determined by performance on
the previous stop trial. If the subject successfully inhibited, the next
stop signal appears 50 ms later, making inhibition more difficult. If
the subject did not successfully inhibit, the signal appears 50 ms
earlier on the next stop trial, making inhibition easier.

**c**. In addition, if time permits, we will implement the Go-No-Go task
described in Durston et al 2003 This task is conceptually identical to
the task described above in (a). However the Durston et al task uses an
event related design and a parametric manipulation.

C.  **Details of secondary procedures:** The main secondary measure we
    will collect consists of genetic relatedness to proband. For all
    twin pairs, zygosity will be determined by DNA analysis using the
    following markers: DIS80 (20 alleles), DI7S30 (13 alleles), *apo*B
    (20 alleles), COL2A1 (10 alleles), *v*WA (9 alleles), and HUMTH01 (6
    alleles). Assuming an average heterozygosity rate of 70% per marker,
    this procedure will falsely classify a DZ pair as MZ in
    approximately 1/482 cases. DNA will be obtained by cheek swab.

Subjects will complete a survey after each imaging session that will
measure their motivation to complete the required tasks during the fMRI
scans. This survey will require each subject to rate the strength of
several emotions (e.g. "boring", "tiring", "interesting", "difficult")
felt during the tasks on a scale from one to ten. Data from these
surveys will be used to analyze the effect of dextroamphetamine on
motivation and to analyze the saliency of the tasks.

**D. Relationship to other studies proposed:** Drs. Leibenluft and Pine
are conducting fMRI studies using the stop task in normal adults
(Leibenluft et al, submitted) and adolescents (Protocol 02-M-0036), as
well as in children with bipolar disorder with and without comorbid ADHD
(protocol #00-M-0198). These data will later be examined in relation to
data from the present study.

VI\. Provision of Care to Research Subjects

A.  Concomitant clinical care: During their participation in this study,
    subjects will have access to a variety of clinical care and
    resources. A medical doctor will supervise all procedures and will
    provide medical care to any subject who feels discomfort or pain
    during any part of the study. All subjects with ADHD will have the
    option of consultation with a licensed clinician to discuss
    treatment options and current psychiatric status. Participation in
    this study may provide the opportunity for a subject to assess the
    effectiveness of a dextroamphetamine treatment on his/her ADHD
    symptoms compared to his/her current treatment. A certified
    clinician will be available during the study to discuss medication
    adjustments based on the effectiveness of the dextroamphetamine
    treatment used in this study and on the treatment history of the
    subject. All data obtained from each subject will be available to
    the subject and his/her family for clinical application.

B.  After care, including plans after completion of protocol, after
    discharge from study and during follow-up: Outpatient consultation
    will be available to all ADHD subjects for 3 months following the
    conclusion of the study. For ADHD subjects, if desired, these visits
    would provide meetings with a licensed clinician expert in ADHD to
    adjust treatments and to discuss medication options and the current
    psychiatric status of the subject. Follow-up consultations with NIH
    clinicians will not be a requisite part of the study protocol; these
    visits will be scheduled solely to provide further consultation for
    subjects who are seeking more information. It is expected that many
    ADHD subjects will prefer to see their treating pediatricians and
    will not utilize this follow-up resource. Healthy subjects will be
    given the phone number of the study physician to contact in case of
    any concerns. All healthy subjects will be contacted one week after
    the completion of testing to make sure that the subject and his/her
    family have no additional questions about the study.

C.  Reasons for discontinuation from study including any required
    transitional care: Participation in this protocol is voluntary.
    Parents may withdraw their children from this study at any time
    without negative repercussion, and children may withdraw assent.
    Subjects who have withdrawn from the study will be eligible for
    consultation with clinical staff as described above.

The research team may discontinue the participation of a subject at any
time. This discontinuation may be the result of an unexpected reaction,
because the subject failed to follow directions or because of the
termination of the study.

D.  Toxicity criteria: Any subjects exhibiting adverse effects of
    dextroamphetamine will be seen by a clinician if desired. At the
    dose prescribed only mild restlessness, anxiety, loss of appetite,
    or insomnia is anticipated. All subjects will be monitored by a
    clinician throughout the imaging sessions and will be available for
    immediate medical assistance if necessary. Clinicians at the NIH
    will be available for 24 hours after the completion of an imaging
    session to treat any adverse events associated with
    dextroamphetamine treatment.

VII\. Human Subject Risks and Protections

A. Consent & assent documentation: The current study examines brain
function and response to a single stimulant dose in both psychiatrically
healthy children and adolescents, and children and adolescents with
ADHD. For the healthy control groups, volunteers will be solicited from
the community.

Parents of healthy volunteers will be informed of the nature of the
assessments, medications and imaging procedures included. Participants
will be informed about the purposes of the research. They will be
advised that the information obtained will utilize a confidential code
and can only be accessed by Drs. Rapoport and Tossell, and will be
treated to group statistical analyses only.

# B. Risks of study participation by phase with means for minimizing risks:

**1. Psychiatric assessment:** Based on our research and clinical
experience with children of this age group to date, no adverse reactions
are anticipated as a result of the assessment procedures. For most of
our studies, the task of completing the face-to-face interviews, tests,
and scales will require a maximum of three hours for both parents and
children. It is highly unlikely that a study participant will become
upset about the questions or interview process used in the study. Each
measure has been used extensively in hundreds of children without
adverse effects. Children may refuse study participation at any time,
and the standard interviewing and data collection procedures will cease,
should any adverse reactions be noted. All subjects completing the
interviews and questionnaires will be provided with phone numbers so
that they can have any questions answered that they feel have not been
satisfactorily addressed. The investigative team has extensive interview
experience, and they will determine if there is a need for clinical
intervention; if necessary, arrangements for appropriate clinical
services will be made.

**2. Functional MRI (fMRI):** Recently, new methods for functional brain
imaging have been developed that use MRI to observe activity-related,
hemodynamic changes with high spatial and temporal resolution. The most
promising method, as is used in the current protocol, examines changes
in blood oxygenation. Because of the different magnetic properties of
oxy- and deoxyhemoglobin, increased levels of blood oxygenation are
associated with increased signal for some MR imaging methods, including
T2\*-weighted gradient echo imaging and echo-planar imaging. Increased
neural activity is associated with this increased signal, presumably
because local, activity-related increases in blood flow are greater than
increases in oxygen extraction, resulting in higher ratios of oxy- to
deoxyhemoglobin. Because the change in signal is due to properties
inherent in normal blood constituents, injection of contrast agents or
tracers and sampling of plasma are unnecessary.

All studies in the current protocol involve presentation of visual
stimuli while the subject is in the scanner, and the subject responds by
pressing buttons with the thumb of his dominant hand. These studies will
be performed in a GE 3 Tesla scanner, though the GE Sigma 1.5 Tesla
scanner may also be used on occasion. All scanners are located in the In
Vivo NMR Center in the Clinical Center. During a scan the subject hears
a loud rhythmic tapping or banging sound. This noise is caused by the
switching of the gradient coils that is necessary to produce the image.
Subjects are warned of this prior to scanning, and most do not find it
to be objectionable.

MRI is widely regarded as a safe, noninvasive procedure for
visualization of brain tissue in both adults and children. The risks
involved with fMRI are the same as those involved in standard anatomic
MRI, since these procedures rely on the same physical properties of
brain tissue. As noted above, this study will be performed on an FDA
approved 3T scanner at the NIMH. FDA standards for minimal risk MRI
require that four criteria be met: 1) a static magnetic field no greater
than 4T; 2) specific absorption rates a) no greater than 4W/kd for the
entire body for 15 minutes, b) no greater than 3W/kg over the head for
10 minutes, and c) no greater than 8W/kg in any gram of tissue in the
head or torso or 12W/kg in any gram of tissue in the extremities for
five minutes; 3) a time rate of change in the field that does not
produce physical discomfort or painful nerve simulation; and 4) a peak
sound pressure level that does not exceed 140 dB or A-weighted R.M.S.
pressure level that does not exceed 99dBA with hearing protection. Each
of these guidelines will be monitored throughout the study to insure
that none are exceeded.

MRI at 1.5 Tesla is a routine clinical procedure, and issues regarding
radio frequency deposition, time varying magnetic fields, and the static
field at 1.5 Tesla do not require detailed discussion. MRI at 3 Tesla is
not used for clinical scanning but is now widely used for research with
healthy human subjects. This includes studies with healthy children. The
gradients for the GE 3 Tesla scanner are higher performance, in terms of
gradient strength and slew rate. The gradients for the 3T scanner have a
maximum gradient strength of 4 G/cm, which is greater than the 2 G/cm
gradient strength of the 1.5 T scanners at the NIH. Gradient strength
allows for higher resolution and for study of water diffusion in tissue.
No studies have documented any detrimental effects of gradient
magnitude. The maximum slew rate, the maximum rate at which the
gradients change in magnitude, of the gradients on the 3T scanner is 150
mT/m/sec, which is greater than that on the 1.5T scanners (120
mT/m/sec). A higher maximum slew rate allows for faster imaging which is
generally better because the shorter readout window (time to collect an
image) causes images to be less contaminated by susceptibility or motion
artifacts. It is well known that if the gradients are switched too
rapidly, peripheral nerve stimulation can take place. The 3T scanner has
identical safeguards as the 1.5 T scanner in that the maximum allowable
slew rate is 66% of the FDA limit. Lastly, because of the higher radio
frequencies associated with the 3T scanner, (i.e. at 1.5 T protons have
a resonance frequency of 63 KHz and at 3T protons have a resonance
frequency of 125 KHz), larger amounts of energy are deposited into the
tissue during scanning. Tissue heating becomes a concern for certain
pulse sequences at higher field strength. Again, the operating system
for the scanner has built-in safeguards that only allow scanning with
specific absorption rates (SAR) of radio frequency that are well below
guidelines established by the Bureau of Radiological Health, FDA. The
operation system limits radio frequency deposition in the head to an
average rate of 10 watts, \< 4 w/kg, which has been shown to raise the
average core temperature approximately 0.3 deg. C. These temperature
changes are within the normal diurnal rhythms (+/- 1 deg. C.) found in
human core temperatures or a change associated with a brisk 20-minute
walk (+/-1 deg. C.).

Based on pilot work, fMRI in children and adolescents has been
considered a minimal risk procedure by the IRBs at New York State
Psychiatric Institute (NYSPI), by the Center for Advanced Brain Imaging
(CABI), the Nathan Kline Institute (NKI), and in previous protocols at
the NIMH. These are institutions where Dr. Pine has conducted previous
fMRI studies. Prior fMRI studies by our group and by other groups
document the innocuous nature of these procedures. Each child who
undergoes fMRI in our laboratory trains in a similar device to increase
familiarity and reduce any stress associated with the novelty of the
procedure. We also interview each child who completes our fMRI studies
following the study. Children rate a set of negative emotions (e.g.
"scared", "angry", "grouchy") using 10-point scales, with a score of 1
indicating "no" degree of negative emotion and a score of 10 indicating
extreme degrees of negative emotion. No child in our studies has rated
the procedures as anything more extreme than a 3, in terms of negative
experiences. Of note, the tolerability of fMRI in our studies, as well
as our ability to generate usable data, may relate to our use of an fMRI
simulator device. Each child studied in our laboratory undergoes
training on our simulation to reduce any apprehension concerning the
procedures of the study.

**3.** **Single dose usage of stimulant:** One significant ethical
consideration is whether the administration of a single dose of
stimulant to a healthy subject might psychologically encourage future
recreational use of the drug. There are several reasons why this is
unlikely. Dextroamphetamine and methylphenidate, when used to treat
children and adolescents with ADHD, are administered at consistent, low
doses for several years. During this type of treatment, no sensitization
to the medication is observed. In addition, long-term follow up of
subjects from the 1980 NIH study (Rapoport et al., 1980) in which
psychiatrically healthy children were administered a single dose of
amphetamine revealed no adverse effects or increased risk of drug abuse
in subjects followed for at least five years after the conclusion of the
study (n=14). The low potential for sensitization and abuse of oral
stimulants has been illustrated by a series of studies that followed
ADHD patients treated with stimulants during childhood and/or
adolescence. Three published studies have found that stimulant-treated
ADHD patients had a [reduced]{.underline} rate of later substance abuse
compared to ADHD patients who were not treated (Total sample size =
1393) (Barkley et al., 2003; Biederman et al., 1999; Wilens et al.,
2003). Only one study found an increased rate of substance abuse among
the stimulant-treated group for tobacco (increase of 50.2% with over 1
year of stimulant treatment; n=84 medicated ADHD, 81 non-medicated ADHD)
and cocaine (82.6% increase with over one year of stimulant treatment; n
= 84 medicated, 81 non-medicated ADHD) (Lambert and Hartsough, 1998).
Most recently, a study followed 100 psychiatrically healthy children
with mild reading disabilities for 16 years after they had completed a
16-week treatment of either methylphenidate or placebo (Mannuzza et al.,
in press). There was no significant difference in the rate of substance
abuse at follow-up between those treated with methylphenidate and those
treated with placebo.

Methylphenidate and dextroamphetamine have been shown to block dopamine
transporters (DATs) resulting in an increase of extracellular dopamine
in several areas of the brain including the striatum and frontal lobe
(Volkow, 2002a). Chronic administration of methylphenidate or
amphetamine has, however, been shown to induce stimulant sensitization
in mice and rats (Achat-Mendes et al., 2003; Battisti et al., 2000;
Brandon et al., 2001; Gaytan et al., 2000; Sokolov et al., 2003). All 6
of these studies introduced the stimulants using intraperitoneal or
intravenous injections; this method results in a much more rapid uptake
and shorter half-life than when the drug is introduced orally (Volkow et
al., 2002b). The longer half-life observed during oral administration
suggests that oral stimulants have a lower potential for abuse and fewer
reinforcing effects than administrations using intravenous or
intraperitoneal injections (Oldendorf, 1992).

A second issue involving the use of stimulants relates to reports of
insomnia and loss of appetite during stimulant treatment. Treatment with
stimulants causes a statistically significant increase of insomnia and
appetite suppression over a placebo (Ahmann et al., 1993; Fine and
Johnston, 1993; James et al., 2000). Although there is risk for these
adverse effects, limiting the exposure of the subjects to a single dose
of stimulant should reduce the possibility of any subject experiencing
more than a few hours of side effects from the medication. Moreover,
with the proposed low dose to be used, the effect of these side effects
on children will remain well within the range of physiological,
affective, and cognitive effects regularly experienced by children in
their every day lives. There are a range of other concerns associated
with stimulant use including constipation, diarrhea, nausea, and
confusion. These effects have never been observed after a single dose of
stimulant and will not be further discussed in this protocol. We have
considerable experience in the use of psychostimulants among both
healthy and impaired children. In a previous NIH healthy volunteer study
using doses of 0.35 mg/kg there were no significant adverse effects
(Rapoport, 1980). Due to the sensitive ethical issues in this study,
dosage for this study will be limited to 0.25 mg/kg in an effort to
further minimize any side effects while still inducing measurable
pharmacological effects on behavior and brain activation patterns. At
this dosage level, adverse effects from a single-dose of
dextroamphetamine will fall within the normal experience of a child's
life and therefore will pose minimal risk.

**4.** **Stimulant-Free Period:** Participation in this study will
require that ADHD subjects who are taking psychostimulants be off these
drugs for at least 36 hours prior to all neuropsychological testing and
imaging sessions. These periods are necessary to allow for a medication
"wash-out" so that all subjects are clear of psychostimulants at the
time of their treatment and imaging for this study. This inconvenience
may result in an increase in inattentive and hyperactive behavior for
some affected subjects during these stimulant-free periods. If there is
any concern about the ability of a subject to tolerate a stimulant
holiday, he/she will be excluded from this study.

**5. Confidentiality:** Every necessary step will be taken to prevent
identification of study participants of violations of confidentiality of
the data. Information will be stored using a confidential code and data
will be treated only as groups. All data entered into a database will
appear only in coded form. Members of the research team will have access
to these coded data. Only staff directly involved in the care of each
subject will have access to clinical documents that contain identifying
information. This will include research assistants, clinical staff, and
the study psychiatrist.

**6. Safety Monitoring:** All procedures will be performed under the
supervision of a medical doctor. If at any point in the study a subject
feels any discomfort or pain, the procedure will be stopped and the
subject will be given medical attention. Families of the subjects will
be provided with phone numbers for emergency coverage, 24-hours/day in
case of adverse effects of medication.

[]{.mark}

> **7. Emergency Treatments:**

a.  **Assessment Phase:** If, during the course of interview and
    assessment procedures, study staff identifies any condition that
    should require immediate clinical intervention or official reporting
    (e.g., suicidality, child abuse), all necessary steps will be taken.
    In the case that staff determines that the child is at significant
    risk for self- or other-destructive behavior, the parent will be
    notified, any mental health or professional persons currently
    treating the child and family will be contacted (with parental
    permission), and necessary treatment steps (e.g., hospitalization,
    referral to a care provider, etc.) will be offered.

b.  **Imaging Phase:** If, during the course of the study, a subject's
    condition deteriorates significantly, the subject will be removed
    from the study. At this point or any other point where subjects are
    removed from the study for non-emergent reasons, short term clinical
    care will be provided by staff within the Child Psychiatry Branch,
    under the direction of the study physician, Dr. Julia Tossell.

c.  **Clinical Care After Study:** The total amount of time that
    out-of-study psychiatric consultation will be provided is expected
    to vary, given the diverse clinical needs of these patients.
    Consultations about treatment options and psychiatric condition by
    the study psychiatrist will be available for up to three months
    following the conclusion of the study.

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8.  **Procedures for** **minimizing risk:**

    a.  **Recruitment and Assessment Procedures:** To reduce subject
        fatigue, the recruitment and assessment procedures may be spread
        out over two visits, with breaks interspersed to reduce any
        discomfort. If, in the opinion of the study staff, PI, subject,
        or his/her family, the assessment procedures or study
        participation is adversely affecting the subject's emotional
        well-being, the clinical circumstances will be reviewed to
        determine what additional steps should be taken.

    b.  **FMRI Procedures:** We routinely use a series of procedures to
        minimize the risk for upset in children and adolescents who
        participate in our prior and proposed studies. Prior to
        screening, through the use of a simulator, subjects are
        habituated to the MRI environment. The procedures are conducted
        in the presence of a trained clinician and subjects will have
        ready access to the team should they experience any problems.
        During scanning the subject can be seen at all times by a person
        standing in front of the bore or through the window between the
        control room and the scanner room. The subject can communicate
        with the control room personnel via an intercom at the operating
        console and can be removed immediately from the scanner if
        necessary. Subjects wear earplugs to minimize exposure to
        excessively loud noises, and the length of each MR study will
        not exceed 90 minutes. Each subject is interviewed immediately
        following the procedure to detect any problems.

    c.  **Stimulant Treatment Procedures:** The risks associated with
        exposure to psychostimulants will be minimized in two ways.
        First, exposure to stimulant treatment will be limited to a
        single dose. Second, stimulant treatments will be administered
        orally. Oral administration lengthens the half-life of the drug
        and effectively prevents any psychological "high" or stimulant
        sensitization. In addition, a trained clinician will be present
        during stimulant treatment to supervise and, if necessary,
        provide assistance.

# C. Benefits of study participation: 

# There are no direct benefits of the study for any group. Indirect benefits vary for each group of subjects:

Healthy controls: Healthy children may learn about the experience of
being in a scientific research project; they will learn about the
research process and about brain imaging. Some children may receive some
sort of science credit or create a science fair project out of the
experience.

ADHD subjects: Participation in this study may help these subjects
better understand the effects of their own medication. The involvement
of these subjects in the experiment may also teach them about clinical
research and the experimental process. Their participation in this study
may also provide these subjects with an opportunity to examine the
effectiveness of this medication on their ADHD symptoms. Participation
in this study will also involve free consultation from a licensed
clinician at NIMH for all subjects in this group.

Healthy twins: Many of the healthy twins may participate in this study
to help further the understanding of their sibling's condition. The
involvement of these children and adolescents may provide this group
with an opportunity to experience first-hand the effects of the
medication that their twins may be taking.

ADHD twins: Participation in this study may help these subjects better
understand the effects of their own medication. The involvement of these
subjects in the experiment may also teach them about clinical research
and the experimental process. Their participation in this study may also
provide these subjects with an opportunity to examine the effectiveness
of this medication on their ADHD symptoms. Participation in this study
will also involve free consultation from a licensed clinician at NIMH
for all subjects in this group.

**D.** **Investigator conflicts of interest:** None.

**E. Privacy and confidentiality provisions:** Information will be
stored using a confidential case number, and no identifiers (name,
address, phone number, etc.) will be used that could allow direct
linking of database information to individual subjects. Where temporary
linking of information with identifiers is needed, such identifiers will
be temporarily attached to the data, and will be removed after
information has been encoded. Information will be stored using a
confidential code and data will be treated only as groups. All data
entered into a database will appear only in coded form. Members of the
research team will have access to clinical documents that contain
identifying information. This will include research assistants, clinical
staff, and the study psychiatrist.

**F. Adverse event reporting:** Adverse events associated with
assessment, placebo and amphetamine administration, and fMRI scanning
will be monitored during each visit. All clinically significant adverse
events will be immediately reported to the IRB. A summary of all adverse
events will be provided to the IRB during each yearly review of the
protocol.

## G. Data and safety monitoring process: The IRB and clinical director will decide if we need to establish a Data and Safety Monitor (DSM) for this study. The Data and Safety Monitor would monitor and report unexpected or serious adverse events associated with this study. The Data and Safety Monitor would follow the guidelines of the NIH and HHS. These duties do not obviate the responsibility of the Principal Investigator to report serious adverse events directly to the IRB, but it allows a further layer of protection and supervision for the subjects. If a DSM is chosen for this study he/she will report any unexpected adverse events to the IRB within 24 hours.

**H. Subject compensation:**

All subjects who participate in any part of this study will be
compensated. Financial compensation will be as follows:

Screening Session - \$70

## 3 Hours

K-SADS: 1 Inconvenience Unit (IU)

Physical Exam: 1 IU

WASI: 1 IU

Visit 1 - \$250

> 4 Hours
>
> fMRI Session: 13 IU
>
> Placebo Treatment: 1 IU

Visit 2 - \$250

> 4 Hours
>
> fMRI session: 13 IU
>
> Amphetamine Treatment: 1 IU
>
> Total possible study compensation: \$570

### VIII. Pharmaceutical, Biologic, and/or Device Information

**A. Source:** Preparation of the placebo and dextroamphetamine
treatments for the "blind" will be completed by the Clinical Center
pharmacy. During this preparation, the pharmacy will keep all records of
treatment randomization; neither the subject nor the research team will
be able to identify any given treatment. A double-blind preparation is
preferable to an open trial because of the minimization of bias.
Dextroamphetamine and placebo treatments will be prepared as liquids so
that proper doses can be administered to each subject based on his/her
body weight.

**B. Relevant pharmacology:** The current study will utilize a
single-dose treatment of dextroamphetamine for both the subjects with
ADHD and the healthy control group. Amphetamine treatment is widely
administered to children and adolescents with ADHD and effectively
increases attention and decreases hyperactivity in individuals who have
been diagnosed with ADHD. Dextroamphetamine is well absorbed after oral
ingestion and reaches peak blood concentrations within two hours of
administration. Mean half-life for dextroamphetamine elimination is
approximately 10 hours and the drug is excreted from the body in urine.
Appropriate dosage for this study will be determined by body weight
(0.25 mg/kg.) and will be comparable to therapeutic dosage. Amphetamines
act as psychostimulants by facilitating the release and blocking the
reuptake of biogenic amines, specifically dopamine, norepinepherine, and
serotonin. This mechanism results not only in psychostimulation, but can
also induce insomnia and loss of appetite at the dosage required for
this study. Amphetamines also inhibit the enzyme monoamine oxidase.
Amphetamines, when administered chronically, have potential for abuse
and can be habit forming.

**C. Toxicity:** Symptoms of dextroamphetamine overdose include the
following: constipation, panic, over-stimulation, restlessness, rapid
respirations, and tremor. Stimulation of the central nervous system can
be followed by depression and/or fatigue. Acute amphetamine overdose can
result in convulsions, coma, and death and requires emergency medical
support of body systems with attention to amphetamine elimination.
Adverse effects are rarely seen at dosages below 20 mg. Subjects in this
study will be administered a single low, therapeutic-level dose of
amphetamine that is not likely to induce toxic effects. A minimum weight
requirement (25 kg) will be established for all subjects. This
requirement will prevent the administration of significant
dextroamphetamine doses to children with low body weights. In the
previous NIH healthy volunteer study using these doses there were no
significant adverse effects. Any adverse effects that result from the
dosage levels utilized in this protocol will fall within the experience
of a healthy child's life and will pose minimal risk.

**D. Incompatibilities:** Volunteers on other medications will be
excluded from this study.

E.  **Administration Procedures:** Single doses of amphetamine will be
    administered orally to all subjects. Oral administration of
    amphetamine is commonly used to treat children and adolescents who
    are afflicted with ADHD. Oral administration is favorable to
    intravenous or intraperitoneal injections due to the longer
    half-life associated with oral stimulants (Volkow, 2002). Due to the
    increased half-life of this type of administration, oral stimulants
    produce no psychological "high" and are less likely to be abused
    than injected stimulants. In addition to the psychological benefits
    of this type of administration, giving the drug orally also
    eliminates the exposure of the subjects to needles that would
    administer intravenous or intraperitoneal stimulants.

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> Appendix Ia: SPECT and PET Studies: Brain Abnormalities in ADHD

+-----+-----+------------+-----------+-------+------------+---------+
| Aut | St  | Sample     | Method    | Locus | Relevant   | Comment |
| hor | udy |            |           |       | Results    |         |
| &   | T   |            |           |       |            |         |
| d   | ype |            |           |       |            |         |
| ate |     |            |           |       |            |         |
+-----+-----+------------+-----------+-------+------------+---------+
| K   | Tc- | 13 ADHD    | Conners   | Hyp   | ↓ rCBF in  | Dif     |
| aya | 99m | children   | teachers  | operf | right      | ficulty |
| et  | HM  |            | ques      | usion | medial     | reg     |
| a   | PAO | 7 healthy  | tionnaire | in    | temporal   | ulating |
| l., | SP  | controls   | rating;   | the   | cortex &   | r       |
| 2   | ECT |            |           | right | right      | esponse |
| 002 | s   | age 7-12   | Du Paul   | m     | lateral    | to      |
|     | can | yrs old    | parents   | edial | temporal   | stimuli |
|     |     |            | and       | tem   | cortex :   | in ADHD |
|     |     | **None     | teacher   | poral | cerebellum | may be  |
|     |     | previously | ques      | c     | ratio in   | m       |
|     |     | treated    | tionnaire | ortex | ADHD.      | ediated |
|     |     | with       | rating.   | and   |            | by      |
|     |     | stimulant  |           | the   | Hyp        | un      |
|     |     | med        | SPECT     | right | operfusion | derfunc |
|     |     | ication**. | imaging   | la    | in right   | tioning |
|     |     |            |           | teral | medial     | of the  |
|     |     |            | For each  | tem   | temporal   | orbital |
|     |     |            | region of | poral | cortex     | frontal |
|     |     |            | interest, | c     | inversely  | cortex  |
|     |     |            | ADHD      | ortex | correlated | and     |
|     |     |            | patients  | in    | with Du    | sub     |
|     |     |            | were      | chi   | Paul       | sequent |
|     |     |            | divided   | ldren | teachers'  | con     |
|     |     |            | into two  | with  | que        | nection |
|     |     |            | groups    | ADHD  | stionnaire | to the  |
|     |     |            | according | when  | rating     | limbic  |
|     |     |            | to degree | com   | scale.     | system. |
|     |     |            | of        | pared |            |         |
|     |     |            | hypo      | with  |            |         |
|     |     |            | perfusion | cont  |            |         |
|     |     |            | and       | rols. |            |         |
|     |     |            | compared  |       |            |         |
|     |     |            | with      |       |            |         |
|     |     |            | symptom   |       |            |         |
|     |     |            | rating    |       |            |         |
|     |     |            | scales.   |       |            |         |
+-----+-----+------------+-----------+-------+------------+---------+
| A   | SP  | 54         | A resting | Left  | ↓          | C       |
| men | ECT | **medicat  | and on    | prefr | perfusion  | hildren |
| and | i   | ion-free** | task      | ontal | in         | with    |
| Ca  | mag | ADHD       | brain     | lobe  | prefrontal | ADHD    |
| rmi | ing | children   | scan were | decr  | cortex     | may not |
| cha | s   | and        | p         | eased | with       | process |
| el, | can | a          | erformed. | act   | in         | at      |
| 1   | us  | dolescents | For the   | ivity | tellectual | tention |
| 997 | ing |            | task,     | in    | stress     | tasks   |
|     | Cer | 18         | patients  | chi   |            | in the  |
|     | tec | medic      | performed | ldren |            | same    |
|     | (   | ation-free | a         | w/    |            | manner. |
|     | 99m | controls   | sta       | ADHD. |            |         |
|     | Tc  | from the   | ndardized |       |            | Large   |
|     | he  | p          | c         |       |            | ADHD    |
|     | xam | sychiatric | ontinuous |       |            | sample; |
|     | eth | outpatient | pe        |       |            | h       |
|     | yl- | clinic w/o | rformance |       |            | owever, |
|     | pro | ADHD ages  | task 5    |       |            | choice  |
|     | pyl | 6-18       | minutes   |       |            | of      |
|     | ene |            | before    |       |            | c       |
|     | am  |            | and 10    |       |            | ontrols |
|     | ine |            | minutes   |       |            | from    |
|     | o   |            | after the |       |            | among   |
|     | xim |            | isotope   |       |            | psyc    |
|     | e). |            | was       |       |            | hiatric |
|     |     |            | injected. |       |            | pop     |
|     |     |            |           |       |            | ulation |
|     |     |            |           |       |            | may not |
|     |     |            |           |       |            | be      |
|     |     |            |           |       |            | best.   |
+-----+-----+------------+-----------+-------+------------+---------+
| S   | N-  | 10 ADHD    | A resting | ↓     | ↑ overall  | Imp     |
| ieg | Iso | patients   | SPECT     | act   | h          | licates |
| et  | pro |            | scan.     | ivity | emispheric | r       |
| a   | pyl | 6 patients |           | in    | I-123 IP   | egional |
| l., | I   | from a     |           | fr    | uptake     | c       |
| 1   | odi | non-ADHD   |           | ontal | asymmetry  | ortical |
| 995 | ne- | mixed      |           | and   | in ADHD    | pe      |
|     | 123 | p          |           | par   | subjects.  | rfusion |
|     | IMP | sychiatric |           | ietal |            | and     |
|     | SP  | group as   |           | re    | ↓ activity | met     |
|     | ECT | controls   |           | gions | in left    | abolism |
|     | s   |            |           | in    | frontal    | abnorm  |
|     | can | age 6-16   |           | ADHD  | and left   | alities |
|     |     |            |           | pati  | parietal   | in      |
|     |     | **None of  |           | ents. | regions in | areas   |
|     |     | the        |           |       | comparison | that    |
|     |     | patients   |           |       | to         | are     |
|     |     | were       |           |       | controls.  | i       |
|     |     | receiving  |           |       |            | nvolved |
|     |     | ps         |           |       |            | in the  |
|     |     | ychotropic |           |       |            | control |
|     |     | m          |           |       |            | of      |
|     |     | edications |           |       |            | atte    |
|     |     | at the     |           |       |            | ntional |
|     |     | time of    |           |       |            | pr      |
|     |     | the        |           |       |            | ocesses |
|     |     | scan**.    |           |       |            | in      |
|     |     |            |           |       |            | c       |
|     |     |            |           |       |            | hildren |
|     |     |            |           |       |            | with    |
|     |     |            |           |       |            | ADHD.   |
+-----+-----+------------+-----------+-------+------------+---------+
| Za  | PET | 10 healthy | A         | ↓     | Globa      | 7/10    |
| met | and | teenagers  | com       | gl    | l/absolute | c       |
| kin | flu |            | puterized | ucose | metabolism | ontrols |
| et  | deo | 10         | auditory- | metab | the same.  | s       |
| al, | xyg | teenagers  | attention | olism |            | iblings |
| 1   | luc | with ADHD  | task      | in an | ↓ glucose  | of      |
| 993 | ose |            | (C        | area  | metabolism | c       |
|     | F18 | Age 13-16  | ontinuous | of    | in 6/60    | hildren |
|     | w   |            | Pe        | the   | specific   | with    |
|     | ere | **7/10     | rformance | left  | brain      | ADHD,   |
|     | u   | ADHD       | Test) was | ant   | regions,   | but     |
|     | sed | patients   | p         | erior | including  | only 2  |
|     | to  | had been   | erformed. | fr    | an area in | c       |
|     | st  | previously |           | ontal | the left   | ontrols |
|     | udy | treated w/ |           | lobe  | anterior   | had     |
|     | br  | s          |           | in    | frontal    | ADHD    |
|     | ain | timulants, |           | chi   | lobe in    | a       |
|     | g   | but all    |           | ldren | ADHD.      | ffected |
|     | luc | had been   |           | with  |            | s       |
|     | ose | medication |           | ADHD. | ↓          | iblings |
|     | m   | free for 3 |           |       | metabolism | that    |
|     | eta | wks prior  |           |       | in that    | parti   |
|     | bol | to PET     |           |       | specific   | cipated |
|     | ism | scan.**    |           |       | region of  | in the  |
|     |     |            |           |       | the left   | study.  |
|     |     |            |           |       | anterior   | Of ADHD |
|     |     |            |           |       | frontal    | group,  |
|     |     |            |           |       | lobe       | 8 had   |
|     |     |            |           |       | inversely  | an      |
|     |     |            |           |       | correlated | a       |
|     |     |            |           |       | with       | ffected |
|     |     |            |           |       | symptom    | parent. |
|     |     |            |           |       | severity.  | Of      |
|     |     |            |           |       |            | control |
|     |     |            |           |       |            | group,  |
|     |     |            |           |       |            | 6 had   |
|     |     |            |           |       |            | ADHD-a  |
|     |     |            |           |       |            | ffected |
|     |     |            |           |       |            | parent. |
+-----+-----+------------+-----------+-------+------------+---------+
| Za  | PET | 50 normal  | A         | ↓     | ↓ global   | Glucose |
| met | and | adults     | com       | gl    | cerebral   | c       |
| kin | flu |            | puterized | ucose | glucose    | erebral |
| et  | deo | 25         | auditory- | metab | metabolism | met     |
| al, | xyg | patients   | attention | olism | in adults  | abolism |
| 1   | luc | w/ ADHD    | task      | in    | w/         | diff    |
| 990 | ose |            | (C        | pre   | hype       | erences |
|     | F18 | age 24- 48 | ontinuous | motor | ractivity. | esp     |
|     | w   |            | Pe        | c     |            | ecially |
|     | ere | **None of  | rformance | ortex | ↓ glucose  | in      |
|     | u   | the        | Test) was | &     | metabolism | areas   |
|     | sed | patients   | performed | sup   | reduced in | in      |
|     | to  | had been   | on all    | erior | 30/60      | volving |
|     | st  | treated at | subjects  | prefr | specific   | control |
|     | udy | any time   | during    | ontal | brain      | of      |
|     | br  | with       | FDG       | c     | regions in | at      |
|     | ain | stimulant  | uptake.   | ortex | ADHD. ↓ in | tention |
|     | g   | medi       |           | in    | premotor   | and     |
|     | luc | cation.**. |           | ADHD  | cortex and | motor   |
|     | ose |            |           |       | superior   | ac      |
|     | m   |            |           |       | frontal    | tivity. |
|     | eta |            |           |       | cortex in  |         |
|     | bol |            |           |       | ADHD.      |         |
|     | ism |            |           |       |            |         |
+-----+-----+------------+-----------+-------+------------+---------+

Appendix Ib: Functional MRI Studies of Brain Abnormality in ADHD

+-----+----+----------+-----------+----------+----------+-----------+
| Aut | S  | Sample   | Method    | Locus    | Relevant | Comment   |
| hor | tu |          |           |          | Results  |           |
| &   | dy |          |           |          |          |           |
| d   | Ty |          |           |          |          |           |
| ate | pe |          |           |          |          |           |
+-----+----+----------+-----------+----------+----------+-----------+
| D   | FM | 7 normal | A go/nogo | ↓        | Fronto   | Evidence  |
| urs | RI | controls | task, so  | ac       | striatal | for       |
| ton | st |          | that the  | tivation | regions  | front     |
| et  | ud | 7 ADHD   | number of | in       | not      | ostriatal |
| al, | y. |          | go trials | region   | a        | in        |
| 2   |    | age 6-10 | preceding | in left  | ctivated | volvement |
| 003 |    |          | a no-go   | caudate  | in the   | in ADHD.  |
|     |    | **       | trial is  | nucleus  | same     |           |
|     |    | Subjects | varied to | in ADHD. | manner.  |           |
|     |    | taking   | tax the   |          |          |           |
|     |    | s        | neural    | ↑        | Children |           |
|     |    | timulant | systems   | ac       | w/ ADHD  |           |
|     |    | me       | u         | tivation | rely on  |           |
|     |    | dication | nderlying | in the   | a more   |           |
|     |    | withheld | cognitive | right    | diffuse  |           |
|     |    | dose on  | control   | superior | network  |           |
|     |    | day of   | with      | frontal  | of       |           |
|     |    | MRI.**   | i         | gyrus    | regions, |           |
|     |    |          | ncreasing | (BA 10), | i        |           |
|     |    |          | levels of | right    | ncluding |           |
|     |    |          | inte      | middle   | more     |           |
|     |    |          | rference. | frontal  | p        |           |
|     |    |          |           | gyrus    | osterior |           |
|     |    |          |           | (BA      | and      |           |
|     |    |          |           | 9/46),   | dors     |           |
|     |    |          |           | right    | olateral |           |
|     |    |          |           | inferior | pr       |           |
|     |    |          |           | parietal | efrontal |           |
|     |    |          |           | lobe (BA | regions. |           |
|     |    |          |           | 40),     |          |           |
|     |    |          |           | b        |          |           |
|     |    |          |           | ilateral |          |           |
|     |    |          |           | p        |          |           |
|     |    |          |           | osterior |          |           |
|     |    |          |           | ci       |          |           |
|     |    |          |           | ngulated |          |           |
|     |    |          |           | gyrus    |          |           |
|     |    |          |           | (BA 31), |          |           |
|     |    |          |           | b        |          |           |
|     |    |          |           | ilateral |          |           |
|     |    |          |           | pr       |          |           |
|     |    |          |           | ecuneues |          |           |
|     |    |          |           | (BA 7),  |          |           |
|     |    |          |           | right    |          |           |
|     |    |          |           | superior |          |           |
|     |    |          |           | temporal |          |           |
|     |    |          |           | gyrus    |          |           |
|     |    |          |           | (BA 22), |          |           |
|     |    |          |           | and the  |          |           |
|     |    |          |           | b        |          |           |
|     |    |          |           | ilateral |          |           |
|     |    |          |           | cortex   |          |           |
|     |    |          |           | (BA18)   |          |           |
|     |    |          |           | in ADHD. |          |           |
+-----+----+----------+-----------+----------+----------+-----------+
| B   | FM | 8 adults | The       | No       | The      | Suggests  |
| ush | RI | with     | counting  | ac       | ACcd,    | ACcd      |
| et  | st | ADHD     | Stroop, a | tivation | pr       | hyp       |
| a   | ud |          | Stroop    | in the   | eviously | oactivity |
| l., | y. | 8 normal | variant,  | c        | shown to | during    |
| 1   |    | controls | was used  | ingulate | play a   | at        |
| 999 |    |          | to        | cortex   | central  | tentional |
|     |    | age      | examine   | of the   | role in  | tasks may |
|     |    | 22-47.   | the       | ADHD     | att      | be a      |
|     |    | **All 8  | f         | group.   | entional | chara     |
|     |    | ADHD     | unctional |          | pro      | cteristic |
|     |    | subjects | integrity |          | cessing, | of adults |
|     |    | had been | of the    |          | was not  | with ADHD |
|     |    | exposed  | anterior  |          | a        | when      |
|     |    | to ADHD  | cingulate |          | ctivated | compared  |
|     |    | medi     | cognitive |          | by       | with      |
|     |    | cations. | division  |          | adults   | controls. |
|     |    | 3/8 ADHD | (ACcd) in |          | with     |           |
|     |    | subjects | adults    |          | ADHD.    |           |
|     |    | were     | with      |          |          |           |
|     |    | unm      | ADHD.     |          | Not      |           |
|     |    | edicated |           |          | caused   |           |
|     |    | for \>=3 |           |          | by poor  |           |
|     |    | months   |           |          | neuronal |           |
|     |    | prior to |           |          | respons  |           |
|     |    | scanning |           |          | iveness. |           |
|     |    | and the  |           |          |          |           |
|     |    | r        |           |          |          |           |
|     |    | emaining |           |          |          |           |
|     |    | 5        |           |          |          |           |
|     |    | patients |           |          |          |           |
|     |    | u        |           |          |          |           |
|     |    | nderwent |           |          |          |           |
|     |    | a 5      |           |          |          |           |
|     |    | h        |           |          |          |           |
|     |    | alf-life |           |          |          |           |
|     |    | me       |           |          |          |           |
|     |    | dication |           |          |          |           |
|     |    | wash-out |           |          |          |           |
|     |    | period   |           |          |          |           |
|     |    | prior to |           |          |          |           |
|     |    | sca      |           |          |          |           |
|     |    | nning.** |           |          |          |           |
+-----+----+----------+-----------+----------+----------+-----------+
| Ru  | FM | 7 males  | Brain     | ↓ power  | ↓ power  | ADHD may  |
| bia | RI | w/ ADHD  | a         | of       | of       | be        |
| et  | st |          | ctivation | response | response | a         |
| a   | ud | 9 normal | was       | in right | in right | ssociated |
| l., | y. | controls | compared  | mesial   | mesial   | with      |
| 1   |    |          | while     | pr       | pr       | subnormal |
| 999 |    | aged     | p         | efrontal | efrontal | a         |
|     |    | 12-18    | erforming | cortex,  | cortex   | ctivation |
|     |    |          | two       | right    | during   | of the    |
|     |    | The ADHD | tasks.    | inferior | both     | p         |
|     |    | subjects | The stop  | pr       | tasks    | refrontal |
|     |    | were     | task      | efrontal | and in   | systems   |
|     |    | either   | required  | cortex,  | right    | which are |
|     |    | **unm    | i         | and left | inferior | re        |
|     |    | edicated | nhibition | caudate  | pr       | sponsible |
|     |    | or       | of a      | in ADHD  | efrontal | for       |
|     |    | me       | planned   | s        | cortex   | hig       |
|     |    | dication | motor     | ubjects. | and left | her-order |
|     |    | free for | response, |          | caudate  | motor     |
|     |    | 1 week   | and the   |          | during   | control.  |
|     |    | prior to | motor     |          | the stop |           |
|     |    | te       | timing    |          | task.    |           |
|     |    | sting**. | task      |          |          |           |
|     |    |          | required  |          |          |           |
|     |    |          | timing of |          |          |           |
|     |    |          | a motor   |          |          |           |
|     |    |          | response  |          |          |           |
|     |    |          | to a      |          |          |           |
|     |    |          | sensory   |          |          |           |
|     |    |          | cue.      |          |          |           |
+-----+----+----------+-----------+----------+----------+-----------+

Appendix Ic: Studies without Psychostimulants that Indicate a
Dopaminergic Role in ADHD

+----+------+------------+-------+-------+--------------+------------+
| A  | S    | Sample     | M     | Locus | Pertinent    | Comment    |
| ut | tudy |            | ethod |       | Results      |            |
| ho | Type |            |       |       |              |            |
| rs |      |            |       |       |              |            |
+----+------+------------+-------+-------+--------------+------------+
| B  | PET  | 6 adults   | A     | ↑ DAT | 30% ↑ in DAT | DAT        |
| on | scan | w/ ADHD    | re    | bi    | density in   | binding is |
| ab | u    |            | sting | nding | left         | higher in  |
| et | sing | 6 healthy  | PET   | pote  | striatum &   | ADHD;      |
| al | ^11^ | volunteers | scan. | ntial | 28% ↑ in DAT | c          |
| ., | C-Al |            |       | in    | density in   | ontradicts |
| 20 | trop |            |       | left  | right        | Volkow et  |
| 03 | ane. |            |       | &     | striatum in  | al., 2003, |
|    |      |            |       | right | ADHD         | see        |
|    |      |            |       | str   | patients     | appendix   |
|    |      |            |       | iatum | compared     | Id.        |
|    |      |            |       | in    | with         |            |
|    |      |            |       | ADHD  | controls.    |            |
|    |      |            |       | pati  |              |            |
|    |      |            |       | ents. |              |            |
+----+------+------------+-------+-------+--------------+------------+
| C  | \[1  | 9 children | A     | ↑ DAT | ↑            | Drug-naïve |
| he | 23I\ | with ADHD  | re    | bi    | specific/    | children   |
| on | ]IPT |            | sting | nding | non-specific | with ADHD  |
| et | SPET | 6 normal   | SPET  | in    | DAT binding  | appear to  |
| a  | scan | children   | s     | basal | ratio in     | exhibit a  |
| l, | to   |            | tudy. | ga    | basal        | complex    |
| 20 | s    | age 7-13   |       | nglia | ganglia in   | dys        |
| 02 | tudy |            |       | in    | ADHD.        | regulation |
|    | DAT  | Children   |       | chi   |              | of the     |
|    | den  | with ADHD  |       | ldren | No           | do         |
|    | sity | **had      |       | w/    | significant  | paminergic |
|    |      | never been |       | ADHD. | correlation  | neurot     |
|    |      | exposed to |       |       | between      | ransmitter |
|    |      | psychosti  |       |       | severity of  | system.    |
|    |      | mulants**. |       |       | scores of    |            |
|    |      |            |       |       | ADHD         |            |
|    |      |            |       |       | symptoms &   |            |
|    |      |            |       |       | specific/    |            |
|    |      |            |       |       | non-specific |            |
|    |      |            |       |       | DAT binding. |            |
+----+------+------------+-------+-------+--------------+------------+
| V  | S    | 9 ADHD     | A     | DAT   | Striatal     | Con        |
| an | PECT | patients   | re    | bi    | \[^          | tradictory |
| Dy | ima  |            | sting | nding | 123^I\]β-CIT | to other   |
| ck | ging | 9 healthy  | SPECT | n the | binding did  | studies,   |
| et | u    | controls   | study | stri  | not differ   | no         |
| al | sing |            |       | atum, | s            | d          |
| ., | \[^1 | age 25-57  |       | die   | ignificantly | ifferences |
| 20 | 23^I |            |       | nceph | between the  | were found |
| 02 | \]2β | **8        |       | alon, | ADHD and     | in DAT     |
|    | -car | patients   |       | or    | comparison   | levels.    |
|    | boxy | were       |       | brain | subjects.    |            |
|    | meth | stimulant  |       | stem, |              |            |
|    | oxy- | naïve,     |       | did   |              |            |
|    | 3β-( | while one  |       | not   |              |            |
|    | 4-io | had not    |       | d     |              |            |
|    | doph | received   |       | iffer |              |            |
|    | enyl | stimulants |       | be    |              |            |
|    | )tro | for 14     |       | tween |              |            |
|    | pane | years**.   |       | the   |              |            |
|    | (    |            |       | two   |              |            |
|    | \[^1 |            |       | gr    |              |            |
|    | 23^I |            |       | oups. |              |            |
|    | \]β- |            |       |       |              |            |
|    | CIT) |            |       |       |              |            |
+----+------+------------+-------+-------+--------------+------------+
| D  | S    | 6 adults   | A     | ↑ DAT | I            | SPECT      |
| ou | PECT | w/ ADHD    | re    | de    | ndependently | could be   |
| gh | im   |            | sting | nsity | of age, DAT  | expanded   |
| er | ages | 30 healthy | SPECT | in    | density ↑    | to         |
| ty | a    | controls   | study | the   | 70% in       | ind        |
| et | fter |            |       | str   | patients w/  | ividualize |
| al | i    | age 21-51  |       | iatum | ADHD.        | treatment  |
| ., | njec | yrs.       |       | in    |              | with       |
| 20 | tion |            |       | a     |              | psych      |
| 00 | of   |            |       | dults |              | ostimulant |
|    | 5-7  |            |       | w/    |              | drugs, to  |
|    | mCi  |            |       | ADHD. |              | evaluate   |
|    | of   |            |       |       |              | new drugs  |
|    | ^1   |            |       |       |              | for        |
|    | 23^I |            |       |       |              | treating   |
|    | al   |            |       |       |              | ADHD, and  |
|    | trop |            |       |       |              | to clarify |
|    | ane. |            |       |       |              | the        |
|    |      |            |       |       |              | patho      |
|    |      |            |       |       |              | physiology |
|    |      |            |       |       |              | of ADHD    |
|    |      |            |       |       |              | and the    |
|    |      |            |       |       |              | mechanisms |
|    |      |            |       |       |              | of action  |
|    |      |            |       |       |              | of         |
|    |      |            |       |       |              | antihyp    |
|    |      |            |       |       |              | eractivity |
|    |      |            |       |       |              | meds.      |
+----+------+------------+-------+-------+--------------+------------+
| E  | PET  | 10         | A 2   | ↑     | Accumulation | Suggests   |
| rn | and  | children   | hr    | \     | of           | an         |
| st | the  | with ADHD  | \[    | [18F\ | \[18F\]DOPA  | a          |
| et | tr   | 10 healthy | F18\] | ]DOPA | in the right | bnormality |
| a  | acer | controls   | FDOPA | in    | midbrain was | in the     |
| l, | \[   |            | PET   | right | higher by    | dopamine   |
| 19 | 18F\ | age 12-17  | ses   | mid   | 48% in the   | pathway of |
| 99 | ]flu |            | sion. | brain | children     | children   |
|    | orod | All        | \[F   | in    | with ADHD    | with ADHD. |
|    | opa. | comparison | 18\]F | chi   | than in the  | Results    |
|    |      | children   | DOPA, | ldren | controls.    | are        |
|    |      | had a      | an    | w/    | This was not | weakened   |
|    |      | sibling    | a     | ADHD  | s            | by the     |
|    |      | with ADHD, | nalog | and   | tatistically | fact that  |
|    |      | except for | of    | corre | significant, | there is   |
|    |      | one child  | DOPA, | lated | but did      | no         |
|    |      | who had a  | is    | with  | correlate    | s          |
|    |      | sibling    | t     | sy    | with symptom | tatistical |
|    |      | with a     | ransp | mptom | severity.    | sig        |
|    |      | diagnosis  | orted | seve  |              | nificance. |
|    |      | of autism. | into  | rity. |              |            |
|    |      | **Subjects | p     |       |              |            |
|    |      | were       | resyn |       |              |            |
|    |      | medic      | aptic |       |              |            |
|    |      | ation-free | ne    |       |              |            |
|    |      | for at     | urons |       |              |            |
|    |      | least 2    | where |       |              |            |
|    |      | wks prior  | it is |       |              |            |
|    |      | to         | conv  |       |              |            |
|    |      | scanning.  | erted |       |              |            |
|    |      | 8/10 ADHD  | by    |       |              |            |
|    |      | children   | DOPA  |       |              |            |
|    |      | had a      | dec   |       |              |            |
|    |      | history of | arbox |       |              |            |
|    |      | stimulant  | ylase |       |              |            |
|    |      | medication | to    |       |              |            |
|    |      | use.**     | \[    |       |              |            |
|    |      |            | F18\] |       |              |            |
|    |      |            | FDOPA |       |              |            |
|    |      |            | &     |       |              |            |
|    |      |            | kept  |       |              |            |
|    |      |            | in    |       |              |            |
|    |      |            | vesi  |       |              |            |
|    |      |            | cles. |       |              |            |
+----+------+------------+-------+-------+--------------+------------+
| E  | PET  | 17 adults  | A 2   | ↓     | Low DOPA     | The        |
| rn | and  | with ADHD  | hr    | F18-r | d            | prefrontal |
| st | the  |            | \[    | atios | ecarboxylase | do         |
| et | tr   | 23 control | F18\] | in    | activity in  | paminergic |
| a  | acer | adults     | FDOPA | ADHD  | prefrontal   | deficits   |
| l, | \    |            | PET   | in    | cortex       | in ADHD    |
| 19 | [18F | age 23-45  | se    | m     | reflects a   | adults may |
| 98 | \]fl | yrs        | ssion | edial | reduction in | not be the |
|    | uoro |            | was   | &     | the activity | primary    |
|    | dopa | **Only 4   | used. | left  | of the       | pa         |
|    |      | of the     |       | prefr | enzyme,      | thological |
|    |      | ADHD       |       | ontal | either       | defect but |
|    |      | volunteers |       | a     | *st          | rather     |
|    |      | had ever   |       | reas. | ructurally*, | result     |
|    |      | been       |       |       | i.e.,        | from an    |
|    |      | treated    |       |       | decreased    | i          |
|    |      | with       |       |       | number of    | nteraction |
|    |      | s          |       |       | synapses, or | of the     |
|    |      | timulants. |       |       | *fu          | primary    |
|    |      | None were  |       |       | nctionally*, | neural     |
|    |      | receiving  |       |       | i.e.,        | deficit    |
|    |      | treatment  |       |       | inhibition   | with       |
|    |      | at the     |       |       | of the       | maturation |
|    |      | time of    |       |       | enzymatic    | and aging  |
|    |      | the        |       |       | activity     | processes  |
|    |      | study.**   |       |       | (decreased   |            |
|    |      |            |       |       | c            |            |
|    |      |            |       |       | oncentration |            |
|    |      |            |       |       | or           |            |
|    |      |            |       |       | affinity).   |            |
+----+------+------------+-------+-------+--------------+------------+

Appendix Id: Studies that Show Central Effects of Psychostimulants

+---+---------+--------+----------+--------+--------------+----------+
| A | Study   | Sample | Method   | Locus  | Pertinent    | Comment  |
| u | Type    |        |          |        | Results      |          |
| t |         |        |          |        |              |          |
| h |         |        |          |        |              |          |
| o |         |        |          |        |              |          |
| r |         |        |          |        |              |          |
| s |         |        |          |        |              |          |
+---+---------+--------+----------+--------+--------------+----------+
| V | SPECT   | 7      | PET scan | ↓ MPH  | ↓ baseline   | Lower    |
| o | imaging | nev    | with &   | i      | DAT measures | baseline |
| l | using   | er-med | w/o 0.5  | nduced | in striatum  | DAT      |
| k | \[^11   | icated | mg/kg of | DA     | in ADHD.     | levels   |
| o | ^C\]rac | adults | MPH.     | c      |              | in ADHD  |
| w | lopride | w/     |          | hanges | Baseline DAT | con      |
| e |         | ADHD   |          | in     | measures     | tradicts |
| t |         |        |          | ADHD   | negatively   | other    |
| a |         | 7      |          | co     | correlated   | studies  |
| l |         | h      |          | mpared | w/           | (see     |
| . |         | ealthy |          | w/     | MPH-induced  | Appendix |
| , |         | co     |          | con    | DA changes   | Ic).     |
| 2 |         | ntrols |          | trols. | in ADHD but  |          |
| 0 |         |        |          |        | not in       |          |
| 0 |         | age    |          | ↓      | controls.    |          |
| 3 |         | 21-38  |          | ba     |              |          |
|   |         |        |          | seline |              |          |
|   |         |        |          | DAT    |              |          |
|   |         |        |          | me     |              |          |
|   |         |        |          | asures |              |          |
|   |         |        |          | in     |              |          |
|   |         |        |          | st     |              |          |
|   |         |        |          | riatum |              |          |
|   |         |        |          | in     |              |          |
|   |         |        |          | ADHD.  |              |          |
+---+---------+--------+----------+--------+--------------+----------+
| V | SPECT   | 6 boys | DAT      | Left   | MPH          | Although |
| l | imaging | with   | levels   | -right | treatment    | no       |
| e | using   | ADHD   | and D2   | asy    | resulted in  | control  |
| s | 123I-Io |        | receptor | mmetry | a            | group,   |
| e | flupane | age    | i        | (R     | dow          | this is  |
| t | to      | 6-10   | ntegrity | i\>Le) | n-regulation | an       |
| a | measure | yrs    | were     | in DAT | of the       | i        |
| l | DAT     |        | measured | ac     | p            | mportant |
| . | levels  | **No   | using a  | tivity | ost-synaptic | study    |
| , | and     | c      | SPECT    | in the | dopamine     | because  |
| 2 | post-s  | urrent | scan     | c      | receptor     | dr       |
| 0 | ynaptic | or     | prior to | audate | with a       | ug-naïve |
| 0 | D2-r    | pr     | any      | nu     | maximum of   | children |
| 3 | eceptor | evious | med      | cleus, | 20% and a    | are      |
|   | in      | pha    | ication. | not    | dow          | e        |
|   | tegrity | rmacol | After    | found  | n-regulation | valuated |
|   |         | ogical | baseline | in the | of the DAT   | in a     |
|   |         | treatm | SPECT    | p      | with a       | baseline |
|   |         | ent**. | studies, | utamen | maximum of   | reading, |
|   |         |        | the boys | in the | 74.7% in the | then     |
|   |         |        | received | drug   | striatal     | treated  |
|   |         |        | MPH at   | -naïve | system.      | with MPH |
|   |         |        | 0.25-0.6 | boys.  |              | for a    |
|   |         |        | mg       | DAT    |              | long     |
|   |         |        | /kg/day. | d      |              | period   |
|   |         |        | After    | ensity |              | of time  |
|   |         |        | 3-4      | in     |              | (3-4     |
|   |         |        | months   | crease |              | months), |
|   |         |        | SPECT    | in     |              | and then |
|   |         |        | studies  | basal  |              | re-ev    |
|   |         |        | were     | ga     |              | aluated. |
|   |         |        | r        | nglia. |              |          |
|   |         |        | epeated. |        |              |          |
|   |         |        |          | D2     |              |          |
|   |         |        |          | dow    |              |          |
|   |         |        |          | n-regu |              |          |
|   |         |        |          | lation |              |          |
|   |         |        |          | after  |              |          |
|   |         |        |          | trea   |              |          |
|   |         |        |          | tment. |              |          |
+---+---------+--------+----------+--------+--------------+----------+
| V | PET and | 11     | Subjects | ↑ DA   | ↑            | Dopamine |
| o | \[^11   | male   | had two  | in     | e            | pathway  |
| l | ^C\]rac | h      | scans;   | st     | xtracellular | study.   |
| k | lopride | ealthy | the      | riatum | DA in        | Sin      |
| o | (D2     | su     | first    | (pu    | striatum by  | gle-dose |
| w | r       | bjects | was      | tamen) | blockade of  | MPH in   |
| e | eceptor |        | p        | after  | DAT after    | adults.  |
| t | radi    | age    | erformed | MPH    | MPH.         | MPH      |
| a | oligand | 23-37  | 60 min   |        |              | signi    |
| l | that    | yrs    | after    |        | ↑ of weak DA | ficantly |
| . | c       |        | placebo  |        | signals in   | i        |
| 2 | ompetes | **None | and the  |        | subjects w/  | ncreased |
| 0 | with    | of the | second   |        | ADHD by MPH  | DA in    |
| 0 | end     | su     | was      |        | may enhance  | brain.   |
| 1 | ogenous | bjects | p        |        | t            | Suggests |
|   | DA for  | were   | erformed |        | ask-specific | role of  |
|   | binding | taking | 60 min   |        | signaling,   | MPH in   |
|   | to the  | medi   | after 60 |        | improving    | all      |
|   | re      | cation | mg of    |        | attention &  | eviating |
|   | ceptor) | at the | oral     |        | decreasing   | ADHD     |
|   |         | time   | MPH.     |        | dist         | s        |
|   |         | of the | Subjects |        | ractibility; | ymptoms. |
|   |         | st     | were     |        | OR           | Only     |
|   |         | udy**. | blind to |        | MPH-induced  | healthy  |
|   |         |        | whether  |        | ↑ in DA may  | s        |
|   |         |        | placebo  |        | enhance the  | ubjects. |
|   |         |        | or oral  |        | salience of  |          |
|   |         |        | MPH had  |        | a task,      |          |
|   |         |        | been     |        | facilitating |          |
|   |         |        | admin    |        | the          |          |
|   |         |        | istered. |        | "interest    |          |
|   |         |        |          |        | that it      |          |
|   |         |        |          |        | elicits" and |          |
|   |         |        |          |        | thereby      |          |
|   |         |        |          |        | improving    |          |
|   |         |        |          |        | performance. |          |
+---+---------+--------+----------+--------+--------------+----------+
| D | \[9     | 17     | SPET     | ↑ DAT  | ↑ binding of | Provides |
| r | 9mTc\]T | *      | scan     | b      | \[99m        | further  |
| e | RODAT-1 | *untre | before   | inding | Tc\]TRODAT-1 | evidence |
| s | SPET    | ated** | and      | in     | to the DAT   | for the  |
| e | scan    | pa     | after    | str    | in untreated | role of  |
| l |         | tients | the      | iatum, | ADHD         | the      |
| e |         | w/     | in       | c      | patients.    | dopa     |
| t |         | ADHD   | itiation | audate | Under MPH    | minergic |
| a |         |        | of MPH   | nu     | treatment,   | system   |
| l |         | 14     | t        | cleus, | specific     | in ADHD. |
| . |         | h      | reatment | &      | binding      |          |
| , |         | ealthy | (3\*5    | p      | decreased    |          |
| 2 |         | co     | mg/ day) | utamen | s            |          |
| 0 |         | ntrols | for 4    | in     | ignificantly |          |
| 0 |         |        | wks.     | ADHD.  | in all       |          |
| 0 |         | age    |          | After  | patients.    |          |
|   |         | 21-64  |          | MPH    | May explain  |          |
|   |         | yrs    |          | trea   | complex      |          |
|   |         |        |          | tment, | d            |          |
|   |         |        |          | DAT    | ysregulation |          |
|   |         |        |          | b      | of the       |          |
|   |         |        |          | inding | dopaminergic |          |
|   |         |        |          | levels | system in    |          |
|   |         |        |          | ↓ in   | ADHD         |          |
|   |         |        |          | all 3  | patients and |          |
|   |         |        |          | areas. | the effects  |          |
|   |         |        |          |        | of           |          |
|   |         |        |          |        | psychoactive |          |
|   |         |        |          |        | drugs.       |          |
+---+---------+--------+----------+--------+--------------+----------+
| K | \[9     | 10     | SPECT    | ↑ DAT  | ↑ specific   | First    |
| r | 9mTc\]T | *      | scan     | d      | binding to   | study to |
| a | RODAT-1 | *untre | before   | ensity | the DAT at   | show     |
| u | SPECT   | ated** | and      | in     | baseline in  | that MPH |
| s | scan    | pa     | after    | st     | subjects w/  | lowers   |
| e |         | tients | the      | riatum | ADHD. After  | i        |
| e |         | ) w/   | in       | (basal | MPH          | ncreased |
| t |         | ADHD   | itiation | ga     | treatment,   | striatal |
| a |         |        | of MPH   | nglia) | specific     | DAT      |
| l |         | 10     | t        | of     | binding of   | avai     |
| . |         | h      | reatment | pa     | Tc-          | lability |
| , |         | ealthy | (3\*5    | tients | 99m-TRODAT-1 | in       |
| 2 |         | co     | mg/ day) | with   | to the DAT ↓ | adults   |
| 0 |         | ntrols | for 4    | ADHD   | in all       | with     |
| 0 |         |        | wks.     | than   | patients.    | ADHD.    |
| 0 |         | Age    |          | of     |              |          |
|   |         | 21-63  |          | con    |              |          |
|   |         | yrs    |          | trols. |              |          |
+---+---------+--------+----------+--------+--------------+----------+

Appendix Ie: Imaging Studies that Examine Central Effects of Stimulant
Medication in ADHD

+----+------+-----------+-----------------+-----+------------+-------+
| Au | S    | Sample    | Method          | Lo  | Relevant   | Co    |
| th | tudy |           |                 | cus | Results    | mment |
| or | Type |           |                 |     |            |       |
| &  |      |           |                 |     |            |       |
| da |      |           |                 |     |            |       |
| te |      |           |                 |     |            |       |
+----+------+-----------+-----------------+-----+------------+-------+
| Sc | PET  | 10 men w/ | MPH dose of 0.5 | ↓   | M          | **No  |
| hw | \    | ADHD      | mg/kg/day 1^st^ | in  | PH-related | he    |
| ei | [^15 |           | wk, 0.75        | r   | changes    | althy |
| tz | ^O\] | Age 23-39 | mg/kg/day for   | CBF | were       | co    |
| er | H~2~ | yrs       | 2^nd^ wk, & up  | bi  | associated | ntrol |
| et | s    |           | to 1.0          | lat | with a ↓   | gro   |
| al | cans | **4       | mg/kg/day for   | era | in rCBF in | up.** |
| ., | used | subjects  | 3^rd^ wk, until | lly | brain      |       |
| 20 | to   | had prior | optimal dose    | in  | areas      | MPH   |
| 03 | mea  | history   | found, barring  | the | related to | ap    |
|    | sure | of MPH    | adverse side    | p   | motor      | pears |
|    | regi | me        | effects. Ave.   | rec | p          | to    |
|    | onal | dication; | dose 19 mg TID. | ent | reparation | mod   |
|    | cere | 2 as      | MPH ingested 60 | ral | and        | ulate |
|    | bral | children  | mins before     | gy  | action,    | brain |
|    | b    | and 2 as  | scan.           | ri, | including  | re    |
|    | lood | adults.   |                 | in  | b          | gions |
|    | flow | Two had   |                 | the | ilaterally | assoc |
|    | (r   | been      |                 | l   | in the     | iated |
|    | CBF) | stimulant |                 | eft | precentral | w/    |
|    |      | free for  |                 | c   | gyri, in   | motor |
|    |      | approx.   |                 | aud | the left   | fun   |
|    |      | 10 yrs,   |                 | ate | caudate    | ction |
|    |      | one adult |                 | nu  | nucleus,   | to    |
|    |      | had been  |                 | cle | and in the | ac    |
|    |      | stimulant |                 | us, | right      | hieve |
|    |      | free for  |                 | and | claustrum. | redu  |
|    |      | several   |                 | in  | Chronic    | ction |
|    |      | months    |                 | the | MPH        | in    |
|    |      | while the |                 | ri  | admi       | ADHD  |
|    |      | other had |                 | ght | nistration | symp  |
|    |      | been      |                 | c   | ↑ rCBF in  | toms. |
|    |      | stimulant |                 | lau | cerebellar |       |
|    |      | free for  |                 | str | vermis.    |       |
|    |      | 8 days    |                 | um, | The degree |       |
|    |      | before    |                 | & ↑ | of change  |       |
|    |      | the       |                 | in  | in ADHD    |       |
|    |      | off-m     |                 | cre | symptom    |       |
|    |      | edication |                 | ase | ratings    |       |
|    |      | scan was  |                 | in  | between    |       |
|    |      | col       |                 | r   | off and    |       |
|    |      | lected**. |                 | CBF | on-        |       |
|    |      |           |                 | in  | medication |       |
|    |      |           |                 | the | states was |       |
|    |      |           |                 | c   | negatively |       |
|    |      |           |                 | ere | correlated |       |
|    |      |           |                 | bel | with rCBF  |       |
|    |      |           |                 | lar | increases  |       |
|    |      |           |                 | ver | in the     |       |
|    |      |           |                 | mis | midbrain,  |       |
|    |      |           |                 | af  | cerebellar |       |
|    |      |           |                 | ter | vermis,    |       |
|    |      |           |                 | MPH | and the    |       |
|    |      |           |                 | t   | precentral |       |
|    |      |           |                 | rea | and middle |       |
|    |      |           |                 | tme | frontal    |       |
|    |      |           |                 | nt. | gyri in    |       |
|    |      |           |                 |     | the        |       |
|    |      |           |                 |     | off-MPH    |       |
|    |      |           |                 |     | condition. |       |
+----+------+-----------+-----------------+-----+------------+-------+
| K  | 99T  | 32 male,  | Various         | ↑   | ↑ rCBF in  | Exa   |
| im | c-HM | never-m   | questionnaires, | per | left &     | mines |
| et | PAO- | edicated, | a psychometric  | fus | right      | how   |
| al | S    | ADHD      | test, &         | ion | prefrontal | never |
| ., | PECT | patients  | neu             | in  | areas &    | -medi |
| 20 |      |           | ropsychological | c   | caudate &  | cated |
| 01 |      | aged 7-14 | battery applied | aud | thalamic   | chi   |
|    |      |           | to the          | ate | areas post | ldren |
|    |      | **The     | drug-naïve      | nuc | MPH        | with  |
|    |      | subjects  | patients &      | lei | treatment, | ADHD  |
|    |      | had never | parents.        | &   | suggesting | react |
|    |      | been      | Patients then   | f   | that MPH   | to 8  |
|    |      | treated   | underwent SPECT | ron | affects    | wks   |
|    |      | with      | scan.           | tal | the        | of    |
|    |      | s         | Subsequently,   | lo  | function   | MPH   |
|    |      | timulants | patients        | bes | of the     | treat |
|    |      | or other  | received MPH    | af  | fro        | ment. |
|    |      | ps        | treatment for 8 | ter | nto-striat | **(no |
|    |      | ychiatric | wks, mean       | MPH | o-thalamic | co    |
|    |      | m         | dosage of 0.7   | t   | circuit,   | ntrol |
|    |      | edication | g/kg. Then      | rea | known to   | group |
|    |      | before.** | reevaluated w/  | tme | be the     | to    |
|    |      |           | a second        | nt. | pathop     | ex    |
|    |      |           | behavioral      |     | hysiologic | amine |
|    |      |           | assessment &    |     | site of    | if    |
|    |      |           | SPECT scan. MPH |     | ADHD.      | n     |
|    |      |           | administered 90 |     |            | ormal |
|    |      |           | mins before     |     |            | chi   |
|    |      |           | Tc-HMPAO        |     |            | ldren |
|    |      |           | injection.      |     |            | react |
|    |      |           |                 |     |            | in    |
|    |      |           |                 |     |            | the   |
|    |      |           |                 |     |            | same  |
|    |      |           |                 |     |            | way   |
|    |      |           |                 |     |            | and   |
|    |      |           |                 |     |            | chi   |
|    |      |           |                 |     |            | ldren |
|    |      |           |                 |     |            | who   |
|    |      |           |                 |     |            | d     |
|    |      |           |                 |     |            | idn't |
|    |      |           |                 |     |            | react |
|    |      |           |                 |     |            | to    |
|    |      |           |                 |     |            | the   |
|    |      |           |                 |     |            | stimu |
|    |      |           |                 |     |            | lants |
|    |      |           |                 |     |            | we    |
|    |      |           |                 |     |            | ren't |
|    |      |           |                 |     |            | i     |
|    |      |           |                 |     |            | nclud |
|    |      |           |                 |     |            | ed)** |
+----+------+-----------+-----------------+-----+------------+-------+
| Ma | PET  | 19 (age   | Baseline PET    | No  | No         | There |
| to | scan | 21-50     | scan. Subjects  | si  | s          | were  |
| ch | with | yrs)      | randomly put    | gni | ignificant | no    |
| ik | \[1  | subjects  | into daily      | fic | main       | r     |
| et | 8F\] | studied   | doses of        | ant | effect of  | obust |
| al | flu  | before    | d-amphetamine   | are | drug or    | meta  |
| ., | orod | and after | sulfate group   | as. | scan for   | bolic |
| 19 | eoxy | MPH       | or of           |     | global     | ef    |
| 94 | -glu | m         | methylphenidate |     | metabolism | fects |
|    | cose | edication | hydrochloride.  |     | or for any | of    |
|    | as a |           | Dose            |     | of 60      | stim  |
|    | tr   | 18        | individually    |     | regions of | ulant |
|    | acer | subjects  | titrated for    |     | interest.  | treat |
|    |      | (aged     | clinical        |     | Both drugs | ment. |
|    |      | 18-47     | effect.         |     | were       | This  |
|    |      | yrs)      | Starting dose   |     | associated | study |
|    |      | studied   | was 5 mg b.i.d. |     | w/         | did   |
|    |      | before    | for both MPH    |     | s          | not   |
|    |      | and after | and             |     | ignificant | have  |
|    |      | d-amp     | d-amphetamine & |     | i          | a     |
|    |      | hetamine. | dose was        |     | mprovement | co    |
|    |      |           | titrated within |     | in         | ntrol |
|    |      | All       | 3 wks to 5-25   |     | behavior.  | g     |
|    |      | subjects  | mg b.i.d. for   |     |            | roup. |
|    |      | were      | MPH and 5-15 mg |     |            |       |
|    |      | diagnosed | b.i.d. for      |     |            |       |
|    |      | with      | d-amphetamine.  |     |            |       |
|    |      | ADHD.     | 2^nd^ PET scan  |     |            |       |
|    |      | **The     | was obtained    |     |            |       |
|    |      | subjects  | after chronic   |     |            |       |
|    |      | took no   | stimulant       |     |            |       |
|    |      | m         | treatment was   |     |            |       |
|    |      | edication | 6-15 wks. On    |     |            |       |
|    |      | for at    | day of 2^nd^    |     |            |       |
|    |      | least one | scan, daily     |     |            |       |
|    |      | month     | dose            |     |            |       |
|    |      | before    | administered 90 |     |            |       |
|    |      | beginning | mins prior to   |     |            |       |
|    |      | the       | injection of    |     |            |       |
|    |      | study,    | glucose tracer. |     |            |       |
|    |      | and most  |                 |     |            |       |
|    |      | had never |                 |     |            |       |
|    |      | been      |                 |     |            |       |
|    |      | treated   |                 |     |            |       |
|    |      | w/        |                 |     |            |       |
|    |      | stim      |                 |     |            |       |
|    |      | ulants.** |                 |     |            |       |
+----+------+-----------+-----------------+-----+------------+-------+

Appendix Ie Continued: Studies that Examine the Underlying
Neurophysiology of Medication Effects on ADHD

+----+------+--------+----------------+---------+----------+---------+
| A  | S    | Sample | Method         | Locus   | P        | Comment |
| ut | tudy |        |                |         | ertinent |         |
| ho | Type |        |                |         | Results  |         |
| rs |      |        |                |         |          |         |
+----+------+--------+----------------+---------+----------+---------+
| L  | 9    | 22     | Each subject   | ↑ rCBF  | When     | I       |
| an | 9mTc | boys   | had imaging    | motor   | ADHD     | ndirect |
| gl | -eth | w/     | sessions 1-3   | cortex  | subjects | support |
| eb | ylcy | ADHD   | wk apart; one  | &       | were not | for     |
| en | stei |        | on MPH &       | p       | taking   | pre     |
| et | nate | 7      | another off    | remotor | MPH,     | frontos |
| al | di   | h      | MPH. On-MPH:   | cortex  | rCBF was | triatal |
| ., | mmer | ealthy | ADHD patients  | bilat   | higher   | dysf    |
| 20 | (    | volu   | received usual | erally; | in the   | unction |
| 02 | ECD) | nteers | prescribed     | in      | motor    | hyp     |
|    | S    |        | dose of MPH    | Bro     | cortex   | othesis |
|    | PECT | age    | (range, 10-30  | dmann's | and      | since   |
|    | s    | 8-11   | mg) 2 hr       | area    | premotor | both    |
|    | can. | yrs    | before the     | (BA) 4  | cortex   | motor   |
|    |      |        | imaging        | and 6;  | bila     | cortex  |
|    |      | ADHD   | session &      | & in    | terally; | and the |
|    |      | cand   | controls       | the     | in       | a       |
|    |      | idates | received       | a       | Br       | nterior |
|    |      | were   | single 10 mg   | nterior | odmann's | ci      |
|    |      | t      | dose. Off-MPH  | ci      | area     | ngulate |
|    |      | reated | scan: MPH      | ngulate | (BA) 4   | receive |
|    |      | with   | withheld for   | gyrus   | and 6;   | inh     |
|    |      | MPH    | 36 hr prior to | (BA 32) | and in   | ibitory |
|    |      | for an | the scan for   | in      | the      | pre     |
|    |      | a      | ADHD patients. | un      | anterior | frontos |
|    |      | verage | Subjects       | treated | c        | triatal |
|    |      | of 12  | completed      | ADHD    | ingulate | input.  |
|    |      | wk     | stimu          | s       | gyrus    | Study   |
|    |      | (range | lus-controlled | ubjects | (BA 32). | may     |
|    |      | 8-16   | version of the | as      | No       | have    |
|    |      | wk)    | "go/no-go"     | c       | dif      | been    |
|    |      | and    | task as in     | ompared | ferences | underp  |
|    |      | demons | Vaidya et al.  | to when | found in | owered. |
|    |      | trated |                | treated | the      |         |
|    |      | a      |                | w/ MPH. | control  |         |
|    |      | cl     |                |         | group.   |         |
|    |      | inical |                |         |          |         |
|    |      | res    |                |         |          |         |
|    |      | ponse. |                |         |          |         |
+----+------+--------+----------------+---------+----------+---------+
| Va | FMRI | 10     | Two go/no go   | ↑       | Improved | This is |
| id | s    | ch     | tasks with &   | s       | response | the     |
| ya | tudy | ildren | without MPH, 1 | triatal | in       | only    |
| et |      | w/     | wk apart, with | act     | hibition | study   |
| al |      | ADHD   | co             | ivation | in both  | that    |
| ., |      |        | unterbalancing | (head   | groups   | uses    |
| 19 |      | 6      | across         | of the  | on one   | fMRI to |
| 98 |      | h      | subjects.      | c       | task &   | inve    |
|    |      | ealthy | **On-MPH: ADHD | audate, | only in  | stigate |
|    |      | co     | took regularly | p       | ADHD     | r       |
|    |      | ntrols | prescribed     | utamen) | subjects | esponse |
|    |      |        | dose (range =  | in ADHD | on the   | to MPH  |
|    |      | age    | 7.5-30 mg) &   | s       | other.   | in      |
|    |      | 8-13   | controls took  | ubjects |          | *       |
|    |      | yrs    | 10 mg, 2-2.5   | while a | ↑        | *normal |
|    |      |        | hrs before     | ↓ in    | frontal  | chi     |
|    |      |        | scanning.      | c       | ac       | ldren** |
|    |      |        | Off-MPH: ADHD  | ontrols | tivation | as well |
|    |      |        | subjects went  | post    | equally  | as      |
|    |      |        | off meds for   | MPH     | in both  | c       |
|    |      |        | 36 hrs before  | tre     | groups,  | hildren |
|    |      |        | scanning.**    | atment. | but ↑    | with    |
|    |      |        |                | Without | striatal | ADHD.   |
|    |      |        |                | MPH,    | ac       |         |
|    |      |        |                | s       | tivation |         |
|    |      |        |                | triatal | in ADHD  |         |
|    |      |        |                | act     | while ↓  |         |
|    |      |        |                | ivation | in       |         |
|    |      |        |                | was ↑   | controls |         |
|    |      |        |                | in      | after    |         |
|    |      |        |                | c       | MPH.     |         |
|    |      |        |                | ontrols |          |         |
|    |      |        |                | than in |          |         |
|    |      |        |                | ADHD    |          |         |
|    |      |        |                | su      |          |         |
|    |      |        |                | bjects. |          |         |
+----+------+--------+----------------+---------+----------+---------+