DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

National Institute of Health National Institute of Mental Health

Intramural Research Program

10 Center Drive M.C. 1381

Bldg. 10, Room 4N-222

Bethesda, Maryland 20892

Date: September 8, 2003

From: Director, Intramural Research Program, NIMH

To:

Subject: New Protocol Entitled "Effects of Single Dose of
Dextroamphetamine in Attention Deficit Hyperactivity Disorder: A
Functional Magnetic Resonance Study"

Your new protocol entitled, "Effects of Single Dose of Dextroamphetamine
in Attention Deficit Hyperactivity Disorder: A Functional Magnetic
Resonance Study" has been reviewed by the CSRP and was approved for
submission to the IRB for review. Please address the attached comments
from the CSRP and submit to the IRB for review.

Robert Desimone, PhD

cc.: Dr. Rosenstein

Dr. Rubinow

Effects of single dose dextroamphetamine in ADHD: fMRI study P1:
Rapoport

This was an excellent protocol.

The overall aim of this study is to better understand the
pathophysiology of ADHD by evaluating the response to amphetamine in
ADHD kids. Specifically, whether the response is similar or different in
ADHD and normal children when performance is equated on a measure of
inhibitory control.

The sample will consist of 14 healthy children and adolescents (9-18
yrs. old), 14 ADHD, 12 pairs of dizygotic is concordant for ADHD, 12
pairs of monozygotyic twins disconcordant for ADHD. The design is a
double-blind, placebo-controlled challenge using a single dose for all
subjects --- 0.25 mg/kg amphetamine). Children currently receiving
psychostimulants will have a 36 hour wash-out period prior to the study.

Two fMRl experiments will provide the main dependent measures. Both
tasks are considered to be measures of inhibitory control and are
commonly used in the ADHD literature. One is a go: no-go paradigm that
has been used previously to study dextroamphetamine effects in fMRI,
thus allowing them to compare their results to previous findings. This
tests last approximately 5 minutes. The second procedure will use the
"stop task". The advantage of this task is that, unlike to go: no-go
task, performance is equated by titrating the timing of the stop signal
based on previous trials. This will allow for the critical, across group
comparison without the confound of performance differences. The analyses
of the brain imaging data will be based primarily on an ROl analysis
directed at the striatum and specific regions of prefrontal cortex.

This is a clearly described study. The design is appropriate and tasks
well motivated. We received 2 out-side reviews. One rated it as
outstanding, the other as excellent, although the numerical scores were
nearly identical, 1.4 and I .5. each had some questions and comments
that the investigators might want to think about.

At the meeting the Board members agreed that this was an excellent
submission. I trust that in addition to the ROl analysis, careful
attention will be paid to other brain regions (e.g., see reviewers

comments on the cerebellum). It also might be worth-while to consider
whether a task could be implemented that would allow for parametric
manipulation of difficulty in response inhibition to directly compare
performance curves and regional changes in the BOLD signal.

Perhaps more importantly, a number of questions and concerns were raised
that may be critical for the IRB approval. One issue concerns substance
abuse. Specifically, it might be necessary to describe your plan for
determining level of substance abuse and smoking in the children, how
these data might be used scientifically for data analysis, and whether
it is necessary to inform the parents. A second issue
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

was to provide a justification in the body of the protocol as to why the
study could not or should not be done in adults. Finally, on page 19
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

(Benefits of study participation) and in the consent and assent forms it
should state in the first sentence of the benefits section that the
study does not provide direct benefit to the subjects and the indirect
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

benefits should be toned down somewhat

Review of "Effects of Single Dose of Dextroamphetamine in Attention
Deficit Hyperactivity Disorder: A functional magnetic resonance study".

Investigator name:

1\) Does the protocol articulate a clear and testable question or
hypothesis?

The protocol sets forth three clearly formulated hypotheses. The
hypotheses are logically based on prior work in field. The hypotheses
are critical questions in the area of neuroimaging of ADHD. Even if the
hypotheses are refuted, the field will be substantially advanced.

2\) Will the experiments covered by the protocol allow the question
under study to be answered?

The experiments relate directly to the hypotheses. Four groups will be
compared:

unrelated ADHD children, dizygotic twins discordant for ADHD,
monozygotic twins discordant for ADHD, and healthy controls. Subjects
will undergo two functional M studies in a double blind placebo
controlled crossover trial of amphetamine. The Go/No Go and Stop Signal
task, well established measures of inhibitory control, will be performed
during the MRI. Drug X diagnosis X genetic relatedness interactions will
be examined for in the brain regions of interest. In summary, the
experiments are well designed and straightforward.

3\) The main purpose of this committee is to review the protocol for
scientific merit, not human subject concerns. However, if you have human
subject concerns that you believe should be brought to the attention of
our IRP, please indicate those here:

No concerns. The single dose amphetamine (.25 mg/kg dose) is well within
the clinical range and has been administered safely to controls in
previous studies. The MRI is without major medical risk.

4\) Please indicate below a category and a numerical priority score for
the work. Would you describe the experiment as: Outstanding 1.4

5\) In two pages or less, please provide specific comments or feedback
for the investigator.

The proposed study is of high significance. There is great public
interest in the matter of stimulant treatment of ADHD. Clarifying the
mechanisms of stimulant action would be

very helpful in dispelling myths about ADHD and its treatment, and would
be move us closer to understanding the pathophysiology of the disorder.

The study is innovative in that it combines techniques from both
genetics and neuroimaging. It will be the first study that directly
compares dizygotic and monozygotic twins on functional brain imaging
studies. This strategy has been useful in schizophrenia studies in
teasing out environmental and genetic factors on brain anatomy. There
are many strengths to the study: the diagnostic and neuropsychological
batteries are well designed and the inclusion and exclusion criteria are
logical. The sample should be quite representative of ADHD children in
the general population.

Use of the Go/No Go study is useful so that the results can be compared
to prior studies. The Stop Signal Task is also a very specific measure
of inhibitory control; the tracking version of the task will equate
performance and thus remove a possible confound.

The technical aspects of the FMRI appear appropriate. The investigators
are highly experienced in this area.

Only minor weaknesses are noted. There is no healthy twin group, so if
twins share some brain function differences compared to non-twins this
might be difficult to resolve. The investigators do not mention
perinatal history (prematurity, etc) as a factor and how it might be
more common in twins. They do not mention history of prior treatment as
a factor. Apparently treatment naïve subjects, those with a positive
response to stimulant in the past and those with a non-response to
stimulant will be included. This data should be gathered, for use as a
possible covariate in the analyses.

The sample is too small for any definitive genetic analysis, but will
provide a first look as to whether any ADHD genotype is related to the
imaging variables.

The tables in the appendix were most informative and would very useful
if published as a review paper. The investigators should consider this,
if they have not already done so.

New Protocol Review Investigator name:

1\) Does the protocol articulate a clear and testable question or
hypothesis?

Yes, the proposal is a very sound and logically based one to examine the
effects

of a single dose of dextroamphetamine in children and adolescents with
Attention

Deficit Hyperactivity Disorder using functional magnetic resonance
imaging

2\) Will the experiments covered by the protocol allow the question
under study to be answered?

Yes, the investigators have included both behavioral and functional
imaging assays that tap the relevant neural circuitry (basal ganglia and
prefrontal cortex), and that realistically relate to the symptoms of
this disorder (inattention and impulsivity). The proposed double blind,
placebo controlled design is appropriate and the inclusion of
monozygotic and dizygotic twins discordant for the disorder will help
constrain explanations of individual differences in response to
treatment.

3\) The main purpose of this committee is to review the protocol for
scientific merit, not human subject concerns. However, if you have human
subject concerns that you believe should be brought to the attention of
our IRP, please indicate those here:

There are no human subject concerns. The investigators are trained in
the methods proposed and with interacting with patient populations in
this context. Moreover, the findings may significantly impact,
diagnosis, treatment and intervention for these disorders.

4\) Please indicate below a category and a numerical priority score for
the

work.

I would rate the proposal 1.5.

5\) In two pages or less, please provide specific comments or feedback
for the investigator.

This is a very sound and logically based proposal to examine the effects
of a single dose of dextroamphetamine in children and adolescents with
Attention Deficit Hyperactivity Disorder using functional magnetic
resonance imaging. A few minor constructive comments for the
investigators follow:

The large age range of 9 to 18 year olds may confound the results of the
study in that there are developmental changes in the dopamine system
across these ages. The proposal may be strengthened if age were thus
treated as either a subject variable of interest and/or covariate in
explaining the response to the pharmacological challenge.

Performance differences between groups is a confound the investigators
raise in their review of the literature on functional imaging studies of
ADHD. The ability to equate behavioral performance was a strong basis
for the selection of the proposed tasks. Yet the go/nogo task proposed
does not allow for equation of performance across groups. Even if the
investigators only analyze correct trials, should the ADHD subjects make
several misses and false alarms, the degree of inhibitory control needed
to perform the task is diminished and therefore not comparable across
groups. A parametric design titrating task difficulty by varying the
number of go trials preceding a nogo trial may be a better task design
(see Durston et al., 2002 Dev Science; 2003 Bio Psychiatry)

The proposed studies target frontostriatal circuitry, but this group has
shown the most compelling differences between children with and without
ADHD in MRI based measures of the cerebellum. A number of manipulations
to the proposed tasks in manipulating the timing of a stimulus in the
go/nogo or stop signal task could effectively activatethis region. Yet,
this region is not discussed or included

as part of the region of interest analysis. The proposal would be
strengthened and most likely more informative if such manipulations and
analyses were done.

The appropriate citation for the go/nogo task they are using - developed
in the branch of the P1 and exported to the Stanford cite for the Vaidya
et al. study - is 1997J Cogn Neuro.

Overall this is a very strong proposal and the investigators are well
positioned with the technical skill and theoretical background to
successfully carry them to completion.