Correspondence with the Journal of the American Medical Association
(JAMA)
December 3, 2012
Dear Dr. Ishii-Takahashi:
Thank you for giving JAMA this opportunity to consider your manuscript, "Neuroimaging-aided
prediction of the effect of methylphenidate in children with attention deficit hyperactivity disorder." I
have been assigned to handle your manuscript.
Your manuscript will be reviewed by me and possibly by external peer reviewers. Every effort will be
made to expedite the review process and to notify you of our decision as soon as possible.
Please refer to the manuscript number in all subsequent communications. You may check the status of
this manuscript by selecting the Check Manuscript Status link on the following Web page:
Do not share this encrypted link with others, as it will automatically log you into your account for
JAMA's Web-based system.
Sincerely yours,
Jody W Zylke, MD
Senior Editor, JAMA
E-mail: Jody.Zylke@jamanetwork.org
Gwenn Gregg
Editorial Assistant, JAMA
E-mail: Gwenn.Gregg@jamanetwork.org
Phone: 312.464.5204
Fax: 866.422.4442
January 22, 2013
Dr. Ayaka Ishii-Takahashi
The University of Tokyo
1
7-3-1 Hongo
Bunkyoku
Tokyo 113-8655
Japan
RE: Neuroimaging-aided prediction of the effect of methylphenidate in children with attention deficit
hyperactivity disorder
Dear Dr. Ishii-Takahashi:
Thank you for submitting your manuscript to JAMA. Only about half of the approximately 6000
manuscripts submitted to us annually are sent for external review by experts and less than 9% are
published in JAMA. Your manuscript was sent for external peer review, which is now complete.
Based on our in-house evaluation and the comments of external reviewers, we will not pursue your
manuscript for publication. I am enclosing the reviewer comments, which I hope you will find helpful.
Thank you for the privilege of reviewing your work.
Sincerely yours,
Jody W Zylke, MD
Senior Editor, JAMA
E-mail: Jody.Zylke@jamanetwork.org
Comments from the reviewers of Journal of the American Medical Association
We have revised our manuscript based on the reviewers’ suggestions. Below, we provide our item-by-item
responses to these comments (reviewer comments are in italics and our responses are in roman font).
Reviewer #1:
(1)The authors performed a randomized, double-blinded, placebo-controlled crossover trial on the effects
of methylphenidate hydrochloride (MPH). However, the exact purpose of the present manuscript is
difficult to summarize because the authors stated and restated the purpose of their study differently in
several sections. In the abstract, the purpose was "to predict the clinical effect of continuous MPH
2
administration based on prefrontal oxygenated hemoglobin concentration change after a single
administration of MPH using near-infrared spectroscopy (NIRS)" (line 41-43). In the introduction, the
purpose was similar but not exactly the same: "develop an objective marker that predicts the efficacy of
continuous MPH administration for ADHD children using near-infrared spectroscopy" (lines 95-97). In
the methods the purpose morphed into "predict clinical effect of MPH assessed by Clinical Global
Impressions-Severity [...] using prefrontal activation during [a stop signal task]" (lines111-112). Was the
purpose to examine the utility of near-infrared spectroscopy in assessing uptake of MPH? Was the
purpose examining the short-term functional neurobiological effects of MPH? Was the purpose examining
the long-term effects of MPH in a 1-year follow-up?
Our aims are below:
We performed a regression analysis as a primary outcome to determine whether [oxy-Hb] at
baseline assessment or ∆[oxy-Hb] (single dose of MPH minus baseline assessment) could predict CGI-S
scores after a 4-to-8-week open trial. As secondary outcomes, we examined (1) whether a single dose of
MPH or placebo affected [oxy-Hb], and (2) whether there were differences in brain function among
NAÏVE, NON-NAÏVE, and HCs at the baseline assessment and during the 4-to-8-week open trial. As
ancillary outcomes, we examined (1) whether [oxy-Hb] at baseline assessment or ∆[oxy-Hb] (single dose
of MPH minus baseline assessment) predicted CGI-S scores after 1 year of MPH administration of MPH,
and (2) whether 1 year of MPH administration affected [oxy-Hb] after washout.
(2)The authors justified their sample size based on an "optimal design" (lines 140-141) for imaging
studies, but purposefully recruited drug naive and non-naive children without justifying the purpose of
these subgroups. Other than in the supplementary materials, I didn't find any other mention of these
subgroups, except for exclusions in some analyses that calls into question whether this study truly had the
sample size necessary for an "optimal" design.
We agree with the reviewer’s comment. One of our secondary aims was to detect the difference in brain
function between drug-naïve and treated groups. We also followed the drug-naïve group for 1-year to
detect changes in brain function, even after drug washout. The drug-naïve group contained 22 subjects,
which was optimal for the neuroimaging study design according to a previous study that showed 15–20
subjects per group appears acceptable.1 However, the non-naïve group contained 8 subjects.
(3) The analyses of the primary outcome were unclear. I didn't understand the "univariate" or the
"between" in the statement "univariate regression analysis was conducted between CGI-S after
continuous MPH administration (Part C) as a dependent variable and mean [oxy-Hb] change at
baseline...as independent variables" (line 200-202). It appears that the authors performed a multivariable
3
regression (one dependent measure and multiple independent variables).
We first performed a univariate regression analysis for each independent variable, which was followed by
a multivariable regression. However we changed analysis to only use a multivariable regression as you
suggested.
(4) It was unclear whether the "between" refers to CGI-S as one of the independent variables or whether
the analyses were stratified between groups defined by CGI-S (groups defined in lines 208-209).
Moreover, if these analyses were performed on changes then they should have a repeated term.
The analyses were stratified between groups defined by CGI-S scores. We used the t-test, not a
repeated-measures ANOVA, because we used the CGI-S score after the 4-8-week open trial, rather than
the amount of change in CGI-S scores between the baseline assessment and after the 4-to-8-week open
trial, as the independent valuable.
(5) The authors do not mention whether there was any attrition over the 1-year follow-up. They
appropriately performed analyses using intention-to-treat principles, which would follow naturally if
there were no patients lost to follow-up.
The intention-to-treat principles were approved for the 4-to-8-week open trial but not for the 1-year
follow-up. We added the following sentence: “Some limitations of our study should also be highlighted.
First, methodological limitations include the smaller number of participants for NON-NAÏVE (N=8), lack
of blindness in Phase 3, and non-negligible dropout rate (7 out of 21 NAÏVE) at the 1-year follow-up.”
Reviewer #2:
This is an interesting study that examines fMRI activation in relation to methylphenidate (MPH) treatment
at baseline, after single dose challenge, after an acute open titration, and after one year of treatment (in a
subgroup). Comments by section follow.
(6)Introduction:
The rationale for this study - to identify a biomarker that predicts response to MPH - seems at first glance
to be important as articulated. But, the potential clinical relevance requires further consideration when
one considers that the large majority of youth with ADHD respond at least in part to MPH (the paper
cites figures for response as being 70%, but this is more accurately the percentage of very good
4
responders), and there are really no disadvantages to trying the treatment. So, this in depth imaging
method is not a procedure that is likely to be used clinically to predict response. That said, it is important
to understand how MPH exerts its effects, and this study adds importantly to that literature. To my way of
thinking, the introduction should be re-shaped a bit to reflect these points.
Some side effects have been reported with continuous administration of MPH. We revised the
introduction section accordingly. Previous studies that predicted the response of MPH stated that
predicting responses in individual patients beyond medication status remains somewhat elusive, 2 and the
role of individualized medicine in clinical practice has become increasingly important.3 Non-responders
to MPH have no benefit or only adverse side effects during treatment with MPH.4,5 We deleted the
sentence, “Furthermore, MPH administration may cause serious side effects including growth
disturbances, sleep disorders, loss of appetite, and cardiovascular complications.”
We changed the explanation of study the aims in the introduction as follows:
The single-dose MPH administration phase used a randomized, double-blind, placebo-controlled,
crossover design, and the subsequent outcome was assessed in a 4-to-8-week open trial and 1-year
follow-up. To our knowledge, no previous study has followed patients for 1 year to predict the effect of
MPH using neuroimaging. We hypothesized that prefrontal activation at baseline assessment, or the
difference in NIRS signal between a single administration of MPH and the baseline assessment, would
predict clinical improvement after mid-term (4-to-8-week) and long-term (1-year) MPH treatment in
drug-naïve patients with ADHD. Notably, we divided children with ADHD into those who had not
received any medication (drug-naïve) and those who had received chronic treatment with MPH
(non-naïve) because the NIRS signals at baseline may be altered by previous MPH treatment.
Method:
(7) The structure of the trial into four parts (A-D as indicated here) is complex and hard to follow as
written. I think it would be easier to follow if the authors referred to each of the sections according to
what it was, rather than by the letter designation A - D.
We agree with the reviewer’s comment. We changed the descriptions as follows:
Part A → baseline assessment, Part B → single-dose trial, Part C → 4-to-8-week open-trial, and Part D →
1-year follow-up.
Sample:
(10) I do not see the relevance of recruiting previously treated subjects in a study aimed to predict
5
response. This approach loads the sample with positive responders and possibly could distort the imaging
findings. It also calls into question the adequacy of the washout, which would not have been an issue if
only medication naïve youth were studied.
We agree with reviewer’s opinion. Therefore, we detected the possibility of prediction only in the
drug-naïve ADHD group.
Longitudinal studies suggest that long-term medication may have an effect on both brain structure 6 and
function.7 One of the secondary aims of our study was to detect any differences in brain function between
the drug-naïve group and the group with a history of MPH use.
We examined NIRS signals in ADHD participants with a history of MPH use after they underwent a
washout period. Wash-out periods of 1 week,7 24 h,8,9 and 18 h10 have been used in previous studies. The
serum level of MPH peaks approximately 6–10 h after administration and becomes undetectable 48 h
after administration. Therefore, 1 week is an appropriate washout duration.
(11)The drop-out rate of > 50% after one year is not unexpected, but it does mean that the sample studied
at that point is biased in favor of good response and tolerability.
In the 1-year follow-up, 14 of the original 22 ADHD participants were followed (drop-out rate: 36%).
This cohort would be biased in favour of a good response and tolerability to MPH. We added the
following sentence to the limitations section of the revised manuscript: “This low retention rate could
have biased our finding toward a favourable response”.
Procedures:
(12) I am not sure if one week washout is sufficient to restore receptor function to what it would have been
pre-treatment (actually, I doubt it) - and this is the main reason for washout in a study using
neuroimaging. I note that the authors obtained scans at the 1 year post-treatment by taking children off
their medication for a week. So presumably, the medication effects on brain function might persist that
long.
We agree with the reviewer’s opinion. Longitudinal studies, however, suggest that long-term medication
may have an effect on both brain structure6 and function.7 One of the secondary aims of our study was to
detect the difference in brain function between the drug-naïve group and the group with a history of MPH
use. We examined NIRS signals in ADHD participants with a history of MPH use after they underwent a
washout period. Wash-out periods of 1 week,7 24 h,8,9 and 18 h10 have been used in previous studies. The
6
serum level of MPH peaks approximately 6–10 h after administration and becomes undetectable 48 h
after administration. Therefore, 1 week is an appropriate washout duration.
Our aim in the 1-year follow-up was (1) to assess differences between NAÏVE and HCs at the baseline
assessment and 1-year follow-up, (2) to examine whether the NIRS signal at baseline assessment predicts
CGI-S scores at the 1-year follow-up, or (3) whether the ∆NIRS signal (single dose of MPH minus
baseline assessment) predicts CGI-S scores at the 1-year follow-up.
(13) It is not clear what the titration approach was and I can't seem to locate it in the supplemental
section the text directs the reader to. Doses seem to be fairly low relative to what we are used to seeing in
the US. Perhaps a comment about this relative to possible international differences might be indicated.
In the Japanese clinical trial conducted by Janssen Pharmaceutical K.K., the mean dose of MPH, was 31 ±
9.8 mg (0.89 mg/kg).11 In a Korean study, the mean dose of MPH was 22 ± 13.1 mg (0.68 mg/kg).5 In our
study, the mean dose of MPH was 25.4 mg (0.91 mg/kg). Therefore, this dose is consistent with other
studies of MPH conducted in Asia. We added these points to the revised manuscript (Appendix 6).
The titration approach is included in the supplemental section (Appendix 5). The dose was determined
from the results of the controlled medication trials described below. MPH was titrated to the optimal
response from an initial dose of 18 mg. During titration, the dosage was increased by 9 mg at weekly
visits. The ADHD-RS and side effect rating scale were obtained weekly. A psychiatrist reviewed the data
obtained each week to determine the optimal MPH dose for each patient.
(14)Can I assume that "baseline changes" (line 169; page 10) refers to differences between the ADHD
youth and the healthy controls? Or perhaps changes in activation with one signal on the test vs. other
signals? This is not clear and of considerable importance.
The baseline [oxy-Hb] changes are based on the NIRS signal of the drug-naïve ADHD group at the
baseline assessment. We revised the sentence “prefrontal activation at baseline assessment, or the
difference in NIRS signal between a single administration of MPH and the baseline assessment, would
predict clinical improvement after mid-term (4-to-8-week) and long-term (1-year) MPH treatment in
drug-naïve patients with ADHD” in the revised manuscript.
Measures:
(15) I understand that the CGI-S, a categorical measure, was used at outcome to define groups of
7
responders and non-responders, to provide a basis for comparison. However, the conventional and most
appropriate approach to measure clinical symptom change is via the ADHD-RS or other validated scale.
CGI-S is most often used as a secondary measure. Further explanation is warranted.
The CGI provides an overall clinician-determined measure that takes into account information including
the patient’s history, psychosocial circumstances, symptoms, behavior, and whether the patient’s
symptoms affected their functioning.12 CGI-S is more pertinent to clinical decision-making than
symptomatic measures. Most of the neuroimaging studies we reviewed attempted to predict the efficacy
of MPH with the Clinical Global Impression Scale by measuring progress and assessing the response to
MPH.5, 13-15 Therefore, we chose the CGI score as a primary outcome assessment tool.
The reviewer makes a good point regarding the ADHD-RS. However, the ADHD-RS was translated into
Japanese in 2007 and has not been standardized in Japan. Therefore, we did not use the ADHD-RS as a
primary outcome measure.
We have added these points to Appendix 9 of the revised manuscript.
Analytic approach:
(16) The pre-post imaging design uses an open medication trial. In order to unbundle time and
medication-related effects, the authors contrast responders (CGI-S < 3) and non-responders (CGI-S > 4).
This approach provides a comparison that can be tested and utilizes all subjects, but it places no split
between the two groups. I would sooner see CGI < 2 to define the responder group, which would ensure a
split between the responders and non-responders. Of course, this approach would result in not being able
to use all the data collected (i.e., case with CGI-S = 3 after treatment).
We added the following sentence to Appendix 9 in the revised manuscript: “In a previous study, a
responder was defined as CGI-S score <3.16 A CGI-S score of 4 was defined as moderately ill—overt
symptoms causing noticeable, but modest, functional impairment or distress—a symptom level that may
warrant medication.12 Therefore, we defined CGI ≥4 as a poor response.”
Results:
(17) The NAÏVE group has minimal change in RIFC with treatment - with activation going somewhat
higher. In contrast, the HC and NON-NAÏVE have decreased activation with treatment. It seems to me
that the finding of significant differences between the groups prior to treatment but not after treatment is
accounted for by movement in the HC and NON-NAÏVE groups, and not NAÏVE, which is not what one
would hope to see.
8
We added the sentence, “Although the effects of habituation,17 procedural learning,18 or developmental
change19 are possible, the [oxy-Hb] amplitude of the repeated measurements was expected to decrease” to
Appendix 2 in the revised manuscript.
(18) As predicted above, the data from the CGI-S = 3 group are hard to interpret, seeming to split
between the CGI-S 2 and 4 groups (i.e., similar to responders in one analysis and non-responders in the
other).
We added the sentence, “In a previous study, a responder was defined as CGI-S score <3.16 A CGI-S score
of 4 was defined as moderately ill—overt symptoms causing noticeable, but modest, functional
impairment or distress—a symptom level that may warrant medication.12 Therefore, we defined CGI ≥4
as a poor response,” to Appendix 9 in the revised manuscript.
Discussion:
(19) This section reviews the findings and attempts places them in context of findings from other studies,
but does not return to the issue of using fMRI to predict MPH response until the last paragraph. To my
mind, the contention that the data here indicate fMRI can be used to predict response to MPH is well
beyond what the data tell us. ？This statement probably should be tempered somewhat.
We agree with the reviewer’s comment. A multi-site study is necessary to replicate the results of this
study for clinical use. The present results indicate that NIRS signals may have an ancillary role as a
biological marker for predicting responsiveness to MPH.
We revised the related text. In the original manuscript, “The present NIRS system may serve as a simple,
neuroimaging-aided clinical decision on continuous MPH administration in children with ADHD” was
changed in the revised manuscript to, “The present NIRS system may serve as a supplemental
neuroimaging modality to aid in clinical decision-making concerning continuous MPH administration in
children with ADHD.”
Reviewer #3 (Remarks to the Author):
The primary purpose of the study was to use an assessment of brain function (blood flow measured by
NIRS) elicited by a classic cognitive task related to inhibition of response - the Stop Signal Task (SST).
This measure was described as a "change" in blood flow, and even though it needs more detailed
description in the manuscript, it also is an innovative feature of the study.
9
The NIRS measure of blood flow "change" associated with the SST - at baseline as well as for an acute
response to a low dose of Concerta® -- was used to predict relative efficacy of chronic treatment with
MPH at 2 time points (after 1 month and 1 year).
The efficacy of the Concerta® dose was evaluated with commonly used clinical instrument -- the Clinical
Global Impression-Severity (CGI-S) scale. The CGI-S is ratings on a 7-point subjective scale performed
by an experienced clinician, which provides a score reflecting severity of illness: 1 (not ill), 2 (borderline),
3 (mildly), 4 (moderately), 5 (markedly), 6 (severely), and 7 (extremely).
The study has both strengths and weaknesses. Three strengths are the use of NIRS, which has promise as
an inexpensive and non-invasive method for assessing brain function; the use of "change" in blood flow
from before to after the performance of the SST (which may be necessary to use the blood flow measure
that lags the task-related brain activation), and the clinical trial methods for assessing acute and chronic
response to MPH (which was based on state-of-the-art methods). Two weaknesses are the relatively small
sample size (n = 30 ADHD cases, sub-grouped by history of prior treatment, with n = 8 positive and n =
22 negative, and n = 30 non-ADHD controls) and subsequently by retention (33% dropout) and degree of
response on the CGI-S scores (which apparently varied slightly from 2 = borderline ill to 3 = mildly ill to
4 = moderately ill), and large changes in NIRS scores over the phases of protocol (over time from
baseline to 1-2 months later, there was about a 50% decreases in
the NIRS score for all conditions in the controls and in most conditions in the participants with ADHD).
There are some questions about details that may need clarification.
1. The most important dependent measure of the study - the NIRS measure of "change" in blood flow to
the brain region of interest (IFC) -- needs a better explanation in the text.
(20) At line 166, the authors provide a cursory description and refer to the supplementary material. There
it suggests that the NIRS "change" is not related to the activity evoked by the SST stimuli that are
described in detail in the text (as a reader might expect), but instead reflects a pre-task vs. post-task
comparison of two baseline scores, representing 10-second averages of continuous NIRS measures taken
before and after the 80-sec SST is performed.
Do the reported "changes" in NIRS discussed in the manuscript and shown in the figure reflect a change
from the initial "baseline" before the SST is performed to a new "baseline" after the SST is performed?
We added the following sentence to Appendix 7 in the revised manuscript:
“The time resolution of NIRS was 0.1 s. NIRS signal changes were analysed using first-order correction
10
to exclude changes unrelated to the SST task. Because the NIRS signal was sometimes unstable at the
beginning of the pre-task period, the pre-task baseline was determined as the mean across the last 10 s of
the pre-task period, and the post-task baseline was determined as the mean across the last 10 s of the
post-task period. A linear fitting was performed on the data between the two baselines, which is consistent
with previous NIRS studies.20”
(21) If so, this should be made clear in the text. The readers unfamiliar with brain imaging studies
probably would not understand this, and those familiar with some other brain imaging methods may
assume that the NIRS "change" is related to responses to the discrete stimulant and responses to them the processes underlying the "GO" and STOP" responses. The authors could state this where the cursory
statement in line 166 is made - and make it clear to all readers that the NIRS "change" is not related to
changes associated with the GO or STOP response to the discrete visual stimuli, but rather the
establishment of a new NIRS "baseline" associated with the task of performing the SST.
We added a figure showing the Stop Signal Task as eFigure 2.
We approved the block design for the cognitive activation task.
2. Figure 3 (Figure 4 in revised manuscript) is a very important figure, and as the first one it needs some
additional explanation to guide the reader.
(22) Do the 3-group (NON-NAÏVE, NAÏVE, and HC) comparisons in this Figure show both
"disorder-related" and a "treatment-related" differences in brain blood flow based on NIRS? It appears
from Figure 3 that the Left-IFC comparison suggests a "disorder-related" decreased activation of Left
IFC (i.e., in both the treated NON-NAÏVE and the untreated NAÏVE subgroups compared to the control
group), while the Right-IFC comparison suggests a "treatment-related" decreased activation (only in the
untreated NAÏVE subgroup). Is this correct?
The differences among NAÏVE, NON-NAÏVE, and HCs were not significant for the left IFC. NAÏVE
demonstrated a tendency of decreased left IFC activation at baseline compared to HCs (P = .09, d =
-0.729, 95% CI = -1.42－-0.152). NON-NAÏVE and HCs showed no significantly differences. Therefore,
the decreased activation in the left IFC was not disorder-related. There was no significant difference
between the HCs and NAÏVE groups after washout of continuous MPH administration for 1 year.
(23) At line 263, the authors discuss a laterality effect, but do not address it in much detail. They point out
that on the NIRS IFC dependent measure shown in Figure 3, the NAÏVE (but not the NON-NAÏVE)
subgroup had lower R than the HC (control group). Was this due to a lateral difference in the NIRS IFC
11
measure of blood flow in the NAÏVE subgroup, but not in the NON-NAÏVE and HC group?
A significant interaction of group × session × laterality was observed (F = 3.743, P = .03). [Oxy-Hb] in
NAÏVE at the 4-to-8-week open trial showed a significantly higher activation during the SST in the right
IFC compared with the left IFC (P = .002, 95% CI = 0.023–0.094). However, in NAÏVE, there was no
significant difference in [oxy-Hb] between the left and IFC at the baseline assessment. [Oxy-Hb] in
NON-NAÏVE at the baseline assessment demonstrated a significantly higher activation during the SST in
the right IFC than in the left IFC (P = .003, 95% CI = 0.032–0.141). No significant difference was
observed in [oxy-Hb] between the left and right IFC at the 4-to-8-week open-trial in NON-NAÏVE. For
HCs, there was no significant difference in [oxy-Hb] between the left and right IFC at the baseline
assessment and 4-to-8-week open-trial.
3. Could the possibility of a Sex effect be evaluated in the analyses?
(24) In Table 1, the sex ratios are reported, and they appear to show that there were NO females in the
NON-NAÏVE subgroup (8:0). Also, the sex ratios and percentages of females differ in absolute values,
with 18% females in the NAÏVE subgroup (18:4) and 30% in the HC group (14:6). Laterality differences
in brain function associated with Sex have been reported, and here a laterality difference in the ADHD
subgroups (and in comparison to the control group) are reported. Are these due to (or independent of)
any Sex effect? Can this be tested with the sample in this study?
The reviewer mentions a good point. To consider the sex effect, a stepwise multiple regression analysis
was conducted with clinical outcome (CGI-S scores) as a dependent variable and with the NIRS signals
and 11 demographic and clinical variables including sex as independent variables. The regression analysis
revealed that sex was not a significant factor.
4. The relationship of NIRS IFC measure and CGI-S classification is described in Figure 3, but more
information is needed to interpret the findings.
(25) In Figure 3, by counting the circles it appears that the number of cases assigned to the CGI-S
responses of 2 (borderline ill), 3 (mildly ill), and 4 (moderately ill) are n = 4, n = 12, and n = 5. Is that
correct? Is this reported somewhere so a count of circles in not required?
We added the description “2, borderline mentally ill [N = 4]; 3, mildly ill [N = 12]; 4, moderately ill [N =
5]” to the legend of Figure 3 in the revised manuscript.
(26) Is the analysis of these data in Figure 3 simply a regression of NIRS blood flow on CGI-S class (2, 3
or 4)? Would a regression of a continuous measure of symptom severity (rating of ADHD symptoms) also
12
be possible?
The reviewer makes a good point. The ADHD-RS was translated into Japanese in 2007. However, the
ADHD-RS has not been standardized in Japan. There is no standardized assessment tool to assess ADHD
symptoms in Japan. We added the following sentences to Appendix 8: “Although the ADHD-RS was
translated into Japanese in 2007 as an assessment tool of symptoms, it has not been standardized in Japan.
Therefore, we chose the CGI score as a primary outcome assessment tool.” In a previous study, a
responder was defined as having a CGI-S score < 3.16 A CGI-S score of 4 was defined as moderately
ill—overt symptoms causing noticeable, but modest, functional impairment or distress—a symptom level
that may warrant medication.12 Therefore, we defined CGI ≥ 4 as a poor response.
(27) Is the discriminant analysis of the classes of CGI-S responses - reported to be a contrast of cases
with a cutoff between 3 and 4 (/= 4) based on a contrast of n = 4 vs. n = 17 cases?
The discriminant analysis of the classes of CGI-S responses, which was reported as a contrast of cases
with a cut-off between CGI ≤ 3 and ≥ 4, is based on a contrast of N = 16 vs. N = 5.
5. One of the large effects shown in Figure 3 appears to be a decrease in the NIRS measures of blood flow
"change" over the successive tests (Part A to Part C), but this is not explained in the manuscript.
(28) At line 269-270, the authors state, "As expected, HC demonstrated significant lower bilateral IFC
activation at part C than at Baseline". Why is this "As expected"? Is this explained somewhere in the
manuscript or in the supplementary material?
We agree with the reviewer’s comment. We added the following sentence to Appendix 2 in the revised
manuscript: “Whereas the effects of habituation,17 procedural learning,18 or developmental change19 could
have been present, the [oxy-Hb] amplitude of the repeated measurements was expected to decrease.”
(29) Is this decrease a general pattern for the ADHD subgroups as well as the HC group? This appears
to be so for all conditions expect for one (RIFC "change" for the NAÏVE subgroup). Can some
explanation for the general decrease in NIRS IFC "change" be offered?
As the reviewer mentioned, the effect of repeated measurements may also decrease the NIRS signal in
NAÏVE or NON-NAÏVE. It is difficult to know the effect of repeated measurements in NAÏVE or
NON-NAÏVE because we did not test repeated NIRS measurements in the ADHD group without the
MPH intervention in this trial design.
13
Therefore, we evaluated NIRS signals in HCs, which did not take MPH, at the same intervals and times
used for ADHD children (the only difference was that the HC children did not take MPH) to detect effects
of repeated measurements.
6. The doses used in clinical treatment seem to be relatively low.
At line 147, the standard dose of Concerta® is given (18 mg). This is a low dose (equivalent to a TID
dose of 5 mg of immediate-release MPH). At line 154, the clinically titrated dose is given (average = 25.4
mg, with a range of 18 to 36 mg), suggesting that about half of the cases staying on 18 mg and the other
half increased to 36 mg of Concerta®. This clinically titrated dose seems relatively low, too.
(30) Why are such low doses used in the study? Is this due to the physical size or ethnicity of the
participants? Or, is it due to the clinical experience of the clinicians who provide treatment for these
patients?
“In the Japanese clinical trial conducted by Janssen Pharmaceutical K.K., the mean dose of MPH, was 31
± 9.8 mg (0.89 mg/kg).11 In a Korean study, the mean dose of MPH was 22 ± 13.1 mg (0.68 mg/kg).5 In
our study, the mean dose of MPH was 25.4 mg (0.91 mg/kg), which is within the range of MPH doses
used in similar studies conducted in Asia.”
(31) The authors do not comment on this or try to explain it, but this needs to be addressed to understand
how the prediction of response (to what appears to be a relatively low acute dose) is related to clinical
response to chronic treatment with a clinically titrated dose (that also appears to be relatively low).
As an acute dose, we aimed to predict the response based on a minimal dose of MPH. We chose the 18
mg capsule as the minimal dose in Japan. In the Japanese clinical trial conducted by Janssen
Pharmaceutical K.K., the mean dose of MPH, was 31 ± 9.8 mg (0.89 mg/kg).11 In a Korean study, the
mean dose of MPH was 22 ± 13.1 mg (0.68 mg/kg).5 In our study, the mean dose of MPH was 25.4 mg
(0.91 mg/kg), which is within the range of MPH doses used in similar studies conducted in Asia.
7.(32) The primary outcome described at lines 168-172 is based on NIRS "change" at Baseline (Part A),
and the secondary outcome is based on "delta" change, which is the difference between NIRS "change"
from Part A and Part C. This needs some additional clarification.
The “delta” change indicates the difference in the NIRS signal between the baseline assessment and after
14
a single dose of MPH.
(33) Is the "change in the single-dose-test (Part B - Part A)" based on the NIRS "change" at baseline
(Part A) minus the NIRS "change" in Part B when tested after the standard 18 mg dose of Concerta® was
administered?
The “change in the single-dose test” indicates the NIRS signal in the single-dose test when tested with the
standard 18 mg dose of Concerta® minus the NIRS signal at the baseline assessment.
(34) Is the "delta" score (Part B - Part A) independent of the baseline score (Part A)? Logically, these
scores may not be independent, since the Part A score is included on both the Baseline "change" and the
"delta" scores. This might be mentioned and may need some discussion in the supplementary material.
In the regression analyses described at line 200-207, there are 13 predictor variables. In the first analysis
both the Baseline "change" and the Part B-Part A "delta" score were included as independent (predictor)
variables, along with 11 others for a total of 13 variables. Was the first test based on dropping our each
variable of the full regression model with all 13 variables? If so, if the Part A "change" and the Part
B-Part A "delta" variables are co-linear, this may affect the significance of either of these variables. This
deserves some comment in the manuscript or in the supplementary material.
As a primary outcome, a regression analysis was conducted to examine whether [oxy-Hb] at the baseline
assessment or ∆[oxy-Hb] change (single dose of MPH minus baseline assessment) predicts CGI-S scores
after the 4-to-8-week open-trial. Therefore, we chose both the NIRS signal at the baseline assessment and
∆[Oxy-Hb] change (single dose of MPH minus baseline assessment) as independent variables for the
stepwise regression analysis.
(35) In the next analysis, a stepwise procedure is described. What was the order of adding the 13
variables in this analysis? The authors report that only the Part B-Part A "delta" variable significantly
predicted clinical efficacy of chronic treatment with MPH (CGI-S at Part C). If the Part A "change" score
were included before the Part B-Part A "delta" score, would it be significant?
We conducted stepwise multiple regression analysis with CGI-S after 4-to-8-week open-trial as a
dependent variable, and [oxy-Hb] at the baseline assessment, ∆[oxy-Hb] (single dose of MPH minus
baseline assessment), MPH dosage, ADHD-RS scores (inattention, hyperactive impulsiveness, and total
score), CBCL scores (internalizing, externalizing, and total score), SST task performance, IQ, age, and
sex as independent variables. We included the baseline assessment score before the single dose of MPH
minus baseline assessment “delta” score, and the single dose of MPH minus baseline assessment “delta”
15
score became significant.
8. At lines 236-244, the authors describe the retention rates, with further explanation in Figure 2.
(36) The authors report a high retention rate for the 1-month chronic treatment (Phase C), with 29 of 30
ADHD cases (21 of 22 of the NAÏVE cases) completing Part C, but a lower 1-year retention rate for Part
D, with only 14 of the 21 cases entering the long-term follow-up completing the final assessment. The
high retention rate at Part C is cited as one of the strengths of the study (that may avoid a selection bias
due to dropout), and the low retention rate at Part D was cited as a possible censoring mechanism that
enriched for favourable response. Some coordination may be needed to be related these two discussion
points about retention in the study, since they may otherwise appear to be in conflict.
We discussed the possibility of a selection bias to the limitations section of the revised manuscript. The
dropout rate was high (36%) in the 1-year follow-up. The low retention rate for the 1-year follow-up was
cited as a possible bias.
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