Chun-Hung Chang, M.D.
Email: b89401068@ntu.edu.tw
Oct 29, 2013
Dr Roger Pinder
Editor-in-Chief
Neuropsychiatric Disease and Treatment
RE:
Ref:
ID: 54964
Title: Acute Stimulation Effect of the Ventral Capsule/Ventral Striatum in Patients
with Refractory Obsessive-Compulsive Disorder – A Double-blinded Trial
Dear Editors:
Thank you for the helpful reviews of our manuscript. Following the suggestions
of the reviewers, we have made the relevant revisions. All the changes and our
specific responses to the comments are given on separate sheets.
We are extremely pleased that, despite the problems noted with the manuscript,
we are encouraged to revise and resubmit the paper. We hope that the paper now
meets the high standards of Neuropsychiatric Disease and Treatment.
Sincerely,
Chun-Hung Chang, M.D.
1
Author’s Responses to Reviewers’ Comments
Ref:
ID: 54964
Title: Acute Stimulation Effect of the Ventral Capsule/Ventral Striatum in Patients
with Refractory Obsessive-Compulsive Disorder – A Double-blinded Trial
Reviewer #1
1). The novelty of this paper is the blinded stimulation, but there are few details on the
blinding procedure. Did patients know that they were going to receive stimulation and
just weren't aware of the settings?.
We have added the information as follows (p 2, Lines 15~19)
…………To reduce operation duration, risk, patients’ discomfort, and to avoid
anesthesia effects, we didn’t perform intraoperative test stimulation. Postoperative test
stimulation was performed at least two weeks after the DBS surgery. The patient sat
comfortably in a chair and was continuously videotaped during each testing. In
accordance with stimulation settings employed by other groups5, 6, 11, we fixed the
pulse width at 210 μs, the stimulation frequency at 130 Hz, and used a monopolar
mode. A test condition was defined as the application of a particular voltage at a
particular contact. Each contact (0, 1, 2, and 3) of the lead was stimulated
2
postoperatively at increasing voltages (0, 2, 4, 6, 8 V) and turned to zero between
each, giving a total of possible test. After completing testing of the left electrode, we
tested the right electrode. One psychiatrist adjusted parameter settings according to
prepaired flowchart, for example, contact 0, 2, 1, 3, or 3, 2, 1, 0 in a specific order.
The patients knew that they were going to receive testing, but not aware of the
settings. Another psychiatrist who evaluated the patient’s response was also blind to
the parameter settings. One camera was used to record their verbal and behavioral
response.
3
2) It often takes months to manifest a meaningful clinical response with VC/VS DBS
in OCD, but the authors stimulation testing took place over an hour. Were they
concerned about unknown washout/washon effects?
We have added the information as follows (p 2, Lines 15~19)
………………術後急性測試並比較三年(36月後)的治療反應
. Mean severity of OCD was a Y-BOCS score of 36.3±2.1 before surgery. At the
end of 36 months follow-up, there was a ???% decrease in OCD severity (Y-BOC
score 24.3±9.1, p=0.001). The Y-BOCS score of the patients decreased from
36/36/33/38 at baseline to ????after 36 months of follow-up respectively. Similar
findings were seen for HAM-D. Baseline HAM-D score was 36.3±6.3. At 36-month
follow-up, there was a ???% decrease in severity of depression (HAM-D
score=????????) (Tabe?).
蔡醫師這四個人手術前跟手術後 36 月(3 年)我不太確定
想請你幫忙
而且稍微試算後 P 值沒有小於 0.05?
Variable
Y-BOCS
total score
Baseline
HAM-D
score
36-month
Baseline
36-month
case1 秦
36
32
30
28
case2 施
36
22
36
20
case3 李
34
16
34
12
case4 蘇
39
36
45
38
4
5
Table . Changes in the Severity of OCD, Depression, and Cognition after 36-month
of DBS surgery.
Variable
Baseline
After
Mean
36-month
[95%CI]
(SD) P value
%
Improvement
of surgery
Y-BOCS total score
36.25±2.06
26.5±9.15
9.75 (7.41)
0.078
[-2.04-21.54]
HAM-D score
36.3±6.3
24.5
?
WAIS-III
WAIS-FIQ
81.25±20.16
83.00±20.54
WAIS-PIQ
70.25±21.72
76.75±26.29
WAIS-VIQ
91.25±17.91
89.00±15.25
6
3) No conclusion can be drawn regarding the predictive nature of acute stimulation.
No correlation statistics are provided, and it is unclear, to this reviewer, what are
"laugh conditions" are.
We have added the information as follows (p 2, Lines 15~19)
…………PubMed 或論文對 smile laughter 的定義
…smile/laughter is a emotional express???
Smile means “a slow, gentle, sideward and upward pull of mouth, without rhythmical
movements or contraction of other facial muscles,” and laughter is smile accompanied
by vocal sounds (Early Hum Dev. 2006 Jan;82(1):61-6. Epub 2005 Sep 26.
Origins of smile and laughter: a preliminary study.
Kawakami K, Takai-Kawakami K, Tomonaga M, Suzuki J, Kusaka T, Okai T.)
But it’s difficult to distinguish smile or laughter because of small voice, rapid progress
from smile to laughter or ???. We recorded smile/laughter when the patient showed
smile or laughter.
.
Smile and clinical outcome (統計還要修改)
The percentage of laugh conditions for four cases was 25%, 43.8%, 62.5% and
12.5%. After 36-month follow, the improvement of the Y-BOCS score was 11.11%,
38.89%, 52.94% and 7.692% respectively. The improvement of the HAMD score was
7
6.67%, 44.44%, 64.71% and 15.56% respectively. Therefore, our finding agreed with
Haq’s group. The
larger
the
percentage
of
laugh
conditions
for
individual patients, the greater the percentage of reduction in YBOCS at 36-month
follow-up
(Spearman's
rho=0.841,
p-value =0.034).
The other correlations
between clinical outcomes and percent of smile/laugh conditions were not statistically
significant (Fig. Table).
8
9
%
% Improvement
Smile/Laughter
conditions
Spearman rho
p-value
Y-BOCS at 36 months
1?
<0.01?
HAM-D score at 36 months
1?
<0.01?
10
4) Is table 2 the contacts from the right or left lead? Were both leads tested? and if so,
what were the results of the second lead
刪掉兩個 score 或
改用 Haq 的統計圖表?
We have added the information as follows (p 2, Lines 15~19)
…………From the left; only show left side of one patient !?
11
Table 2 Results of left ventral capsule/ventral striatum (VC/VS) deep brain
stimulation (DBS) testing with the pulse width at 210 μs, the frequency at 130
Hz. ?????
12
Author’s Responses to Reviewers’ Comments
Ref:
ID: 54964
Title: Acute Stimulation Effect of the Ventral Capsule/Ventral Striatum in Patients
with Refractory Obsessive-Compulsive Disorder – A Double-blinded Trial
Reviewer #2
1. The methodology employed needs to be clearer:
- It is unclear whether the authors performed any intraoperative stimulation testing.
We have added the information as follows (p 2, Lines 15~19)
…………To reduce operation duration, risk, patients’ discomfort, and to avoid
anesthesia effects, we didn’t perform intraoperative test stimulation. Postoperative test
stimulation was performed at least two weeks after the DBS surgery.
13
- It is unclear to me whether smile and laughter events were determined solely by the
rater at the time of their occurrence, or whether some events were discovered on video
review afterwards.
We have added the information as follows (p 2, Lines 15~19)
……Smile means “a slow, gentle, sideward and upward pull of mouth, without
rhythmical movements or contraction of other facial muscles,” and laughter is smile
accompanied by vocal sounds (Early Hum Dev. 2006 Jan;82(1):61-6. Epub 2005 Sep
26.Origins of smile and laughter: a preliminary study. Kawakami K, Takai-Kawakami
K, Tomonaga M, Suzuki J, Kusaka T, Okai T.)
But it’s difficult to distinguish smile or laughter because of small voice, rapid progress
from smile to laughter or ???. We recorded smile/laughter when the patient showed
smile or laughter at per contact, voltage setting (by the rater at the time of their
occurrence). And we rated mood change (euphoria) according to 10-point Liker scale.
14
- The authors state that they used a scale of "0 to 10 that best described his current
mood and obsession; 0 would mean 'No euphoria/No obsession', and 10 would mean
'Best possible euphoria/Worst obsession' " I assume there were two separate scales (no
euphoria/euphoria and obsessive sx/worst obsessive sx) and not a single combined
scale, but this should be made explicit.
We have revised the information as follows (p 2, Lines 15~19)
……We evaluated mood at each condition via a ten-point Liker scale. 0 would mean
'No euphoria, and 10 would mean 'Best possible euphoria ". Figure 2 showed that if
smile/laughter was noted, euphoria increased with voltage.
15
- How often were patients seen after implantation for programming adjustment?
We have added the information as follows (p 2, Lines 15~19)
……Psychiatric evaluations were conducted preoperatively, postoperatively, and at
follow-up visits every 3 months
16
- Why was a 15month endpoint chosen rather than the more typical 12, 18, or 24?
We have added the information as follows (p 2, Lines 15~19)
……Psychiatric evaluations were conducted preoperatively, postoperatively, and at
follow-up visits every 3 months. Till now 36-month followup data was available.
17
- I did not see mention of how lead coordinates were calculated. Was it from
post-operative MRI? CT? What formula was employed?
We have added the information as follows (p 2, Lines 15~19)
……A high resolution, T1-weighted image (T1WI) with 0.7 mm slice thickness was
obtained one day before the surgery using a 1.5T magnetic resonance imaging (MRI)
scanner. We applied a Leksell stereotactic frame under local anesthesia. A
high-resolution head computed tomography (CT) scan with a slice thickness of 1.25
mm was performed. The images were sent to a workstation with BrainLAB, and then
the MRI and CT-based images were fused. Electrodes were implanted according to a
set of anatomical landmarks -- anterior commissure (AC) and posterior commissure
(PC), AC-PC plane, and the anterior limb of the internal capsule -- using a Leksell
stereotactic frame under general anesthesia.
18
- when calculating the percentage of laughter/euphoria events: were laughter events
and euphoric events totaled together? Were they counted on a per voltage setting basis,
or on a per-contact basis?
We have added the information as follows (p 2, Lines 15~19)
……We count smile/laughter and euphoria separatively. When we noted smile/laugter,
we asked the patient if experienced mood change. If the patient felt euphoria, he
pointed out the score 0-10 at 10-point Likert scale. On a per contact and voltage
setting base. For example, smile/laughter was noted on Contact 0, voltage 6.
19
- It is unclear whether Table 2 is meaningful without more information on the
variability in contact coordinates between patients. For example, depending on the arc
angle, contact 3 could be in dramatically different locations in different patients,
preventing meaningful comparison of euphoria and obsession values or of
patient-reported side effects.
We have added the information as follows (p 2, Lines 15~19)
……Table showed the coordinates of contact 0, 1, 2, 3 of each patient.
20
21
Table 5
Coordinates (x, y, z) according to Schaltenbrand-Wahren atlas for all contact sites.
Case number
Left side
x
y
z
0
7.1
1.2
-2.3
1
8.4
2.4
0.4
2
10.4
3.6
3
3
12.5
4.6
5.7
Contact
1
0
1
2
3
2
0
1
2
3
3
4
0
1
2
3
22
2. I would like additional information in the Results section:
- did the authors explore the possibility of a voltage dependent effect on
euphoria/smile? Were patients more likely to smile or be euphoric at higher voltages?
This can be inferred from the data, but I did not see whether this was statistically
examined.
We have added the information as follows (p 2, Lines 15~19)
……We evaluated mood at each condition via a ten-point Liker scale. 0 would mean
'No euphoria, and 10 would mean 'Best possible euphoria ". Figure 2 showed that if
smile/laughter was noted, euphoria increased with voltage. Voltage dependent effect
was noted if the patent showed smile/laughter on the contact.
23
- Only the lead tip locations appear to be given (Table 1). The x,y,z coordinates of
each contact will be crucial to make full use of this data and to compare the authors'
results to those of other trials.
放上四人四點的座標 擔心產生更多問題? 不放?
放一個人? 放四個人? 若放
四個人 table1 要刪掉 xyz
We have added the information as follows (p 2, Lines 15~19)
24
…………Table showed the coordinates of contact 0, 1, 2, 3 of each patient.
25
Table 5
Coordinates (x, y, z) according to Schaltenbrand-Wahren atlas for all contact sites.
Case number
Left side
x
y
z
0
7.1
1.2
-2.3
1
8.4
2.4
0.4
2
10.4
3.6
3
3
12.5
4.6
5.7
Contact
1
0
1
2
3
2
0
1
2
3
3
4
0
1
2
3
合計
998
908
90
來源: 虛擬資料，僅供舉例之用
26
- Did patients' depressive symptoms improve over the 15 month follow up period?
- - was there any evaluation of cognition before or after surgery? Were any effects of
stimulation/surgery on cognition observed?
We have added the information as follows (p 2, Lines 15~19)
……. Mean severity of OCD was a Y-BOCS score of 36.3±2.1 before surgery. At
the end of 36 months follow-up, there was a ???% decrease in OCD severity (Y-BOC
score 24.3±9.1, p=0.001). The Y-BOCS score of the patients decreased from
36/36/33/38 at baseline to ????after 36 months of follow-up respectively. Similar
findings were seen for HAM-D. Baseline HAM-D score was 36.3±6.3. At 36-month
follow-up, there was a ???% decrease in severity of depression (HAM-D
score=????????) (Tabe?).
27
Table . Changes in the Severity of OCD, Depression, and Cognition after 36-month
of DBS surgery.
Variable
Baseline
After
Mean
36-month
[95%CI]
(SD) P value
%
Improvement
of surgery
Y-BOCS total score
36.25±2.06
26.5±9.15
9.75 (7.41)
0.078
[-2.04-21.54]
HAM-D score
36.3±6.3
24.5
?
WAIS-III
WAIS-FIQ
81.25±20.16
83.00±20.54
WAIS-PIQ
70.25±21.72
76.75±26.29
WAIS-VIQ
91.25±17.91
89.00±15.25
Note: WAIS-III, Wechsler Adult Intelligence Scale III; FIQ, Full scale Intelligence
Quotient; PIQ, Performance scale Intelligence Quotient; VIQ, Verbal scale
Intelligence Quotient; Y-BOCS, Yale-Brown Obsessive Compulsive Scale;
28
3. I would like to see some additional points dealt with in the discussion:
- Haq looked solely at bipolar intraoperative stimulation as a predictive response and
did not explicitly establish that postoperative stimulation predicted long term
improvement. This adds to the novelty of the - Previous papers have noticed that
unilateral smiles were easier to induce than bilateral smiles, and that bilateral smiles
were easier to induce than laughter. Did the authors notice a similar effect?
We have revised the information as follows (p 2, Lines 15~19)
……Haq looked solely at bipolar intraoperative stimulation as a predictive response
and did not explicitly establish that postoperative stimulation predicted long term
improvement. We are the first report to evaluated the postoperative stimulation
predicted long term improvement. We also noted unilateral smiles were easier to
induce than bilateral smiles, and that bilateral smiles were easier to induce than
laughter.
29
- Other groups have examined patients with much longer OCD symptom durations,
usually 15 years or more.
Do the authors have any insight into why this might be?
We have added the information as follows (p 2, Lines 15~19)
……OC 病史要超過 15 年以上 為什麼? 發生於兒童青少年表示與腦部發展異常
相關??
30
Minor Points:
1. P5 par 1: "However, whether or not acute stimulation test can provide substantial
information for chronic stimulation is not currently documented in these papers. Haq
et. al. first reported that acute stimulation-induced laughter may predict long-term
OCD response to DBS."
This statement appears contradictory. As the authors note, the paper of Haq et al
states that acute stimulation predicts the effects of chronic stimulation.
We have revised the information as follows (p 2, Lines 15~19)
… … However, whether or not acute stimulation test can provide substantial
information for chronic stimulation is limited. Haq et. al. reported that acute
stimulation-induced laughter may predict long-term OCD response to DBS.
31
2. P6 par 1: "Treatment resistance was defined as failure to improve meaningfully
after pharmacotherapy, including adequate trials of at least three serotonin reuptake
inhibitors (SRIs) and cognitive-behavioral therapies."
We have revised the information as follows (p 2, Lines 15~19)
……Treatment resistance was defined as failure to obtain improvements following
multiple trials of pharmacotherapy at maximally tolerated doses, and one or more
adequate trials of cognitive behavioral therapy.
32
3. Table 1: The standard convention is to represent left sided values on the AP plane as
a negative number.
We have added the information as follows (p 2, Lines 15~19)
……left sided values on the AP plane as a negative number.
33
4. Table 1: Though the authors are likely using the standard x,y,z conventions, for ease
of reading the table should specify which value represent
the AP, the mediolateral,
and the rostrocaudal axes.
We have added the information as follows (p 2, Lines 15~19)
……We have revised the information as follows (p 2, Lines 15~19)
x,y,z value is given for each patient, which presumably represents the lead tip.
……‡ AC-PC, anterior commissure-posterior commissure
§ Coordinate, the coordinate of the particular lead was presented as the distance
lateral to the midline, the distance anterior to the mid-commissural point, and the
distance inferior to the AC-PC plane.
where x=lateral, y=anteroposterior, z=axial.
The lateral
(X),
antero-posterior
(Y),
and axial (Z)
measurements
34
5. Table 1: A single x,y,z value is given for each patient, which presumably represents
the lead tip. This should be stated.
We have revised the information as follows (p 2, Lines 15~19)
x,y,z value is given for each patient, which presumably represents the lead tip.
……‡ AC-PC, anterior commissure-posterior commissure
§ Coordinate, the coordinate of the particular lead was presented as the distance
lateral to the midline, the distance anterior to the mid-commissural point, and the
distance inferior to the AC-PC plane.
where x=lateral, y=anteroposterior, z=axial.
The lateral
(X),
antero-posterior
(Y),
and axial (Z)
measurements
35
36
3. It would be helpful to know how long the SSRI trials were for (or at least the
minimum length) as well as the minimum length of time CBT was tried for in order to
compare these patients to those in previous and ongoing trials.
有可能請助理在統計這四人手術前
做個幾次 SSRI?
幾次 CBT? (我可以幫忙
問昌宏)
不過我看大部分論文都沒有啊
有一篇有
We have revised the information as follows (p 2, Lines 15~19)
……Treatment resistance was defined as failure to obtain improvements following
multiple trials of pharmacotherapy at maximally tolerated doses, and one or more
adequate trials of cognitive behavioral therapy.
37