CLINICAL ARTICLE

J Neurosurg 127:1172–1180, 2017

Efficacy of deep rTMS for neuropathic pain in the lower

limb: a randomized, double-blind crossover trial of an
H-coil and figure-8 coil
Takeshi Shimizu, MD,1,2,7 Koichi Hosomi, MD, PhD,1,2,7 Tomoyuki Maruo, MD, PhD,1–3
Yuko Goto, MD, PhD,1,2 Masaru Yokoe, MD, PhD,1,4 Yu Kageyama, MD, PhD,2,5
Toshio Shimokawa, PhD,6 Toshiki Yoshimine, MD, PhD,2,7 and Youichi Saitoh, MD, PhD1,2,7
Departments of 1Neuromodulation and Neurosurgery, 2Neurosurgery, and 4Neurology, Osaka University Graduate School of
Medicine; 7Center for Pain Management, Osaka University Hospital, Suita; 3Department of Neurosurgery, Otemae Hospital,
Osaka; 5Department of Neurosurgery, Saitama Children’s Medical Center, Saitama; and 6Clinical Research Center, Wakayama
Medical University, Wakayama, Japan

OBJECTIVE Electrical motor cortex stimulation can relieve neuropathic pain (NP), but its use requires patients to un-
dergo an invasive procedure. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) using
a figure-8 coil can relieve NP noninvasively, but its ability to relieve lower limb pain is still limited. Deep rTMS using an
H-coil can effectively stimulate deep brain regions and has been widely used for the treatment of various neurological
diseases; however, there have been no clinical studies comparing the effectiveness of figure-8 coils and H-coils. This
study assessed the clinical effectiveness of 5 once-daily stimulations with H-coils and figure-8 coils in patients with NP.
METHODS This randomized, double-blind, 3-way crossover trial examined 18 patients with NP who sequentially re-
ceived 3 types of stimulations in the M1 for 5 consecutive days; each 5-day stimulation period was followed by a 17-day
follow-up period before crossing over to the next type of stimulation. During each rTMS session, patients received a 5-Hz
rTMS to the M1 region corresponding to the painful lower limb. The visual analog scale (VAS) and the Japanese version
of the short-form McGill Pain Questionnaire 2 (SF-MPQ2-J) were used to measure pain intensity. The primary outcome
was VAS score reduction immediately after and 1 hour after intervention.
RESULTS Both the VAS and SF-MPQ2-J showed significant pain improvement immediately after deep rTMS with an
H-coil as compared with the sham group (p < 0.001 and p = 0.049, respectively). However, neither outcome measure
showed significant pain improvement when using a figure-8 coil. The VAS also showed significant pain improvement 1
hour after deep rTMS with an H-coil (p = 0.004) but not 1 hour after rTMS using a figure-8 coil. None of the patients ex-
hibited any serious adverse events.
CONCLUSIONS The current findings suggest that the use of deep rTMS with an H-coil in the lower limb region of the
M1 in patients with NP was tolerable and could provide significant short-term pain relief.
Clinical trial registration no.: UMIN000010536 (http://www.umin.ac.jp/ctr/)
https://thejns.org/doi/abs/10.3171/2016.9.JNS16815
KEY WORDS repetitive transcranial magnetic stimulation; neuropathic pain; deep rTMS; H-coil; lower limb pain;
figure-8 coil

S
timulation of the motor cortex is a technique devel- cortex stimulation (EMCS) targeting the primary motor
oped by Tsubokawa et al. for the treatment of pa- cortex (M1) achieved good pain relief in half of the tested
tients with thalamic pain syndrome after stroke.23 A patients with refractory neuropathic pain (NP).20 How-
previous study by our group showed that electrical motor ever, EMCS requires invasive implantation of intracranial

ABBREVIATIONS ANOVA = analysis of variance; BDI = Beck Depression Inventory; CPSP = central poststroke pain; EMCS = electrical motor cortex stimulation; FBSS =
failed–back surgery syndrome; H-coil = Hesed coil; M1 = primary motor cortex; NP = neuropathic pain; PGIC = patient global impression of change; RMT = resting motor
threshold; rTMS = repetitive transcranial magnetic stimulation; SF-MPQ2-J = short-form McGill Pain Questionnaire 2, Japanese version; SCD = subacute combined degen-
eration; SCI = spinal cord injury; TCS = tethered spinal cord syndrome; TMS = transcranial magnetic stimulation; VAS = visual analog scale.
SUBMITTED April 2, 2016. ACCEPTED September 15, 2016.
INCLUDE WHEN CITING Published online February 3, 2017; DOI: 10.3171/2016.9.JNS16815.

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 Efficacy of deep rTMS for neuropathic pain in the lower limb

electrodes and a pulse generator. In addition, targeting the had lasted for more than 6 months. We determined the
lower-limb region of the M1 often requires a complicated sample size by referring to our previous study.6 All pa-
procedure and tends to provide insufficient relief of lower- tients were recruited through the outpatient clinic at the
limb pain. Osaka University Hospital from April 2013 to December
Transcranial magnetic stimulation (TMS) is a nonin- 2014 and diagnosed based on the grading system for NP.22
vasive method that can be used to safely stimulate corti- Underlying diseases consisted of central poststroke pain
cal neurons,22 and high-frequency repetitive TMS (rTMS) (CPSP), failed–back surgery syndrome (FBSS), diabetic
over the M1 has shown clinical effectiveness in treating neuropathy, subacute combined degeneration (SCD) of
patients with NP.1,6,8,11,14,19 In a previous randomized cross- the spinal cord, tethered spinal cord syndrome (TCS),
over trial by our group, we demonstrated that rTMS using and spinal cord injury (SCI). Patients consented to main-
a figure-8 coil over the M1, as compared with sham stimu- taining their current drug regimen and not using opioid
lation, provided significant pain relief in patients with NP.8 rescue medication before completing the trial. Exclusion
In that trial, the efficacy rate for alleviation of lower-limb criteria included implanted devices, history of seizures,
pain tended to be lower than that for upper-limb pain.8 any metal implanted in the head, dementia (Mini-Mental
Given those results, we speculated that the difference in State Examination score < 24), higher brain dysfunction,
pain relief between upper- and lower-limb pain was attrib- and major depression. Written informed consent was ob-
utable to differences in the distance from the coil to the tained from all patients before inclusion in the study. The
targeted M1 region. The lower-limb M1 locates in a deep protocol was reviewed and approved by the institutional
brain region, while the figure-8 coil only permits stimula- ethics review board at Osaka University Hospital. We
tion of the superficial cortex of the brain. Therefore, using registered the protocol with the University hospital Medi-
a figure-8 coil for rTMS targeting the lower-limb M1 re- cal Information Network (UMIN) Clinical Trials Regis-
quires high-intensity stimulation that can cause scalp pain try (http://www.umin.ac.jp/ctr), and its registration no. is
and increase the risk of seizure. UMIN000010536.
A newly developed variant of TMS uses a Hesed coil
(H-coil) and is referred to as “deep TMS.” This tech- Randomization and Masking
nique can achieve an improved deeper penetration and a We conducted a randomized, double-blind crossover
slower decay of the electric field as a function of distance trial that consisted of 3 different stimulations: deep rTMS
than the figure-8 coils.16,18 Lefaucheur et al. examined using an H-coil, rTMS using a figure-8 coil, and sham
the depth of TMS in healthy volunteers; they found that stimulation. Patients sequentially crossed over to these 3
rTMS using an H-coil could stimulate the hand area of types of stimulation, and the independent data center de-
M1 even at a distance of 5.5 cm from the scalp, while termined the order of stimulation for each patient. Accord-
rTMS using a standard figure-8 coil stimulated M1 at a ing to the permuted-block randomization method, patients
distance of 2.0 cm from the scalp.11 Several studies us- were randomly assigned to 1 of 6 groups (Fig. 1). Patients
ing head models revealed that the H-coil makes it pos- and assessors were blinded to the assignment until after
sible to stimulate deep brain regions effectively without study completion.
inducing an unbearable field in the cortical regions.17,18,24
Deep rTMS using an H-coil has been reported to be an
effective treatment for a variety of neurological and psy- Procedures
chopathological disorders that require targeting of deep Patients received 5-Hz rTMS (500 pulses/session) using
brain regions.5,9,15,21 Based on the results of these previ- a figure-8 coil, H-coil, or sham stimulation in their lower-
ous studies, the H-coil will be increasingly used to treat limb M1 for 5 consecutive days (Days 1–5), followed by
several neurological disorders. The need now arises for a a 17-day follow-up period. Each stimulation period was
clinical evaluation comparing the efficacy of deep rTMS separated by a minimum 17-day follow-up period start-
using an H-coil versus rTMS using a figure-8 coil for pa- ing on Day 6. This treatment interval was derived from
tients with NP; however, there has been no such com- the results of a previous study with the same stimulation
parative study thus far. parameters, which reported that 17 days was enough time
The purpose of the present study was to assess the ef- for the rTMS effects to be washed out.8 Figure 2 presents
ficacy of deep rTMS using an H-coil versus rTMS using a the time schedule of the present study.
figure-8 coil in patients with NP in their lower limbs. We To evaluate the effect of rTMS on pain relief in the low-
postulated that deep rTMS using an H-coil would relieve er limb during the stimulation period, the visual analog
pain as well as rTMS using a figure-8 coil and that the H- scale (VAS) and the Japanese version of the short-form
coil would provide this relief because it would stimulate McGill Pain Questionnaire 2 (SF-MPQ2-J) were used im-
deep brain regions more effectively. mediately before, immediately after, and 1 hour after the
intervention.2,13 During the follow-up period (Days 6–22),
the patients recorded their VAS and SF-MPQ2-J scores
Methods daily at the same time as the intervention. On Day 5, we
Patients also obtained the Patient Global Impression of Change
A total of 18 patients (12 men and 6 women) with in- (PGIC) score.3 The Beck Depression Inventory (BDI) was
tractable NP in the lower limb were included in this study. obtained at baseline (before stimulation) and on Days 5
Each patient experienced NP that was refractory to ordi- (after stimulation) and 22 to assess the severity of depres-
nary medical, surgical, or pharmaceutical treatments and sion symptoms. The BDI consists of 21 questions about

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FIG. 1. Trial profile. A flowchart shows the organizational structure of the study, with numbers of patients initially enrolled (n = 18).
There were no dropouts during the study. The number of patients in each stimulation group is indicated.

how the patient has been feeling in the past week. All stimulator intensity needed to cause a motor response in
of the evaluation scores were written by patients and as- the targeted lower limb. We kept the front surface of the
sessed by blinded assessors who observed the incidence of helmet facing forward to ensure that the coil orientation
adverse events. The primary outcome was the short-term was the same. The resting motor threshold (RMT) was de-
change in the VAS score, while the secondary outcomes fined as the minimum stimulator intensity needed to evoke
were the short-term and long-term changes in the SF- at least 1 visible muscle twitch in the extensor hallucis
MPQ2-J score, the long-term changes in the VAS score, brevis muscle while maintaining a relaxed position.4 The
the PGIC score, and the changes in the BDI. Short-term H-coil was then tightly fixed into the same position with
effect means that the pain relief was observed immedi- a belt during the stimulation. The position of the coil was
ately after intervention and 1 hour later. Long-term effect recorded based on nasal point and external earhole posi-
means that the pain relief was observed during the follow- tion on Day 1 to ensure that we could conduct the stimula-
up period as compared with Day 1 before the intervention. tion at the same position on Days 2 through 5. Each daily
session consisted of 10 trains of 5 Hz at 90% intensity of
Deep rTMS, or H-Coil rTMS RMT. Each train consisted of a 50-second intertrain in-
We performed deep TMS using an H-coil (H10, terval. A total of 500 pulses were applied in each session.
HMMC) connected to a Magstim Rapid2 stimulator (Mag-
stim Company). The H-coil was designed for effective ac- Figure-8 Coil rTMS
tivation of neuronal structures within the motor cortex, A MagPro R60 (Magventure) was used with a figure-8
including the deeper structures of the lower limb region of coil (MC-B70, Magventure) for the TMS. The coil posi-
the M1 with hemispheric symmetry. The H-coil and sham tion was determined during each daily session by evoking
coil were installed within the system. The mode of opera- visible muscle twitches with the Brainsight TMS naviga-
tion was switched by unlabeled magnetic cards to ensure tion system (Rogue Research Inc.) to ensure the optimal
that the patients and assessors remained blinded to which positioning needed to stimulate the M1 of the lower limbs.
stimulation would be administered, real or sham. We placed the coil in such a way that the induced current
To determine the coil position, we first placed the cen- ran in an anteroposterior direction. All patients underwent
ter of the helmet to install the H-coil at a point 1 cm lateral rTMS with a figure-8 coil using the same parameters as
and 1 cm posterior from Cz. Next, we identified the loca- the deep rTMS. In cases in which coil positioning failed
tion and angle of the helmet by identifying the minimum to evoke the twitch response, patients underwent rTMS

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 Efficacy of deep rTMS for neuropathic pain in the lower limb

FIG. 2. Evaluation time schedule. Current pain intensity of the patient was evaluated using the VAS and the SF-MPQ2-J. On each
stimulation day, pain intensity was examined at 3 time points: immediately before, immediately after, and 1 hour after the interven-
tion. The Patient Global Impression of Change (PGIC) was obtained on Days 5 and 22. The severity of depression symptoms was
measured by the BDI on Day 1 (before stimulation), Day 5 (after stimulation), and Day 22.

with the maximum intensity that they could bear (i.e., during the follow-up period (Days 6–21) as the indepen-
scalp pain caused by the stimulation). In such sessions, dent variable. We also performed paired t-tests with the
we set the stimulation intensity to 100 A/msec, which was Bonferroni correction between Day 1 and each day of the
the same as in the previous study.6 The stimulation using follow-up period to assess when the pain that was offset
MagPro at 100 A/msec was almost equivalent to the stim- during treatment returned. Paired t-tests were performed to
ulation produced using Magstim (Whitland) at the maxi- evaluate the BDI change induced by each stimulation, and
mum output.10 Wilcoxon signed-rank tests were performed to compare
the PGIC score between each stimulation. In all analyses,
Sham Stimulation p values less than 0.05 were considered statistically signifi-
Sham stimulation was delivered using a sham coil that cant. Data were analyzed with R version 3.1.1 (R Founda-
was placed in the same helmet that encased the active tion for Statistical Computing).
deep TMS coil (Brainsway). Activation of the sham coil
produced scalp sensations, acoustic artifacts, and facial Results
muscle activation similar to the active coil. In the sham
mode, the electric current was delivered in opposite direc- We enrolled 18 patients with intractable NP in their
tions in each of the double wires. Hence, the induced elec- lower limbs. Although 4 of the 12 patients with CPSP had
tric field in the sham mode was negligible, while repro- upper-limb pain in addition to lower-limb pain, they were
ducing the auditory and visual sensations of the real TMS asked to report only lower-limb pain that was the most
mode.12 In addition, the nontangential orientation relative painful.
to the scalp and the elements canceling the electric field The 18 enrolled patients received the 3 types of stimula-
ensured that there was a rapid reduction of the field as a tions in a randomly assigned order. We asked patients if
function of distance.9 The method for determining sham they could distinguish between the various stimulations,
coil orientation was the same as for the real stimulation but none was able to confidently detect the sham stimu-
using an H-coil, as described above. lation. TMS with the H-coil induced the twitch response
in all patients during all sessions, but TMS with the fig-
Statistical Analysis ure-8 coil failed to induce the twitch response in 2 patients
Statistical analyses of short-term VAS and SF-MPQ2-J through all 5 sessions and in 1 patient in 1 session. Table 1
outcomes were performed using the pain scores calculated presents the baseline clinical characteristics of the patients.
immediately before the stimulation on each day and the re- Four patients did not take any drugs because no drug could
duced values observed after stimulation. The reduced pain relieve the pain to any degree. There was no detectable car-
values after deep rTMS using both an H-coil and a figure-8 ry-over effect for either the VAS or the SF-MPQ2-J scores.
coil were compared with those from the sham stimulation
by using a linear mixed-effects model analysis (random Short-Term Effects of rTMS on VAS Changes (Primary
effect: patient, fixed effect: type of stimulation [dummy Outcome)
variables were applied for rTMS using an H-coil and fig- Deep rTMS using an H-coil resulted in the best pain
ure-8 coil, and the sham stimulation was baseline] and day improvement among all 3 types of stimulation immedi-
[Day 1–5]). A 2-sample t-test was performed to compare ately after and 1 hour after stimulation. The mean VAS
the clinical effectiveness of rTMS in 12 patients with CPSP reductions (standard error of the mean) immediately after
and 6 patients with noncerebral lesions. To evaluate carry- stimulation were 5.36 (1.03) for deep rTMS using an H-
over effect, a paired t-test was applied to the values at Day coil, 3.36 (0.78) for rTMS using a figure-8 coil, and 1.71
1 for each period. To evaluate the long-term effect of each (0.59) for the sham stimulation. The mean VAS reduc-
type of stimulation, we used repeated measures analysis of tions at 1 hour after stimulation were 3.14 (0.77) for deep
variance (ANOVA) with the VAS and SF-MPQ2-J scores rTMS using the H-coil, 2.25 (0.51) for rTMS using the fig-
as the dependent variable and the Day 1 value or each day ure-8 coil, and 0.97 (0.80) for the sham stimulation (Fig.

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TABLE 1. Baseline patient characteristics

Pain
Case Painful Underlying Location Duration VAS SF-MPQ2-J
No. Sex Age (yrs) Side Disease of Lesion (mos) Score Score BDI Op Daily Medication
1 M 64 Lt FBSS Lumbar 36 89 127 50 SCS Pregabalin 600 mg,
vertebra tandospirone 15 mg,
sodium valproate
300 mg, tramadol
hydrochloride 8T
2 M 57 Rt CPSP Putamen 12 72 67 5 None
3 M 53 Rt FBSS Lumbar 63 62 81 31 SCS, Pregabalin 600 mg,
vertebra block clonazepam 1.5 mg,
amitriptyline 30 mg
4 M 50 Rt CPSP Putamen 28 68 165 16 SCS trial Tramadol hydrochloride
3T
5 F 66 Lt CPSP Thalamus 42 82 49 7 None
6 M 62 Lt CPSP Thalamus 96 97 68 16 Clonazepam 0.5 mg,
imipramine 25 mg
7 M 69 Lt CPSP Subcortical 36 46 83 13 SCS trial Pregabalin 150 mg,
duloxetine
8 M 70 Rt DN Peripheral 132 60 140 8 SCS Pregabalin 150 mg,
nerve amitriptyline 20 mg,
codeine phosphate
120 mg
9 M 66 Rt CPSP Putamen 84 62 41 11 SCS trial Gabapentin 1200 mg,
duloxetine
10 M 75 Lt CPSP Putamen 180 75 85 10 SCS trial Pregabalin 75 mg, clon-
azepam 1.5 mg
11 F 75 Lt CPSP Putamen 15 84 125 5 Pregabalin 300 mg
12 M 53 Rt CPSP Putamen 9 78 110 12 Gabapentin 300 mg
13 F 62 Rt CPSP Putamen 14 34 18 8 SCS Pregabalin 150 mg,
amitriptyline 10 mg
14 M 61 Lt CPSP Thalamus 24 72 86 3 SCS trial None
15 F 76 Rt TCS Spinal cord 144 65 63 24 Pregabalin 100 mg, tra-
madol hydrochloride
4T, diazepam 4 mg
16 F 56 Lt SCD Spinal cord 96 56 82 30 SCS trial Gabapentin 1800 mg,
carbamazepine 500
mg, duloxetine
17 F 73 Rt CPSP Putamen 180 60 108 6 SCS Clonazepam 0.5 mg,
gabapentin 1200 mg
18 M 23 Lt SCI Spinal cord 60 52 41 2 None
Mean 61.7 (12.2) 69.5 (55.5) 67.4 (15.2) 85.5 (37.1) 14.3 (12.0)
(SD)
DN = diabetic neuropathy; SCS = spinal cord stimulation.

3). Analysis of the linear mixed-effects model revealed stimulation and 4.93 (1.19) at 1 hour after stimulation. A
a significant effect of the H-coil immediately after (p < 2-sample t-test showed no significant difference in pain
0.001) and 1 hour after (p = 0.004) stimulation compared relief between patients with CPSP and those with noncere-
with sham stimulation. There were no significant changes bral lesions immediately after and 1 hour after deep rTMS
to the VAS score with rTMS using a figure-8 coil (Table (p = 0.108 and 0.340, respectively).
2). There were also no significant variations in VAS scores
among the stimulation days. The mean VAS reduction val- Short-Term Effects of rTMS on SF-MPQ2-J Changes
ues following deep rTMS in 12 patients with CPSP were Similar to the changes seen in VAS scores, deep rTMS
4.62 (1.23) just after stimulation and 2.24 (0.87) at 1 hour with an H-coil resulted in the best pain improvement
after stimulation. The mean VAS reduction values in 6 pa- among the 3 types of stimulation immediately after and 1
tients with noncerebral lesions were 6.83 (1.53) just after hour after stimulation. The mean SF-MPQ2-J reductions

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 Efficacy of deep rTMS for neuropathic pain in the lower limb

FIG. 3. The mean VAS reduction in the short term (primary outcome). The mean VAS reduction just after stimulation was 5.36
(SEM 1.03) using rTMS with an H-coil, 3.36 (3.33) using rTMS with a figure-8 coil, and 1.71 (2.50) for sham stimulation. The mean
VAS reduction 1 hour after stimulation was 3.14 (0.77) with the H-coil, 2.25 (0.51) with the figure-8 coil, and 0.97 (0.80) with sham
stimulation.

immediately after stimulation were 8.43 (2.13) for the deep of patients nor the number of sessions was higher when
rTMS using an H-coil, 6.05 (1.60) for the rTMS using a using the H-coil versus the figure-8 coil. No patient was
figure-8 coil, and 5.95 (1.65) for the sham stimulation. The eliminated from the study because of adverse events re-
mean SF-MPQ2-J reductions at 1 hour after stimulation lated to the stimulation. One patient slipped and broke the
were 5.10 (1.43) for the H-coil, 3.68 (1.18) for the figure-8 phalanges in her foot during the follow-up period, but she
coil, and 3.71 (1.68) for the sham stimulation. Analysis of could assess the intensity of targeted pain separately from
the SF-MPQ2-J reduction using the linear mixed-effects the pain caused by the fracture. Another patient suffered
model revealed a significant effect for the H-coil (p = from painless contact dermatitis during sham stimulation.
0.049) but not for the figure-8 coil (Table 3). There was We thought that these events did not strongly affect pain
statistically significant interday variation in SM-MPQ2-J scoring. These events did not have any relevance to the
changes at 1 hour after stimulation. stimulation.

Long-Term Effects of 5 Consecutive Days of rTMS Discussion

Repeated-measures ANOVA revealed no significant
long-term effects on VAS scores (F = 1.3, p = 0.21 using This is the first double-blind crossover trial to assess
H-coil; F = 1.1, p = 0.36 using figure-8 coil; F = 1.3, p = the efficacy of rTMS over the lower limb region of the M1
0.19 sham) or SF-MPQ2-J scores (F = 1.7, p = 0.051 us- using an H-coil and a figure-8 coil in patients with NP in
ing H-coil; F = 1.3, p = 0.18 using figure-8 coil; F = 1.5, their lower limbs. We demonstrated that deep rTMS using
p = 0.10 sham) for all types of stimulation. There was no an H-coil was effective for treating intractable NP, even in
significant difference between Day 1 and each day of the the lower limbs, while rTMS using a figure-8 coil resulted
follow-up period. in no significant pain relief. The present study also showed
that rTMS using an H-coil relieved pain without any se-
rious adverse events. Results of the present study were
Changes in PGIC and BDI Scores compatible with findings of a previous study that assessed
Neither the H-coil nor the figure-8 coil resulted in sig- the clinical effect of deep rTMS in patients with painful
nificantly better PGIC scores compared with those ob- diabetic neuropathy in their lower limbs, and the clinical
tained following sham stimulation, even during the stimu- effect of the H-coil was not compared with that of the fig-
lation period (H-coil, p = 0.346; figure-8 coil, p = 0.346). ure-8 coil in that study.15 In the present study, we assessed
In addition, none of the 3 types of stimulation caused any the clinical effects of deep rTMS with an H-coil and rTMS
significant changes in BDI scores during the stimulation using a figure-8 coil in patients with FBSS, SCD, SCI,
period (H-coil, p = 0.543; figure-8 coil, p = 0.621; sham, and CPSP; we report that deep rTMS provides pain relief
p = 0.647). to these patients both immediately after and 1 hour after
stimulation. Our study also indicates that deep rTMS tends
Safety Measurements to relieve pain better in patients with noncerebral lesions
Table 4 presents the adverse events observed during the than in those with CPSP. These results are compatible with
study. Of the adverse events reported, neither the number those in our previous study in which patients with a nonce-
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TABLE 2. Short-term results of VAS reduction (primary outcome) TABLE 3. Short-term results of SF-MPQ2 reduction
Stimulation (compared w/ sham) Stimulation (compared w/ sham)
Period Figure-8 Coil H-Coil Day Period Figure-8 Coil H-Coil Day
Immediately 1.569 3.503 −0.218 Immediately 1.574 6.578 −1.095
after stimu- (p = 0.059) (p <0.001*) (p = 0.363) after stimu- (p = 0.639) (p = 0.049*) (p = 0.257)
lation lation
1 hr after stimu- 1.199 3.443 −0.339 1 hr after stimu- 0.072 1.152 −2.082
lation (p = 0.318) (p = 0.004*) (p = 0.328) lation (p = 0.967) (p = 0.517) (p <0.001*)
Random effect: patient, fixed effect: day and type of stimulation. Random effect: patient, fixed effect: day and type of stimulation.
* p < 0.05 statistically significant. * p < 0.05 statistically significant.

rebral lesion were found to be more suitable candidates for RMT for 5 consecutive days. In our experience, however,
high-frequency rTMS to M1.19 significant pain relief was no longer observed by 17 days
We believe the clinical advantage of the H-coil is after the end of 10 daily sessions of rTMS using a figure-8
largely attributable to its ability to deliver stimulation to coil (5-Hz stimulation of 500 pulses) in 64 patients with
a deeper cortical region than the figure-8 coil, thus creat- NP.8 We suggest that the difference in the durability of
ing a greater physiological effect. A previous head model pain relief following rTMS in these 2 studies was affected
simulation study has shown that deep TMS using the H- by the difference in the coils, the stimulating parameters
coil results in a significantly improved depth penetration (e.g., number of pulses per session), the frequency of stim-
and a much slower rate of decay as a function of distance ulation, and also the background of the patients’ pain con-
from the coil.24 In our study, deep TMS using the H-coil ditions. The present study demonstrated that there was no
induced muscle twitches even among patients who did not carry-over effect at 17 days after the end of 5 days of stim-
respond to TMS when using the figure-8 coil. In the cur- ulation with rTMS using either H-coils or figure-8 coils.
rent study, there were 2 patients in whom muscle twitches The durability of the rTMS effect would be required for
could not be induced by TMS using the figure-8 coil. In longer effectiveness. There were no statistically significant
these 2 patients, deep rTMS provided a larger VAS reduc- long-term effects of rTMS with either the H-coil or fig-
tion than the figure-8 coil immediately after and at 1 hour ure-8 coil. We think it is because SF-MPQ2-J measures,
after stimulation. These results indicate that deep rTMS which consist of 22 questions and 4 group components,
can generate a physiological effect more efficiently in the can consider not only the intensity but also the quality of
deeper region of the human brain. In the previous head the pain condition. In fact, subgroup analysis revealed that
model simulation study, electric field attenuation was di- deep rTMS could significantly relieve only the neuropathic
rectly proportional to the depth of the target. The results component (p = 0.021). Our finding that there are no sig-
of our study also indicated that the resting motor threshold nificant long-term effects of rTMS for lower limb pain in-
for each patient correlated to the distance from the coil to dicates that the stimulus conditions should be improved for
the superficial layer of the lower limb region of the M1 a longer durability of effect in the clinical setting. Daily or
(Supplementary Materials). Therefore, it is our belief that weekly stimulation for more consecutive days is one solu-
the physiological advantage of the H-coil is attributable to tion for improving the long-term effect of rTMS. For daily
the depth of the electric field that can be induced in the rTMS, adaptation for home use may make it possible in
deep brain region. The possibility that the broadness of the future.7
the distributed electric field is related to the physiological Our study has several potential limitations. First, the
effect remains controversial. issue of blinding for the 2 coils needs to be considered.
In addition, our study also demonstrated that deep TMS Since the obvious difference in the shapes of the 2 coils
using an H-coil was a safe, noninvasive method of stimu- could not be concealed, we had to explain to patients prior
lation and free from any serious adverse events. Accord-
ing to the results of the previous head model stimulation TABLE 4. Adverse events
study, deep TMS using an H-coil did not cause any higher
electrical field in the superficial brain regions, even when Figure-8
stimulating the brain regions.24 Although a double-cone Parameter H-Coil Coil Sham
coil can produce very strong fields that can stimulate the
Total no. of patients reporting 2 (8) 4 (9) 3 (5)
leg motor area, these fields decay quite fast in relation to
adverse events
distance from the coil. As a result, since the double-cone
coil must generate strong stimulations to superficial brain Adverse event
regions to effectively stimulate deep brain regions, it has Headache 1 (4) 1 (1) 0
been suggested that this method may cause greater pain to Dizziness 1 (1) 3 (8) 1 (4)
patients, making repetitive stimulations difficult.24 Pain in upper limbs 1 (3) 0 1 (1)
Onesti et al. previously reported that the effects of deep Fracture of phalanges in foot 0 1 0
rTMS with an H-coil might last 3 weeks in patients with
Contact dermatitis 0 0 1
painful diabetic neuropathy.15 The stimulation protocol
consisted of 1500 pulses at 20 Hz and 100% intensity of Data are expressed as numbers of patients (number of sessions).

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Rafael Rossi de Andrade Bezerra - [email protected] - CPF: 010.060.132-45
 Efficacy of deep rTMS for neuropathic pain in the lower limb

to the study that we would be performing 3 types of stimu- al: Effectiveness of deep transcranial magnetic stimulation
lation without actually providing any details on the differ- combined with a brief exposure procedure in post-traumatic
ences they might experience. Although the assessors were stress disorder—a pilot study. Brain Stimulat 6:377–383,
2013
also blinded to the specific treatment being used, studies 10. Kammer T, Beck S, Thielscher A, Laubis-Herrmann U,
using a parallel design should be considered in the future. Topka H: Motor thresholds in humans: a transcranial mag-
The second potential limitation involves the number of pa- netic stimulation study comparing different pulse waveforms,
tients. Crossover studies with multiple arms often need a current directions and stimulator types. Clin Neurophysiol
high number of patients. A larger-scale study is necessary 112:250–258, 2001
to reach definitive conclusions. The underlying disease 11. Lefaucheur JP, Drouot X, Ménard-Lefaucheur I, Keravel Y,
within our patients was heterogeneous and dominated by Nguyen JP: Motor cortex rTMS in chronic neuropathic pain:
CPSP (66.7%). The heterogeneity of drugs may also be one pain relief is associated with thermal sensory perception im-
provement. J Neurol Neurosurg Psychiatry 79:1044–1049,
of the study’s limitations. The number of patients in the 2008
current study was not large enough to conduct subgroup 12. Levkovitz Y, Roth Y, Harel EV, Braw Y, Sheer A, Zangen
analyses for investigating the effects of underlying dis- A: A randomized controlled feasibility and safety study of
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LH: Non-invasive brain stimulation techniques for chronic
In patients with NP, deep rTMS using an H-coil was a pain. Cochrane Database Syst Rev (9):CD008208, 2010
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nificant short-term pain relief of the lower extremities. Stefano G, et al: H-coil repetitive transcranial magnetic stim-
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Eur J Pain 17:1347–1356, 2013
Acknowledgments 16. Roth Y, Amir A, Levkovitz Y, Zangen A: Three-dimensional
We thank the Strategic Research Program for Brain Sciences distribution of the electric field induced in the brain by trans-
from MEXT and AMED of Japan for partial support of this study. cranial magnetic stimulation using figure-8 and deep H-coils.
J Clin Neurophysiol 24:31–38, 2007
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controlled trial. Pain 154:1065–1072, 2013 Prof. Zangen is an inventor of the deep transcranial magnetic
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 T. Shimizu et al.

of deep rTMS. The department of Neuromodulation and Neuro- Hosomi, Maruo, Goto, Yokoe, Kageyama, Yoshimine. Study
surgery is a joint research chair established with sponsorship by supervision: Saitoh, Shimizu, Hosomi, Yoshimine.
Teijin Pharma Limited.
Supplemental Information
Online-Only Content
Author Contributions Supplemental material is available with the online version of the
Conception and design: Saitoh, Shimizu, Hosomi, Maruo. Acqui- article.
sition of data: Saitoh, Shimizu, Hosomi, Maruo, Goto, Yokoe, Supplementary Materials. https://thejns.org/doi/suppl/10.3171/​
Kageyama. Analysis and interpretation of data: Shimizu, Hosomi, 2016.9.JNS16815.
Shimokawa. Drafting the article: Shimizu, Goto. Critically revis-
ing the article: Saitoh, Shimizu, Hosomi, Goto, Shimokawa, Correspondence
Yoshimine. Reviewed submitted version of manuscript: all Youichi Saitoh, Department of Neuromodulation and Neurosur-
authors. Approved the final version of the manuscript on behalf of gery, Osaka University Graduate School of Medicine, 2-2 Yama-
all authors: Saitoh. Statistical analysis: Shimizu, Hosomi, Shimo- daoka, Suita, Osaka 565-0871, Japan. email: [email protected].
kawa. Administrative/technical/material support: Saitoh, Shimizu, osaka-u.ac.jp.

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