Journal of Clinical Neuroscience 47 (2018) 72–78

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Journal of Clinical Neuroscience

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Clinical commentary

The optimal stimulation site for high-frequency repetitive transcranial

magnetic stimulation in Parkinson’s disease: A double-blind crossover
pilot study
Masaru Yokoe a,b,c, Tomoo Mano a,d, Tomoyuki Maruo a,d, Koichi Hosomi a,d, Toshio Shimokawa e,
Haruhiko Kishima d, Satoru Oshino d, Shayne Morris d, Yu Kageyama d, Yuko Goto a,d, Takeshi Shimizu a,d,
Hideki Mochizuki b, Toshiki Yoshimine d, Youichi Saitoh a,d,⇑
a
Department of Neuromodulation and Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
b
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan
c
Department of Neurology, Minoh City Hospital, Osaka, Japan
d
Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
e
Clinical Research Center, Wakayama Medical University, Wakayama, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Many reports have shown improvements in motor symptoms after repetitive transcranial magnetic stim-
Received 31 July 2017 ulation (rTMS). However, the best stimulation area in the brain has not currently been determined. We
Accepted 30 September 2017 assessed the effects of high-frequency rTMS (HF-rTMS) on the motor and mood disturbances in
Parkinson’s disease (PD) patients and attempted to determine whether the primary motor area (M1),
the supplementary motor area (SMA), and the dorsolateral prefrontal cortex (DLPFC) were the best treat-
ment targets. In this randomized, double-blind crossover design study, we investigated the efficacy of 3
consecutive days of HF-rTMS over the M1, SMA, and DLPFC and compared these HF-rTMS to sham stim-
ulations. We used motor and non-motor scales to evaluate the parkinsonian symptoms. The changes in
the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) scores after the application of HF-rTMS
over the M1 and SMA were significantly greater than those after the sham stimulation. However, after
the application of HF-rTMS over the DLPFC, the UPDRS-III scores were similar to those after the sham
stimulation. No significant improvements were demonstrated in the mood disturbances after the stimu-
lations over any of the targets. In conclusion, the application of HF-rTMS over the M1 and SMA signifi-
cantly improved the motor symptoms in the PD patients but did not alter the mood disturbances.
Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction
Parkinson’s disease (PD) is a progressive, debilitating neurode-
generative disease that affects dopaminergic neurotransmission,
thereby resulting in motor and non-motor symptoms. The non-
motor symptoms are the most common symptoms in PD patients
Abbreviations: rTMS, repetitive transcranial magnetic stimulation; PD, Parkinson’s
disease; M1, primary motor cortex; SMA, supplementary motor area; DLPFC,
dorsolateral prefrontal cortex; VAS, visual analogue scale; AES, the Apathy
Evaluation Scale; MADRS-S, the Self-Rated the Montgomery Åsberg Depression
Rating Scale version; SDS, the Self-Rating Depression Scale; STN, the subthalamic
nucleus.
⇑ Corresponding author at: Department of Neuromodulation and Neurosurgery,
Osaka University Graduate School of Medicine, Osaka, Japan 2-2 Yamadaoka, Suita,
Osaka 565-0871, Japan.
E-mail address: neurosaitoh@mbk.nifty.com (Y. Saitoh).
and progress throughout the course of the disease. Although the
non-motor symptoms deteriorate the patients’ quality of life, treat-
ments for PD primarily focus on improving the motor symptoms.
Repetitive transcranial magnetic stimulation (rTMS) is an emerg-
ing adjunctive therapeutic modality that is used to treat movement
disorders. rTMS is a non-invasive technique in which the cerebral
cortex is repeatedly stimulated by a train of magnetic pulses.
Pascual-Leone et al. first reported improvements in the upper
extremity movements of PD patients who had received rTMS [1].
Thus, many subsequent clinical trials have examined the use of
rTMS in PD and reported that rTMS was clinically effective in the
treatment of the motor symptoms in PD patients [2–9].
Many studies have demonstrated that PD patients exhibit an
ameliorated motor function in the hand and even gait after the
application of high-frequency (HF)-rTMS over the primary motor
area (M1) [4,7]. There are also a number of state-of-the-art

https://doi.org/10.1016/j.jocn.2017.09.023
0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
 M. Yokoe et al. / Journal of Clinical Neuroscience 47 (2018) 72–78 73

randomized controlled trials that have reported negative results
[10–14]. Both positive and negative results have been reported
regarding the application of HF-rTMS over the supplementary
motor area (SMA); thus, the efficacy of HF-rTMS over the SMA
remains inconclusive [15,16]. Another study attempted to improve
the mood disturbances in PD patients, and after the application of
rTMS over the left dorsolateral prefrontal cortex (DLPFC), the
results demonstrated positive effects in terms of the patients’
depression level [17]. However, many studies have reported that
there were no beneficial effects associated with this treatment.
Moreover, a few other studies have reported positive effects and
improvements in the motor symptoms in PD patients after the
application of rTMS over the DLPFC [17–19]. Although mood dis-
turbances are responsible for a large number of PD impairments,
the main focus of PD treatments is the improvement of the motor
symptoms. A meta-analysis has demonstrated that rTMS improves
motor symptoms in PD patients, and a subgroup analysis has
shown that HF-rTMS over the M1 and low-frequency (LF) rTMS
over other frontal regions significantly improved the motor symp-
toms, but the HF-rTMS appears to be better [20,21]. However, to
date, meta-analyses that examine the effects of rTMS on mood dis-
turbances in PD patients have not been conducted.
In the most recent study, rTMS over the M1 was an effective
treatment for the motor symptoms, but rTMS over the DLPFC did
not show a mood benefit [9]. HF-rTMS over the SMA has also been
suggested to modestly improve the motor symptoms in patients
with PD [15]; however, no studies have compared the application
of HF-rTMS over the M1 to that over the SMA. Each of the previous
rTMS studies examined different parameters (e.g., coil type, stimu-
lus locations, frequency, intensity, and sham stimulation). These
considerable methodological differences across studies, such as
the rTMS parameters and the evaluation methods, appear to be
simple explanations for the controversial results. These results
indicate a noteworthy lack of consensus regarding the specifica-
tions of the optimal stimulation area for PD treatment. Therefore,
we sought to determine which cortical area is the most promising
target for HF-rTMS therapy in patients with PD by conducting a
double-blind, placebo-controlled, crossover study. The aim of this
exploratory study is to identify an appropriate outcome measure
for subsequent studies.
2. Material and methods
2.1. Trial design
This randomized, double-blind, placebo-controlled crossover
study examined the effect of a bilateral stimulation over the M1,
SMA, or DLPFC compared with that observed after a sham stimula-
tion. At each location, the rTMS was repeated for 3 consecutive
days. To minimize any carryover effects between the different loca-
tions, the subjects underwent an interval of 4 or more days prior to
any subsequent stimulation. Fig. 1 shows the timeline of the rTMS
protocol. The independent statistician generated the random allo-
cation sequence by the independent statistician generated the ran-
dom allocation sequence. Patients continued to take their
medications during the study period to evaluate the additive effect
of the rTMS. All rTMS sessions were performed at the same time of
day throughout the daily treatment cycle. At the start of the study,
all patients had been taking a fixed dose of their usual anti-PD
medication for at least 2 weeks. Both the patients and the assessors
were blinded to the group assignments until after the study was
completed.

Fig. 1. Study design. This study used a placebo-controlled, crossover design. The treatments performed in all PD patients included rTMS over the M1, SMA, DLPFC and sham
stimulation (placebo). All treatments were performed daily over a period of three days each. The order of the rTMS treatments was randomly assigned. The patients and
assessors were blinded to the group assignments until after the completion of the study. To evaluate the effect of each rTMS session, all examinations were performed
immediately before and approximately 1 h after each rTMS session. Over the three days during which the patients were assessed, all evaluations were conducted at the same
time after the patients had received their medication and before their next medication requirement.
74 M. Yokoe et al. / Journal of Clinical Neuroscience 47 (2018) 72–78
2.2. Participants
We enrolled all patients with PD in this clinical study using pre-
viously defined diagnostic criteria for PD [22]. All patients were
recruited through the outpatient department at the Osaka Univer-
sity Hospital (Osaka, Japan). All patients were currently receiving
dopaminergic replacement therapy and were tested in the ‘on’
state (1 h after the anti-PD medication) [9]. Patients were excluded
from the study if they had dementia (Mini Mental Status Examina-
tion score < 24) [23], a history of seizures, implanted devices,
marked action tremors or marked bradykinesia according to a clin-
ical assessment based on the UPDRS criteria, severe depression, or
severe disabling dyskinesia that would disturb the stimulation.
These criteria were established to ensure safety, and we excluded
patients with severe parkinsonism, which was defined as a score
of 4 on each item of the UPDRS-III. The calculations of the levodopa
equivalent daily dose were based on a previously reported conver-
sion formula that has been successfully used to determine daily
doses [24]. The patients continued to take their medications during
the study to evaluate the additive effect of the rTMS. All rTMS ses-
sions were performed at the same time of day throughout the daily
treatment cycle. At the start of the study, all patients had been tak-
ing a fixed dose of their usual anti-PD medication for at least 2
weeks. After a full explanation of the study procedures, informed
consent was obtained from each patient in accordance with the
Declaration of Helsinki. The Ethics Committee of Osaka University
Hospital approved this study protocol (Number 12028). This clini-
cal trial was registered with the University Hospital Medical Infor-
mation Network Clinical Trials Registry (Number:
UMIN000010523).
2.3. rTMS
The application of the rTMS was performed using the Magstim
Super Rapid Magnetic Stimulator (Magstim Company, Whitland,
UK), which was connected to a 70-mm diameter figure-8 coil (or
an equivalent sham coil). After connecting the figure-8 coil to a
magnetic stimulator that delivered a biphasic pulse, the coil was
then placed over the M1 hand area, the SMA, or the DLPFC. To tar-
get the optimal position for the stimulation and ensure that the
cortical location was the same in each patient, our study used
navigation-guided rTMS (Brainsight Frameless, Rogue Research
Inc., Montreal, Canada), which utilized MRI-guidance to monitor
the position and direction of the coil and the position of the
patient’s head. Trackers with reflectors that were recognized by
the optical position sensor camera were attached along with other
MRI-guided navigation systems. The M1 hand area was deter-
mined by moving the coil in 1 cm increments according to a visual
detection of muscle twitches, and the resting motor threshold
(RMT) was defined as the minimal intensity necessary to induce
at least one visible muscle twitch. The SMA stimulation was
administered with a coil centered 3 cm anterior to the M1, and
the DLPFC stimulation was administered 5.5 cm anterior to the
M1 according to previous studies. The participants who underwent
the surface electromyography were asked to maintain a relaxed
position during the initial measurements. The minimum stimula-
tor intensity that was capable of evoking a 50-lV amplitude
motor-evoked potential in the target muscle (the extensor hallucis
brevis) in at least 50% of 10 consecutive trials was defined as the
resting motor threshold. High-frequency rTMS (HF-rTMS) was
applied using an intensity of 100% of the RMT at a frequency of
10 Hz. The pulse trains lasted 5 s with an inter-train interval of
25 s. Since 10 trains were delivered on both sides, a total of 1000
pulses were applied to each patient during a session. All rTMS
parameters that were used in this study were consistent with pre-
viously established guidelines [25,26]. The initial treatment was
performed on the side that was contralateral to the more severely
affected side. Then, we treated the opposite side.
2.4. Sham stimulation
We utilized a realistic sham stimulation method that was per-
formed in the same location as the sham stimulation [26]. Electri-
cal stimuli (10 Hz), which were the same as those used during the
real-rTMS, were given through electrodes that had been fixed on
the head. Consistently with the findings of a previous study [27],
we applied intensities that were 2 times the sensory threshold
for the skin electrical stimulation for a duration of 0.2 ms. All stim-
ulation parameters were the same as those used in the real-rTMS,
and the delivered electrical pulses were synchronized with the
TMS pulses using a sham figure-8 coil (Magstim Company). Due
to the high electrical resistance of the skull, this electrical stimula-
tion had a negligible effect on the cortex. However, these pulses do
stimulate the local cutaneous and muscle nerves, thereby causing a
sensation that can be felt by the patient. Several stimuli of each
type were delivered during the measurements of the RMT during
the real-rTMS and the sensory threshold during the sham stimula-
tion. Since all subjects received these stimulations for the first
time, they were not able to distinguish the real-rTMS from the
sham stimulations. Moreover, to ensure that the subjects could
not distinguish between the sham and the real-rTMS stimulations,
the electrodes were attached to the scalp during both procedures.
The optical navigation system prevented the electrodes from inter-
fering with the navigation. Compared to other previous sham pro-
cedures [5,7], our procedure was more realistic because it provided
the same sounds and sensations as those that occur during a real-
rTMS.
2.5. Clinical evaluations
Two independent physicians, who were blinded to the type of
stimulation, performed all clinical evaluations. Based on the
methodology of a previously published study [26,27], the outcome
measures were evaluated prior to and approximately 1 h after each
rTMS session. During each session, the same time interval was
used after the administration of the medication. The assessment
of the motor symptoms included the UPDRS-III, the 10-m walk test,
the self-assessment motor score [28], and the visual analog scale
(VAS) of motor symptoms [28]. The non-motor symptoms were
assessed at baseline and Day 3 using the Apathy Evaluation Scale
(AES) [29], the self-rated Montgomery-Åsberg Depression Rating
Scale version (MADRS-S) [30], and the Self-Rating Depression Scale
SDS) [31]. In addition, all subjects also completed the Parkinson’s
Disease Questionnaire-39 (PDQ-39) to assess the motor and mood
disturbances [32].
2.6. Statistical analysis
We used the average reduction in the UPDRS-III scores from the
three treatment days to evaluate the effectiveness of the rTMS in
each location (M1, SMA, DLPFC) and the sham stimulation. The
reductions in the UPDRS-III scores are presented as the mean and
SD. To analyze the differences in each rTMS location between the
sham and each rTMS, we used a paired t-test with a Bonferroni cor-
rection (i.e., p-values less than 0.05/3 = 0.016 were considered sig-
nificant). The AES, MADRS-S, PDQ-39, SDS, self-assessment motor
test, VAS scores, and the 10-m walk test outcomes were all evalu-
ated similarly to the UPDRS-III scores. To evaluate the carryover
effects and order effects, a one-way repeated measures ANOVA
was applied to the values on Day 1 of each session. The data were
analyzed using SPSS software (SPSS ver.20, IBM, Chicago, IL, USA).
 M. Yokoe et al. / Journal of Clinical Neuroscience 47 (2018) 72–78 75

3. Results
A total of 19 patients (8 men, 11 women; mean age, 69.1 ± 8.4
years; age range, 52–84 years; Hoehn and Yahr stage 2–4) enrolled
and completed the study. At the end of each of the treatment ses-
sions, none of the patients were able to identify which type of rTMS
(real or sham) they had received. The clinical characteristics of the
study population are presented in Table 1. The average RMT was
78.2 ± 9.94. One participant experienced a mild headache during
the DLPFC stimulation session that spontaneously resolved, and
the strength or unpleasantness was similar regardless of the site
and the type of stimulation (i.e., real or sham). The self-reported
data obtained from each of the medical questionnaires indicated
that there were no serious adverse effects.
We combined all data from the three sessions of each test.
Table 2 shows the UPDRS-III scores and the results of the AES,
MADRS-S, PDQ-39, SDS, self-assessment motor test, VAS, and the
10-m walk test. Compared with the sham stimulations, significant
changes were observed in the UPDRS-III total scores after the stim-
ulation over the M1 and SMA (pre-post score; [M1] 3.28 ± 2.25
points, [SMA] 1.90 ± 2.27 points, [DLPFC] 1.37 ± 2.12 points, [sham]
0.23 ± 1.69 points; [M1] p < .001, [SMA] p = .012, [DLPFC] p =
.085) (Table 2; data combined from all 3 sessions). Fig. 2 demon-
strates that these changes tended to be better with the application
of the HF-rTMS over the M1 than that over the SMA and DLPFC,
although these changes were not statistically significant. The
UPDRS-III sub-score analyses indicated significant amelioration of
the upper limb scores after the M1 and SMA stimulations versus
the sham stimulation (pre-post score; [M1] 2.19 ± 1.62 points,
[SMA] 1.12 ± 1.66 points, [DLPFC] 0.82 ± 1.63 points, [sham] 0.5
8 ± 1.58 points; [M1] p < .001, [SMA] p < .001, [DLPFC] p = .059).
Likewise, akinesia was also significantly ameliorated after the
application of the HF-rTMS over the M1 versus the sham stimula-
tion (pre-post score; [M1] 1.28 ± 1.26 points, [SMA] 0.40 ± 1.01
points, [DLPFC] 0.19 ± 1.11 points, [sham] 0.46 ± 1.00 points;
[M1] p < .001, [SMA] p = .088, [DLPFC] p = .164). Despite the
improvement in the lower limb items of the UPDRS-III with the
application of HF-rTMS over the M1, when the pre- to post-HF-
rTMS was compared to the pre- to post-sham stimulation, the walk
time and the number of steps taken to walk 10 m were similar
after the application of rTMS in all three locations. Consistent with
this observation, the instantaneous lower limb functions improved
after the M1 stimulation, but the endurance of the lower limb func-
tions and the trunk function did not improve.
No significant differences were observed in the self-assessment
mood, AES, MADRS-S, and SDS scores between the rTMS in each
location and the sham stimulation (Table 2). Additionally, the
changes in the PDQ-39 motor and non-motor scores from before
and after the rTMS stimulations were similar to those observed
in the patients who received the sham stimulation.
No detectable carryover effects (p = .851) or order effects (p =
.905) were observed in the entire study (Supplemental Fig. 1).
4. Discussion
To the best of our knowledge, this study is the first to investi-
gate the following three most promising areas for the application
of HF-rTMS in PD therapy: the M1, SMA, and DLPFC. The main find-
ing in our study was that compared with the sham stimulations,
the UPDRS-III scores improved after the application of bilateral
rTMS over the M1 and SMA. The sub-score analyses also demon-
strated improvements in the upper limb scores of the UPDRS-III
after the application of rTMS over the hand area of the M1 and
SMA. These results indicate that the M1 and SMA may be potential
sites for rTMS in the treatment of the motor dysfunction in PD
patients. In contrast, the changes in the UPDRS-III scores following
the bilateral rTMS over the DLPFC were not different from those
observed after the sham stimulation. No significant changes were
observed in either the depression or apathy scores after the appli-
cation of HF-rTMS in any of the cortical areas. Our current results
are partially consistent with our previous study that found
improvements in the UPDRS-III scores in PD patients who received
the application of HF-rTMS bilaterally over the M1 [33]. Multiple
studies have demonstrated the positive effects on the motor symp-
toms in PD patients after the application of HF-rTMS over the M1
[4,7,9]. HF-rTMS over the M1 may partially compensate for the
underactive basal ganglia-thalamocortical outflow to the frontal
motor cortical areas and induce lasting enhancement in cortical
excitability, thus leading to a clinical improvement. Furthermore,
the application of rTMS over the DLPFC has been commonly used

Table 1
Clinical data of the PD patients at baseline.

Pt. No. Sex Age (years) Disease duration (years) Hoehn & Yahr stage MMSE UPDRS Part3 LEDD RMT (%) Stimulus
(mg/day) Pattern
1 F 73 10 4 26 37 667 75 DMCS
2 F 64 8 3 30 34 666 64 SMCD
3 F 80 13 4 30 37 900 72 DMSC
4 F 72 14 4 29 20 1350 75 MCDS
5 M 70 7 4 27 37 1024 85 CMSD
6 F 80 13 4 25 22 969 80 SDLC
7 M 72 10 3 29 39 1024 81 MSDC
8 F 70 12 4 27 30 965 85 MCSD
9 M 65 7 3 30 29 836 78 MSCD
10 F 64 9 3 30 18 855 90 SDMC
11 F 64 15 4 30 55 1260 76 SMDC
12 F 71 10 4 26 19 1120 75 DCMS
13 F 74 8 3 30 34 524 54 SCDM
14 M 57 3 2 30 26 175 90 CSDM
15 M 73 11 4 25 32 1200 80 SCMD
16 M 78 7 3 28 26 763 92 DSMC
17 F 76 10 3 29 17 830 88 MDSC
18 M 45 6 4 30 28 860 63 CMDS
19 F 65 7 4 28 32 850 82 CSMD
mean (SD) M:F = 7:12 69.1 (8.4) 9.5 (3.2) 3.5 (0.6) 28.4 (1.8) 30.1 (9.2) 886.2 (270.4) 78.2 (9.94)

M; male, F; female, MMSE: Mini Mental Status Examination, UPDRS-III; the Unified Parkinson’s Disease Rating Scale part III, LEDD: levodopa equivalent daily dose, RMT:
resting motor threshold, In the boxes of Stimulus Pattern, abbreviations are listed below, M: M1, S: SMA, D: DLPFC, C: Sham, SD: standard deviation Anti PD medication
dosage is expressed as levodopa equivalent daily dose (LEDD) following published formulas: 1.0 mg pergolide = 1.0 mg, pramipexole = 5 mg, ropinirole = 1.5 mg, cabergoline
= 10 mg, bromocriptine = 300 mg, entacapone = 100 mg, amantadine = 100 mg levodopa.
76 M. Yokoe et al. / Journal of Clinical Neuroscience 47 (2018) 72–78

Table 2
Results of changes in clinical scores after stimulations (n = 19).

Mean (SD) P-values (vs. sham)

M1 SMA DLPFC Sham M1 SMA DLPFC
UPDRS-III total score 3.28(2.25) 1.90 (2.27) 1.37 (2.12) 0.23 (1.69) <0.001*** 0.012* 0.085 (n.s.)
Axial score 0.46 (0.89) 0.47 (0.60) 0.35 (0.87) 0.26 (0.78) 1.000 (n.s.) 1.000 (n.s.) 1.000 (n.s.)
Upper limb score 2.19 (1.62) 1.12 (1.66) 0.82 (1.63) 0.58 (1.58) <0.001*** <0.001*** 0.059 (n.s.)
Lower limb score 1.98 (1.72) 0.95 (1.41) 0.82 (1.48) 0.16 (0.76) 0.001** 0.170 (n.s.) 0.383 (n.s.)
Tremor 0.49 (0.96) 0.11 (0.61) 0.37 (0.92) 0.05 (0.34) 0.054 (n.s.) 0.730 (n.s.) 0.212 (n.s.)
Rigidity 1.00 (1.29) 0.49 (0.88) 0.39 (0.91) 0.21 (0.56) 0.058 (n.s.) 0.899 (n.s.) 1.000 (n.s.)
Postual stability 0.11 (0.30) 0.14 (0.37) 0.18 (0.30) 0.19 (0.30) 0.861 (n.s.) 1.000 (n.s.) 1.000 (n.s.)
Akinesia 1.28 (1.26) 0.40 (1.01) 0.19 (1.11) 0.46 (1.00) <0.001*** 0.088 (n.s.) 0.164 (n.s.)
Bradykinesia 0.12 (0.32) 0.16 (0.26) 0.18 (0.39) 0.09 (0.31) 1.000 (n.s.) 1.000 (n.s.) 1.000 (n.s.)
Walk time (sec) 2.49 (3.88) 4.21 (8.74) 2.62 (7.01) 1.74 (9.26) 0.743 (n.s.) 0.742 (n.s.) 1.000 (n.s.)
Number of steps 1.70 (3.89) 2.93 (3.76) 0.83 (5.50) 2.20 (8.70) 1.000 (n.s.) 1.000 (n.s.) 1.000 (n.s.)
Self-assessment score 2.72 (4.04) 3.54 (4.32) 3.47 (3.65) 2.83 (4.04) 1.000 (n.s.) 1.000 (n.s.) 1.000 (n.s.)
VAS 0.24 (0.84) 0.12 (0.14) 0.07 (0.11) 0.06 (0.08) 1.000 (n.s.) 0.220 (n.s.) 1.000 (n.s.)
AES 1.47 (5.15) 1.16 (5.10) 1.63 (5.68) 0.90 (5.25) 1.000 (n.s.) 1.000 (n.s.) 1.000 (n.s.)
MADRS-S 2.11 (8.08) 2.42 (7.87) 0.95 (6.98) 3.16 (8.23) 1.000 (n.s.) 1.000 (n.s.) 0.247 (n.s.)
SDS 0.52 (7.96) 0.37 (6.37) 1.53 (7.02) 0.63 (6.33) 1.000 (n.s.) 1.000 (n.s.) 0.625 (n.s.)
PDQ-39 6.26 (24.00) 7.16 (24.92) 7.58 (26.78) 2.63 (29.25) 1.000 (n.s.) 1.000 (n.s.) 0.247 (n.s.)

*; p < .05; *; p < .01; **; p < .001***, n.s.; not significant.
UPDRS-III; the Unified Parkinson’s Disease Rating Scale part III, VAS; visual analogue scale, AES; Apathy Evaluation Scale, MADRS-S; Self-Rated the Montgomery Åsberg
Depression Rating Scale version, SDS; Self-Rating Depression Scale, PDQ-39; 39-item Parkinson’s Disease Questionnaire, SD: standard deviation.

Fig. 2. The reduction values observed in the UPDRS-III total scores for each of the patients with PD. The true stimulations were compared with the sham stimulation at all
sites.

to treat depression, including depression in PD patients. Pal et al.
reported that rTMS (5 Hz, 600 pulses per day for 10 days) over
the left DLPFC in PD patients resulted in non-statistically signifi-
cant improvements in motor function and beneficial effects on
depression [34]. Currently, the therapeutic mechanisms of rTMS
in motor and mood disturbances in PD remain unclear and are con-
troversial. Findings from positron emission computerized tomog-
raphy studies that explored cortical activation in patients with
akinesia-predominant parkinsonism have suggested hypoactivity
in the SMA and dorsal premotor areas [35], including decreased
activity in the SMA and reduced efferent feedback in the basal
ganglia-thalamocortical motor loop [36]. Furthermore, although
HF-rTMS has been reported to have facilitatory effects, LF-rTMS
has been suggested to be inhibitory [1]. A previous report demon-
strated that HF-rTMS (5 Hz) over the SMA could modestly amelio-
rate the motor symptoms in PD patients [15]. However, a
subsequent study by the same group compared two types of rTMS
protocols that used different stimulation frequencies for applica-
tion in PD patients. These researchers reported a long-lasting ben-
eficial therapeutic effect of LF-rTMS (1 Hz) but not of HF-rTMS (10
Hz) or realistic sham stimulations [16]. A recent subgroup analysis
in a meta-analysis demonstrated that HF-rTMS in frontal regions,
including the SMA, was not significant, but LF-rTMS was significant
[21]. In our current study, we demonstrated positive effects on the
motor symptoms in PD patients after the application of HF-rTMS
over the SMA. However, the protocols differed between the studies.
Our rTMS was performed with 10 Hz (100% RMT) for 3 consecutive
days, but previous studies used different protocols. A recent study
further reported that differentiating between the inhibitory and
facilitatory effects with different frequencies of rTMS is very diffi-
cult to achieve [37]. The application of HF-rTMS over the M1
reportedly generates increases in the blood oxygen level-
dependent signal in the SMA [38]. Other studies have suggested
that the application of HF-rTMS over the M1 could potentially
facilitate cortical neuronal excitability [39,40]. The application of
HF-rTMS over the M1 has been reported to enhance the gain of
the SMA-M1 interactions in PD patients, thereby leading to the
modulation of the trans-synaptic activation of the SMA and the
amelioration of the motor symptoms [41]. In PD patients, the sub-
thalamic nucleus (STN) has been reported as a common site for
DBS. Therefore, Fox et al. proposed strong connectivity between
the STN and the M1 and SMA but not the left DLPFC [42]. Thus,
 M. Yokoe et al. / Journal of Clinical Neuroscience 47 (2018) 72–78
it may be impossible to establish sufficiently strong evidence
regarding the effectiveness of the rTMS application over the DLPFC
on motor symptoms. However, many treatment studies have
attempted to determine the effect of the HF-rTMS application over
the left DLPFC in patients with major depressive disorders. In fact,
most of these studies have reported positive effects when rTMS is
applied over the left DLPFC. Furthermore, in normal subjects, using
a circular coil to apply several trains of 10-Hz rTMS over the left
DLPFC resulted in a reduction in [11C]-raclopride binding in the
left dorsal caudate nucleus [43]. In addition, this procedure also
induced the release of endogenous dopamine in the ipsilateral cau-
date nucleus. Pal et al. examined depression in PD patients and
found beneficial effects after the application of rTMS over the left
DLPFC [34]. However, our current study was not able to demon-
strate any significant effect on mood disturbances after the bilat-
eral application of HF-rTMS over the DLPFC.
Our study, however, also demonstrated that there are no signif-
icant carryover effects, suggesting that the durability of the rTMS
effect would be required for longer effectiveness. In terms of clin-
ical therapy applications, daily or weekly stimulation for more con-
secutive days could improve the long-term effects of rTMS. Our
current study certainly lacks statistical power to show such a dif-
ference between each stimulation. These results are too limited
to conclude which is the best stimulation area for rTMS or support
any recommendations regarding therapeutic uses. This study has
set the groundwork for potential subsequent studies to investigate
the effects of rTMS for a prolonged period and with a larger group
of PD patients.
A few studies, including our own, have attempted and failed to
determine the effect of rTMS on mood disturbances in PD [9,34].
Intractable chronic pain is a sensory and emotional symptom of
PD. Although the application of rTMS over the M1 has been shown
to ameliorate this pain [44,45], the detailed mechanism underlying
this action remains unknown. In the current study, we also mea-
sured the effect of rTMS over the M1 on mood disturbances. How-
ever, our findings indicated that there were no significant changes
in mood disturbances.
5. Conclusions
Our current study confirmed that the application of HF-rTMS
over the M1 or the SMA was able to significantly ameliorate the
motor symptoms, but it did not clearly ameliorate the mood dis-
turbances in the PD patients. Moreover, the bilateral application
of HF-rTMS over the DLPFC did not significantly ameliorate either
the motor or mood disturbances in the PD patients. Our findings
may support the development of an optimal protocol for rTMS
treatment in PD patients. Further investigations of the specific
motor and mood disturbances in conjunction with new analyses
of functional brain images will not only be of great interest but
should also benefit the clarification of this mechanism.
Declaration of interest
The authors report no conflicts of interest concerning the mate-
rials or methods used in this study or the findings specified in this
paper. The Department of Neuromodulation and Neurosurgery,
Osaka University Graduate School of Medicine is a joint research
department sponsored by Teijin Pharma Limited.
Previous presentation
Part of this paper was previously presented as a poster presen-
tation on 31 March 2017 at the 13th International Conference on
77
Alzheimer’s and Parkinson’s Diseases and Related Neurological
Disorders in Vienna, Austria.
Sources of financial support
This study was partly supported by the Strategic Research Pro-
gram for Brain Sciences by the Ministry of Education, Culture,
Sports, Science and Technology of Japan (15dm0107049h0003),
the General Insurance Association of Japan, and the Japan Agency
for Medical Research and Development (15hk0102029h0001).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.jocn.2017.09.023.
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