Original Paper
Eur Neurol 2017;78:28–32
DOI: 10.1159/000477440
The Efficacy of High-Frequency Repetitive
Transcranial Magnetic Stimulation for
Improving Apathy in Chronic Stroke Patients
Nobuyuki Sasaki a Takatoshi Hara b Naoki Yamada b Masachika Niimi c
Wataru Kakuda d Masahiro Abo b
a
Department of Rehabilitation Medicine, International University of Health and Welfare Atami Hospital, Atami, and
b
Department of Rehabilitation Medicine, The Jikei University School of Medicine, c Department of Rehabilitation
Medicine, Tokyo Metropolitan Bokutoh Hospital, and d Department of Rehabilitation Medicine, International
University of Health and Welfare Mita Hospital, Tokyo, Japan
Keywords
Apathy · Stroke · Rehabilitation · Transcranial magnetic
stimulation · Chronic · Neuropsychological impairments
Abstract
Although repetitive transcranial magnetic stimulation
(rTMS) for hemiparesis is beneficial, so far no study has ex-
amined the usefulness of rTMS for apathy. Thirteen patients
with chronic stroke were assigned randomly to 2 groups:
rTMS group (n = 7) and sham stimulation group (n = 6). The
patients received 5 sessions of either high-frequency rTMS
over the region spanning from the dorsal anterior cingulate
cortex (dACC) to medial prefrontal cortex (mPFC) or sham
stimulation for 5 days. The severity of apathy was evaluated
using the Apathy Scale (AS) and the severity of depression
was evaluated using the Quick Inventory of Depressive
Symptomatology (QIDS) serially before and after the 5-day
protocol. The AS and QIDS scores were significantly im-
proved in the rTMS group, although they were not changed
in the sham stimulation group. The degree of change in the
AS score was significantly greater in the rTMS group than
that in the sham stimulation group. The degree of change in
the QIDS score was greater in the rTMS group than that in
the sham stimulation group, although the difference was
© 2017 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/ene
Received: February 28, 2017
Accepted: May 9, 2017
Published online: June 3, 2017
not statistically significant. The application of high frequen-
cy rTMS over the dACC and mPFC may be a useful interven-
tion for apathy due to stroke. © 2017 S. Karger AG, Basel
Introduction
Apathy is a frequent residual consequence of stroke
that occurs in at least 30% of stroke patients and inhibits
their rehabilitation and activities of daily living [1]. Al-
though the development of medical technology has in-
creased the number of patients surviving stroke, those
with apathy will be constrained to live the rest of their
lives with no delight. Recently, repetitive transcranial
magnetic stimulation (rTMS), which can increase or de-
crease cortical activity and modulate neural networks, has
been developed as an effective treatment for major de-
pressive disorder (MDD) [2]. This new technology is also
expected to improve neuropsychological impairments
due to stroke. Although there have been a lot of studies
regarding the efficacy of rTMS for improving hemiparesis
due to stroke in the chronic [3] and acute phases [4], no
study has assessed the therapeutic use of rTMS for apathy
in stroke patients. This study was designed primarily to
Universidad Nacional Autonóma de México
132.247.242.252 - 5/14/2018 9:16:36 PM
Nobuyuki Sasaki
Department of Rehabilitation Medicine
International University of Health and Welfare Atami Hospital
13-1, Higashi Kaigan-cho, Atami-Shi, Shizuoka 413-0012 (Japan)
Downloaded by:
E-Mail nobsasa1005 @ gmail.com
examine whether rTMS improves the apathy of chronic
stroke patients. Its secondary aim was to investigate the
presence or absence of adverse effects of rTMS for depres-
sion.
Materials and Methods
The studied subjects were 13 consecutive outpatients with
chronic stroke meeting all of the following inclusion criteria: (1)
more than 1 year after stroke onset; (2) clinical diagnosis of supra-
tentorial intracerebral hemorrhage without invasion into the cere-
bral cortex or cerebral subcortical infarction in the territory of the
middle cerebral artery confirmed with non-contrast brain CT or
MRI; (3) age at intervention was between 40 and 85 years; (4) no
surgical management including intravascular surgery; (5) no dis-
turbance of consciousness (eye opening score of 4 and best verbal
response of 5 on the Glasgow Coma Scale); (6) no apparent apha-
sia (ability to understand and follow verbal commands appropri-
ately); (7) no serious general complications requiring intensive
medical management (e.g., pneumonia, heart failure, urinary tract
infection, and malnutrition); and (8) no pathological conditions
referred to as contraindications for rTMS in the guidelines (e.g.,
patients with metal within the brain such as clips for aneurysms,
patients with a cardiac pacemaker, pregnant women, or a frequent
history of seizures) [5].
The subjects were assigned randomly to the rTMS group and
the sham stimulation group on the basis of the date of their entry
into this study. Since this was a pilot study conducted to investigate
the efficacy of rTMS, we did not perform any power analyses. All
patients were scheduled to receive 5 sessions of either rTMS or
sham stimulation over 5 consecutive days as out-patient treat-
ment. The severities of apathy and depression of the subjects were
evaluated serially before and after the 5-day treatment protocol,
and the degree of changes in the assessments with the intervention
was compared between both groups. The Ethics Committee of our
hospital approved the study protocol, and informed consent was
obtained from each patient before entry into the study.
Application of rTMS and Sham Stimulation
For the delivery of rTMS, an 80-mm, double-cone coil and Mag-
Pro R30 stimulator (MagVenture Company, Farum, Denmark)
were used. For high-frequency (HF)-rTMS, 10-s trains of 10 Hz
were applied repeatedly with 50-s inter-train intervals over a pe-
riod of 20 min (2,000 pulses per session). Before deciding on the
intensity of stimulation, we assessed the resting motor threshold
(RMT) of the intact leg motor area for each subject. RMT was de-
fined as the one with the least intensity that could evoke a visible
dorsiflex movement of the intact ankle when the coil was placed
vertically over the leg motor area. The intensity of rTMS in the
present study was 80% of RMT.
The stimulated site was defined from MRI findings as the up-
per-middle of the forehead extending from the external auditory
meatus to 30° above the orbitomeatal line, where the center of con-
tact between the 2 circles of the coils was placed vertically over the
midsagittal plane (Fig. 1). Sham stimulation was performed with a
pseudo coil that was not connected to the stimulator. The patients
in the sham stimulation group received only recorded sounds of
10-Hz stimulus from a speaker for 20 min.
HF-rTMS for Poststroke Apathy
Fig. 1. Photograph of repetitive transcranial magnetic stimulation
(rTMS) application using a double-cone coil. The stimulated site
was defined from MRI findings as the upper-middle of the fore-
head extending from the external auditory meatus to 30° above the
orbitomeatal line (OM line), where the center of contact between
the 2 circles of the coils was placed vertically over the midsagittal
plane.
During the rTMS session, the patients sat in a reclining wheel-
chair with their heads strapped to the headrest. In terms of safety,
the patients were monitored clinically through medical and neu-
rological examinations during the study period. Vital signs, in-
cluding blood pressure, heart rate, and consciousness level, were
assessed before and after each rTMS session. According to the se-
verity of cognition, conventional rehabilitation programs such as
attention process training for 40–60 min were provided daily for
all patients during the study period by therapists who were blind
to the allocation of the studied groups.
Clinical Measures of Apathy and Depression
The severity of apathy was evaluated using the Apathy Scale (AS)
[6] and the severity of depression was evaluated using the Quick
Inventory of Depressive Symptomatology (QIDS) [7]. Immediately
before the first application and immediately after the last application
of HF-rTMS or sham stimulation, these evaluations were performed
by an occupational therapist in our department who was blind to the
allocation and provided no training to the patients to ensure a bias-
free outcome evaluation. The brunnstrom recovery stage was ad-
ministered to all patients to evaluate hemiparesis immediately be-
fore the first intervention by a physical therapist in our department
who was also blind to the allocation of the patients.
Statistical Analyses
Data are expressed as the mean ± SD. Clinical characteristics
before intervention and baseline motor function were compared
between both groups using unpaired t tests for parametric data
(age and time between onset and rTMS), the Mann-Whitney U test
for non-parametric data (AS, QIDS, and brunnstrom recovery
stage), and the chi-square test for categorical data (gender, subtype
of stroke, and cerebral lesion side). In each patient group, signifi-
cant changes in the AS and QIDS following the intervention were
analyzed using the Wilcoxon signed-rank test. Following the inter-
vention, the Mann-Whitney U test was performed to compare the
extent of improvement (100 × [pre-intervention – post-interven-
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Eur Neurol 2017;78:28–32 29
DOI: 10.1159/000477440
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 Table 1. Comparison of clinical characteristics between both groups

Characteristic rTMS (n = 7) Sham (n = 6) Statistics

Age at admission, years 66.1±11.2 62.8±10.1 ns

Gender, male/female, n (%) 5 (71)/2 (29) 6 (100)/0 (0) ns
Subtype of stroke, CI/ICH, n (%) 5 (71)/2 (29) 2 (33)/4 (67) ns
Side of cerebral lesion, right/left, n (%) 4 (57)/3 (43) 3 (50)/3 (50) ns
Period between onset and rTMS, years 4.1±2.9 5.3±5.7 ns
BRS for the upper limb 3.4±1.0 3.2±0.8 ns
BRS for the fingers 3.1±1.1 2.2±1.2 ns
BRS for the lower limb 3.7±1.0 3.3±0.5 ns
AS at the beginning of rTMS 15.9±6.3 14.3±7.4 ns
QIDS at the beginning of rTMS 17.0±6.7 14.2±4.3 ns

Data are expressed as the mean ± SD, unless otherwise indicated.

RTMS, repetitive transcranial magnetic stimulation; CI, cerebral infarction; ICH, intracerebral hemorrhage;
BRS, Brunnstrom recovery stage; AS, Apathy Scale; QIDS, quick inventory of depressive symptomatology; ns,
not significant.

p = 0.02

1.0

0.5 0.5

QIDS
Fig. 2. Comparison of the extent of the im-
AS

provement in the Apathy Scale (AS; a) and

0
Quick Inventory of Depressive Symptom-
0
atology (QIDS; b). The extent of improve-
ment in the AS was significantly greater in –0.5
the rTMS group than that in the sham stim- a rTMS Sham b rTMS Sham
ulation group.

tion]/pre-intervention [%]) in the AS and QIDS between both
groups. All statistical analyses were performed using SPSS version
19 (SPSS, Inc., Chicago, IL, USA). A p value <0.05 was considered
to be statistically significant.
Results
Thirteen patients were enrolled into the study during
the study period; 7 and 6 chronic stroke patients were as-
signed to the rTMS group and sham stimulation group
respectively. All patients completed the study protocol.
No patient experienced any pathological symptoms or de-
terioration of neurological symptoms. None of the pa-
tients were able to recognize the protocol they were receiv-
ing during the rTMS sessions, since none had experienced
rTMS before entry into the study and none had detailed
knowledge of rTMS. The clinical characteristics of the
study patients in both groups are presented in Table 1. For
all studied patients, the age at admission was between 48
and 82 (mean 64.6 ± 11.2 years), and the time between ad-
mission and intervention ranged from 1.0 to 16.8 years
(mean 4.7 ± 4.3 years). Diagnosis was confirmed by brain
CT or MRI as cerebral infarction in 7 patients and intrace-
rebral hemorrhage in 6 patients. The differences in the
clinical characteristics of the 2 groups were insignificant.
Moreover, differences in the AS and QIDS scores for both
groups before intervention were insignificant.
The AS score had significantly improved in the rTMS
group (from 15.9 ± 6.3 to 9.3 ± 6.0; p < 0.05), although it had
not changed much in the sham stimulation group (from
14.3 ± 7.4 to 13.8 ± 8.3). Similarly, the QIDS score had sig-
nificantly improved in the rTMS group (from 17.0 ± 6.7 to
9.9 ± 6.0; p < 0.05), although it had not changed in the sham
stimulation group (from 14.2 ± 4.3 to 11.7 ± 5.1; Fig. 2). The
degree of change in the AS score was significantly greater
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30 Eur Neurol 2017;78:28–32 Sasaki/Hara/Yamada/Niimi/Kakuda/Abo

DOI: 10.1159/000477440
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Table 2. Changes of assessment scores between rTMS interventions
rTMS Sham
pre post statistics pre post statistics
AS 15.9±6.3 9.3±6.0 0.02 14.3±7.4 13.8±8.3 ns
QIDS 17.0±6.7 9.9±6.0 0.03 14.2±4.3 11.7±5.1 ns
Data are expressed as the mean ± SD.
RTMS, repetitive transcranial magnetic stimulation; AS, Apathy Scale;
QIDS, quick inventory of depressive symptomatology; ns, not significant.
in the rTMS group than that in the sham stimulation group
(47.5 ± 31.9 vs. 1.7 ± 27.8%, respectively, p = 0.02). The de-
gree of change in the QIDS score was greater in the rTMS
group than that in the sham stimulation group, although
the difference was not statistically significant (38.2 ± 32.3
vs. 18.4 ± 21.8%, respectively, p = 0.23; Table 2).
Discussion
Although many studies have been performed on the
efficacy of rTMS in hemiparesis due to stroke, studies on
its effects on cognitive dysfunction are scarce. To our
knowledge, this is the first report of the application of
rTMS for apathy in stroke patients. The AS scores of the
rTMS group decreased significantly without any adverse
events. In addition, our protocol also improved the QIDS
scores of the rTMS group.
Marin defined apathy as diminished motivation not
attributable to a diminished level of consciousness, cogni-
tive impairment, or emotional distress [8]. More recently,
Levy et al. redefined apathy as a “quantified and observ-
able behavioral syndrome consisting of a quantitative re-
duction of voluntary (or goal-directed) behaviors,” posit-
ing that an evaluation of motivation should be based on
observable behaviors and emotions [9]. However, cur-
rently, there is still confusion over the definition and di-
agnostic criteria of apathy. In particular, apathy is often
confused with depression both conceptually and clinical-
ly. In the QIDS used to evaluate depression in the current
study, 1 of the 16 questions asks about the general inter-
ests of the person [7].
The mechanism underlying apathy is categorized into
3 subtypes, which consist of emotional-affective process-
ing, cognitive processing, and most importantly, auto-ac-
tivation processing. The prefrontal cortex (PFC) and bas-
al ganglia are known to be involved in apathy. These re-
gions can be further divided based on the above 3 subtypes
HF-rTMS for Poststroke Apathy
into the orbital-medial PFC, which is responsible for
emotional-affective processing, the dorsolateral PFC
(DLPFC), which is responsible for cognitive processing,
and the dorsal anterior cingulate cortex (dACC) and me-
dial PFC (mPFC), which are responsible for auto-activa-
tion processing [10]. With regard to the dACC, a past
study reported that dACC ablation had an effect on action
initiation, but not on action selection, in patients who un-
derwent therapeutic bilateral cingulotomy [11].
In the current study, we stimulated the region span-
ning from the dACC to mPFC, which is the most impor-
tant region for apathy as mentioned above. There were 2
other reasons why we chose this region. The first was a
technical reason. Although a double-cone coil can stim-
ulate deeper regions than an 8-figure coil, which is gen-
erally used for rTMS [12], it is difficult to stimulate very
deep regions such as the orbital-medial PFC. Even with
this coil, it is not impossible to stimulate very deep re-
gions when the stimulation intensity is markedly high.
However, since the magnetic field widely stimulates the
scalp surface in such cases, patients often cannot tolerate
the pain of the stimulation, and the locality of the stimu-
lation is decreased. In our protocol stimulating the re-
gion from dACC to mPFC using double-cone coil, none
of the subjects complained of intolerable pain. The sec-
ond reason was the possibility of an adverse effect on
depression. RTMS for MDD has been studied earlier
than rTMS was studied for stroke, and it has been ap-
proved by the Food and Drug Administration in the
United States as a therapeutic method. Both facilitatory
HF-rTMS to the left DLPFC and inhibitory low-frequen-
cy rTMS to the right DLPFC have been indicated to be
effective for MDD patients by some meta-analytic stud-
ies [13]. That is, it is possible that the left and right
DLPFC play distinctively different roles in depression.
The subjects in the current study were stroke patients
with a hemispheric lesion, and it is unclear how their left
and right DLPFC contributed to their symptoms of de-
pression. Since no studies regarding rTMS for poststroke
depression (PSD) have been reported, we did not choose
the DLPFC as a stimulation site. We believe that our
method was effective and safe because the AS scores im-
proved and the QIDS scores did not deteriorate as a re-
sult of the treatment. In recent years, the efficacy of
HF-rTMS to the dorsomedial PFC in MDD has been re-
ported [14], and it is possible that our rTMS stimulated
the dorsomedial PFC, which in turn improved the QIDS
scores in the current study.
PSD is a symptom that presents in patients who have
disability related to stroke such as paralysis and higher
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DOI: 10.1159/000477440
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brain dysfunction, and thus is essentially different from
MDD. In a study using diffusion tensor imaging in pa-
tients with small vessel disease, which is a subtype of
stroke, apathy following stroke was directly associated
with white matter microstructural changes, while depres-
sion emerged secondary to motivational loss and cogni-
tive impairment [15]. That is, PSD maybe a symptom that
is an extension of apathy, and it is possible that the im-
provement in the QIDS scores was due to the improve-
ment of apathy in the current study.
This study had some limitations. First, the long-lasting
effect of improving apathy was not evaluated in this study.
Future study is necessary to verify such point. Second, we
did not apply any neuroimaging techniques, such as func-
tional MRI or positron emission tomography. Neuroimag-
ing techniques should be applied to investigate the differ-
ence in functional neural reorganization with the interven-
tion between the treatment and nontreatment groups.
Third, the studied patients represented a heterogeneous
group with regard to the stroke type and baseline stroke se-
verity. Differences in the beneficial effect of rTMS should be
assessed among various types of stroke and stroke severity.
Conclusion
Our proposed rTMS protocol using a double-cone
coil is a safe and feasible intervention to achieve recov-
ery from apathy in patients with stroke in the chronic
phase. Apathy not only significantly reduces quality of
life but also interferes with rehabilitation efforts for the
impairments of stroke including paralysis. Therefore,
our approach for poststroke apathy is considered im-
portant.
Disclosure Statement
The authors report no conflicts of interest. The authors alone
are responsible for the content and writing of the paper.
Funding Sources
Funding for this study was provided by a Grant-in-Aid for Sci-
entific Research from the Japan Society for the Promotion of Sci-
ence (No. 26350589).

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