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Regular Article
Increase of frontal cerebral blood volume during
transcranial magnetic stimulation in depression is related
to treatment effectiveness: A pilot study with near-infrared
spectroscopy
Toshikazu Shinba, MD ,
1,2
*Nobutoshi Kariya, MD,
2
Saori Matsuda, BS,
2
Hanae Matsuda, MS
2
and Yusuke Obara, BS
2
1
Department of Psychiatry, Shizuoka Saiseikai General Hospital, Shizuoka, and
2
Maynds Tower Mental Clinic, Tokyo, Japan
Aim: Alterations of cerebral blood flow have been
reported in studies of depression treated by transcra-
nial magnetic stimulation (TMS). However, the rela-
tion between these changes in activity during
stimulation and the effectiveness of TMS is not
known. The aim of this study was to determine
whether changes in frontal cerebral blood volume
measured as frontal hemoglobin concentration
(fHbC) during TMS are correlated with clinical out-
comes of treatment.
Methods: Fifteen drug-resistant patients with depres-
sion underwent a standard treatment regimen of TMS
to the left dorsolateral prefrontal cortex. We recorded
fHbC during stimulation at the start and end of the
TMS treatment series using near-infrared spectros-
copy. Symptom severity was determined using the
Montgomery–Åsberg Depression Rating Scale.
Results: At the start of the TMS series, fHbC
increased during stimulation in a majority of
patients with no relation to symptom severity.
However, at the end of the series, fHbC increase
during stimulation was negatively correlated with
the Montgomery–Åsberg Depression Rating Scale
score and positively with the score reduction.
Patients showing a decreasing response of fHbC
during TMS at the end of the series experienced less
clinical improvement.
Conclusion: These results suggest that the mainte-
nance of frontal activation during stimulation in the
course of TMS series is related to the effectiveness in
the treatment of depression. Measurement of fHbC
during stimulation is informative in the clinical use
of TMS.
Key words: frontal cerebral blood volume, hemo-
globin concentration, major depressive disorder,
near-infrared spectroscopy during transcranial mag-
netic stimulation, treatment effectiveness.
TRANSCRANIAL MAGNETIC STIMULATION
(TMS) delivered in a standardized high-
frequency pulse sequence to the left dorsolateral
prefrontal cortex (DLPFC) is a safe and effective
treatment for patients with major depressive
disorder who have not received benefit from
antidepressant medication.
1–5
Although the clinical
application of TMS as an antidepressant is well
established in randomized clinical trials, the exact
biological mechanism underlying its clinical effec-
tiveness is not well understood. The present study
intended to examine the role of frontal cerebral
hemodynamic change during stimulation in the
clinical effectiveness of TMS.
Previous reports on depression have shown that
TMS applied to the left DLPFC modulates cerebral
blood flow (CBF) in several brain regions, including
*Correspondence: Toshikazu Shinba, MD, PhD, Department of
Psychiatry, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-
ku, Shizuoka 422-8527, Japan. Email: t156591@siz.saiseikai.or.jp
Received 7 October 2017; revised 17 April 2018;
accepted 13 May 2018.
©2018 The Authors
Psychiatry and Clinical Neurosciences ©2018 Japanese Society of Psychiatry and Neurology
602
Psychiatry and Clinical Neurosciences 2018; 72: 602–610 doi:10.1111/pcn.12680
the frontal cortex.
6–8
Based on these findings, stud-
ies have investigated the relation between changes
in brain metabolic activity and treatment effective-
ness. The antidepressant effects of TMS are associ-
ated with functional changes in the frontal brain, as
well as changes in functional connectivity among
the regions, including the frontal cortex.
9,10
TMS
nonresponders also showed significant hypoperfu-
sion in the superior frontal cortices (Brodmann area
10) compared to responders.
11
These findings indicate that frontal CBF changes
are related to treatment efficacy in depression. How-
ever, in most studies, data have been collected
before and after the stimulation. Monitoring these
measurements during stimulation is important given
that primary changes in these systems could be
related to treatment effectiveness. Although in sev-
eral studies, CBF was measured during TMS in
healthy subjects,
12
the relation between these mea-
surements and clinical efficacy in the treatment of
depression has yet to be determined.
In the present study, it was hypothesized that CBF
change in the frontal cortex during stimulation is
related to amelioration of symptoms. We used near-
infrared spectroscopy (NIRS) to measure frontal
cerebral hemoglobin concentration (fHbC) reflect-
ing cerebral blood volume during stimulation and
assessed the relation with treatment effectiveness.
NIRS is a non-invasive method to assess CBF by
measuring hemoglobin concentration using near-
infrared light absorption in the brain, and has been
widely applied to mental disorders, including
depression.
13
Although spatial resolution is less pre-
cise in NIRS in comparison with other techniques,
including functional magnetic resonance imaging
and single-photon emission computed tomography,
NIRS has the advantage in the temporal resolution
and was adequate for simultaneous measurement
with magnetic stimulation in the present study. The
results support the usefulness of fHbC measurement
during TMS for evaluating its clinical effectiveness.
METHODS
Subjects
Fifteen subjects who had been diagnosed with major
depressive disorder according to the DSM-IV
14
and
who sought treatment at Maynds Tower Mental
Clinic, Tokyo, Japan, participated consecutively in
the present pilot study (mean age SD, 45.4 10.8
years; 11 men, four women; all were right-handed).
Patients who had neurological disorders or other
psychiatric disorders were excluded from the study.
The age of onset, the duration of illness, and the
number of depressive episodes were 38.7 9.6 years,
6.7 4.5 years, and 1.2 0.6, respectively.
Depression symptoms were evaluated using the
Montgomery–Åsberg Depression Rating Scale
(MADRS),
15
and the mean score of the patients was
24.1 8.0 at the start of the TMS treatment. After
the treatment, the score decreased to 10.2 7.9.
Eleven patients showed a decrease by 10 points or
more, but none was completely free from depressed
symptoms. The reduction rate in the MADRS score
was calculated as the difference between the MADRS
score at the start and the end of treatment divided
by the MADRS score at the start (100 ×[start
–end] / start), and was 59.5 23.7%.
According to clinical history, all patients recruited
for this study had failed to receive sufficient clinical
benefit from treatment with multiple types of anti-
depressant medications for more than a year, and
were therefore considered to be treatment resistant.
Benzodiazepines were also used in some cases due
to symptomatic severity during TMS treatment; the
patients continued to take their currently prescribed
antidepressant or antianxiety medications without
any change in dose (89.6 85.8 mg [fluvoxamine-
equivalent] and 5.9 6.4 mg [diazepam-equiva-
lent], respectively).
16–18
Six patients were not taking
antidepressants at the time of the TMS treatment
series.
All study procedures were reviewed and approved
by the Institutional Review Board of Maynds Tower
Mental Clinic. All subjects signed informed consent
before any study procedures were performed.
TMS procedures
All TMS treatments were performed with the Neuro-
Star TMS Therapy System (Neuronetics, Inc.,
Malvern, PA, USA). Stimulation was performed
according to standard procedures as described in the
product documentation. During the initial treatment
session, the location of the motor strip was identi-
fied by single-pulse stimulation, with specific identi-
fication of the location for movement of the
contralateral thumb. Motor threshold (MT) was
obtained using an automated algorithm (MT Assist,
Neuronetics, Inc.). The mean MT in all patients was
©2018 The Authors
Psychiatry and Clinical Neurosciences ©2018 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2018; 72: 602–610 NIRS during TMS in depression 603
1.25 0.18 standard motor threshold (SMT; a unit
used for stimulation intensity in NeuroStar). The
stimulation site at the left DLPFC was then identi-
fied by advancing the coil 5.5 cm anterior to the MT
location, using a mechanical head-support system,
along a parasagittal line with a rotation point cen-
tered about the patient’s nose. Treatment parameters
were standardized for each session at the treatment
location with a magnetic field intensity of 120% of
MT, at a pulse frequency of 10 pulses/s, with a 4-s
on time and a 26-s off time for a total exposure of
3000 pulses per session. Each treatment took
37.5 min and was performed 5 days per week for
6 weeks for a total of 30 treatments (Fig. 1).
NIRS measurement
On the first (start) and last (end) day of the TMS
treatment series (Fig. 1), fHbC was monitored while
the stimulation session was underway. Data were
obtained continuously within the 37.5-min TMS ses-
sion with the treatment session being uninterrupted
for these assessments. We assessed fHbC by measur-
ing oxygenated hemoglobin (oxyHb) using
continuous-wave NIRS with the projection and
detection probes separated by 5 cm on the forehead
(two white circles in Fig. 1, NIRO-300, Hamamatsu
Photonics, Hamamatsu, Japan). The center of the
probes was set at Fpz, and the separation interval of
the probes was 5 cm to cover bilateral frontal
poles.
19
The NIRS apparatus uses three wavelengths
of near-infrared light. The path length was set at
30 cm and the oxyHb index was calculated using
the following equation: oxyHb concentration ×
30 (M ×cm).
19
The fHbC response to TMS was cal-
culated as the difference between the averaged
oxyHb index during stimulation and the average of
1-min pre-stimulation baseline data (horizontal
line, Fig. 2).
Because the path length in the continuous-wave
NIRS measurement is not known and was set at
30 cm in the present study, the difference from the
real path length may have lessened the credibility of
the data. However, the direction of the fHbC
response during TMS, positive or negative, with ref-
erence to the baseline is not affected by the path
length, and actually varied depending on the TMS
session (Fig. 3a); fHbC increased during some stim-
ulations (fHbC increase) and reduced during others
(fHbC decrease). At the initial session, most of the
patients showed fHbC increase during stimulation.
On the other hand, the fHbC decrease pattern was
observed more at the end of the treatment series. In
the present study, we divided the patients into two
groups with different directions of changes at the
end of the treatment series: the HbC increase group
and the fHbC decrease group.
Statistical analysis
The data were analyzed after TMS treatment was
over. Spearman’s correlation coefficients were used
to identify possible correlations between fHbC and
MADRS scores to test whether the former were
related to clinical outcome. The difference in MADRS
scores, MT levels, medications, and other demo-
graphic data between the fHbC increase and decrease
groups were checked using the Student’st-test or
Fisher’s test (Prism5, GraphPad Software, La Jolla,
CA, USA). The alpha level of the statistics was set at
0.05. Normal distribution of the data was confirmed
by Kolmogorov–Smirnov normality test when the
Student’st-test was used (P> 0.1). Cohen’sd(d)was
calculated to examine the effect size.
RESULTS
Relation between fHbC during stimulation
and MADRS score
Figure 4 shows the correlation between the fHbC
response and the MADRS score. There was no signif-
icant correlation between the fHbC response and
First
treatment
NIRS
Last
treatment
TMS
TMS treatment series (6 weeks)
Figure 1. Frontal cerebral hemoglobin concentration was
recorded by near-infrared spectroscopy (NIRS) at the forehead
(white circles: projection and detection probes) during tran-
scranial magnetic stimulation (TMS) at the first and last treat-
ments in the 6-week TMS treatment series.
©2018 The Authors
Psychiatry and Clinical Neurosciences ©2018 Japanese Society of Psychiatry and Neurology
604 T. Shinba et al.Psychiatry and Clinical Neurosciences 2018; 72: 602–610
the MADRS score at the start of the TMS treatment
(r=−0.36, P> 0.05, d= 0.77), but a negative corre-
lation was found between these two parameters at
the end of the treatment series (r=−0.77, P= 0.004,
d= 2.39). The score reduction rate in the MADRS
score was positively correlated with the fHbC
response at the end of the treatment series (r= 0.54,
P= 0.036, d= 1.29).
MADRS scores in the fHbC increase and
decrease groups
In the present study, the subjects were divided into
two groups (fHbC increase or fHbC decrease) based
on the fHbC response during stimulation at the end
of the TMS treatment series (Fig. 3a). At the start of
the series, the majority of the subjects showed an
increase in fHbC during stimulation. At the end of
the series, some patients maintained an increased
fHbC response (fHbC increase group, n= 9),
whereas other patients exhibited a decreased fHbC
response during stimulation (fHbC decrease group,
n= 6). Table 1 summarizes the demographic, NIRS,
and MADRS data. The fHbC responses during TMS
of both groups were statistically different at the end
of the treatment series (P< 0.001), but not at the
start (P> 0.05). The difference between the fHbC at
the start and end in the decrease group (end –start)
was significantly larger than that in the increase
group (P< 0.001). There were no significant differ-
ences in age, sex, or MT level between the two
groups (P> 0.05, Table 1). The MADRS score at the
beginning and end of the treatment in the fHbC
increase group was significantly lower than that in
the decrease group (t= 2.787, P= 0.015, d= 1.21
and t= 3.301, P= 0.006, d= 1.33, respectively). The
score reduction rate in the MADRS at the end of the
treatment series was significantly greater in the fHbC
increase group compared to the fHbC decrease
group (Fig. 3, B, P= 0.030, d= 1.10).
Medication
As for the daily use of medication, fluvoxamine-
equivalent doses of antidepressants and diazepam-
equivalent of doses of antianxiety drugs were calcu-
lated based on the clinical doses recommended by the
manufacturers (Table 1).
16–18
There was no significant
difference between the two groups (P> 0.05).
DISCUSSION
Frontal activation during TMS and
treatment effectiveness
Previous studies have shown that TMS induces
increase in CBF after a series of stimulation ses-
sions.
7,20
However, in these studies, post-TMS CBF
was measured more than 1 day after the end of the
treatment series. The present study is unique in
assessing CBF during stimulation. Moreover, no rela-
tion with therapeutic efficacy was observed at the
initial session with a majority of the patients show-
ing frontal activation during stimulation, but the
relation became significant at the end of the treat-
ment series (Fig. 4). The subjects with higher frontal
cerebral blood volume responses during stimulation
at the end of the treatment series had lower MADRS
scores and a greater reduction in MADRS score. The
activation was mainly seen in the patients showing
clinical recovery at the end of the treatment, and
–150 –120
0
150
0
120
300
microM*cm
TMS TMS
Increase Decrease
Figure 2. Increase and decrease responses of the frontal hemoglobin concentration (fHbC) during transcranial magnetic stimula-
tion (TMS). The fHbC response was calculated as the relative change in the oxygenated hemoglobin index during stimulation
from the 1-min pre-stimulation baseline (horizontal line).
©2018 The Authors
Psychiatry and Clinical Neurosciences ©2018 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2018; 72: 602–610 NIRS during TMS in depression 605
would be related to the outcome of TMS therapy.
The dose of medication or the MT level had no
effect on the present findings.
The results may suggest that the failure to main-
tain activation and the shift to deactivation of the
frontal cortex during stimulation in the course of
treatment are related to inability to reduce depres-
sive symptoms by TMS, as assessed through the
MADRS. It was considered that alteration of respon-
siveness of the frontal cortex to stimulation could be
due to dysfunction of the brain in the depressed
patients not responding to TMS treatment. MADRS
data suggest that the failure to maintain frontal acti-
vation to TMS is related to the severity of depressive
disorder at the start of the treatment series. TMS
treatment may be more effective for depression with
milder symptoms. Obtaining the frontal cerebral
blood volume data during stimulation at the begin-
ning and end of the treatment series can allow us to
assess the pathophysiological changes of the brain
in depression as well as the therapeutic efficacy and
validity of TMS. Further studies with other neuronal
measurements are warranted.
21
It is known that the prefrontal cortex has rich
bilateral connections with various cortical and sub-
cortical areas.
22
Stimulation of the DLPFC in the
present study should activate various brain areas,
including the frontal brain itself in relation to symp-
tom recovery. The presence of activation at the end
of the treatment series may suggest that the patients
with greater recovery have received the ameliorative
effect of TMS sufficiently during the treatment series.
On the other hand, the activation may be dimin-
ished in the nonresponding patients in the course of
treatment series, leading to insufficient clinical
effects. This finding may be related to the previous
report by Richieri et al.
11
which showed significant
hypoperfusion in several brain regions of depressed
patients resistant to TMS treatment, including the
bilateral superior frontal cortices, although the
hypoperfusion in this report was present in the pre-
stimulation baseline state. The underlying brain
mechanisms of altered activity during stimulation in
the nonresponding patients of the present study
should be assessed in future research with more fre-
quent measurements in the treatment series.
In the present study, we analyzed the frontal cere-
bral blood volume data in two ways, correlation
analysis and comparison of the mean in two groups,
fHbC increase and decrease, because of the method-
ological limitation in continuous-wave NIRS with
the path lengths unknown.
19
However, the results
from the two kinds of analyses are the same and
confirm our conclusions. The data regarding the
300
300
150
150
0
0
–150
–150
Start of
the TMS series
fHbC Response
Increase group Decrease group
End of
the TMS series
microM*cm
(a)
(b) fHbC response and %reduction of MADRS score
Increase group Decrease group
0
20
40
60
80
100
%
Figure 3. (a) The subjects were divided into two groups based
on the frontal hemoglobin concentration (fHbC) response
during transcranial magnetic stimulation (TMS) at the end of
the treatment series (fHbC increase and fHbC decrease groups;
circle: individual data; horizontal line: average). The increase
group showed an increase in fHbC, whereas the decrease
group exhibited a decrease in fHbC. (b) The reduction (%) in
the Montgomery–Åsberg Depression Rating Scale (MADRS)
scores at the end of the treatment series in the fHbC increase
and fHbC decrease groups (circle: individual data; horizontal
line: average). There was a significantly greater reduction in the
MADRS scores in the fHbC increase group compared to the
fHbC decrease group (P= 0.030).
©2018 The Authors
Psychiatry and Clinical Neurosciences ©2018 Japanese Society of Psychiatry and Neurology
606 T. Shinba et al.Psychiatry and Clinical Neurosciences 2018; 72: 602–610
fHbC increase and decrease will be interesting when
the clinical usage of NIRS measurements is consid-
ered in the TMS treatment of depression, because
the increase or decrease discrimination would be
simple and convenient. The present results suggest
that the fHbC increase and decrease groups may be
grossly assimilated to responders and nonre-
sponders, respectively. It has been reported in a pos-
itron emission tomography study that responders to
treatment with antidepressant or placebo for
6 weeks showed activation in several cortical
regions, including frontal areas.
23
The present find-
ing further indicates that frontal activation is related
to the therapeutic response by TMS.
Previous studies have reported that CBF could be
used to predict the effectiveness of treatment. High
activity in the neocortical, anterior cingulate, and
limbic areas before the start of treatment is related
to the TMS treatment response.
24–26
A task-related
change in CBF can also predict the clinical response
to TMS.
27
In addition to these pretreatment data,
the present study revealed the usefulness of moni-
toring frontal CBF during TMS, which will lead to
understanding of the direct neural response to TMS
regarding the treatment outcome.
Stimulation sites and parameters
As for the stimulation parameters, the present study
used TMS at a stimulation frequency of 10 Hz to the
left DLPFC. A lower stimulation frequency has been
shown to have different effects on regional brain
–150 0
40 40
100
Start
MADRS score
%reduction of
MADRS score
End
fHbC response at the end of the series (microM*cm)fHbC response at the start of the series (microM*cm)
r = –0.77
r = 0.54
150
–150 0 150
100 × (Start – End) / Start
Figure 4. The relation between frontal cerebral hemoglobin concentration (fHbC) response during transcranial magnetic stimu-
lation (TMS) at the start (Start) and the end (End) of the treatment series and the Montgomery–Åsberg Depression Rating Scale
(MADRS) scores as well as with the reduction rate (%) of the MADRS scores at the end of the series: 100 ×(Start –End) / Start.
At the start of the treatment series, no correlation was observed between the fHbC response and the MADRS score. However, at
the end of the series, fHbC was significantly correlated with both the MADRS score and the reduction in MADRS score. The
regression lines are also shown in the figures.
©2018 The Authors
Psychiatry and Clinical Neurosciences ©2018 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2018; 72: 602–610 NIRS during TMS in depression 607
activity in depressed patients.
6
High-frequency TMS
leads to an overall increase, whereas low-frequency
TMS produces a decrease in CBF.
8
In addition, stim-
ulation of the right brain hemisphere
28,29
and
change in the coil orientation lead to different
effects in CBF.
30
Further studies with different stimu-
lation sites and parameters would reveal more ade-
quate ways to use CBF to evaluate the treatment
efficacy and severity of depression.
Limitations
This was a pilot study with a small number of
patients and high male-to-female ratio. Future stud-
ies with a larger sample size will be important,
because the individual variation could be large. It is
also underlined that the results are valid for the
patients who do not show sufficient improvements
with antidepressant medication. Future studies are
necessary to expand the assessment to depression in
general.
In the present study, we only measured frontal
cerebral blood volume at the start and end of the
TMS treatment series, and the data in the middle of
the treatment series are lacking. It was not examined
in the present study whether frontal response pat-
tern in the middle of the series was fHbC increase or
decrease. Multiple fHbC measurements in the course
of TMS treatment series are necessary to consolidate
the interpretation of the present finding on frontal
cerebral blood volume in regard to the treatment
outcome. Increasing the measurement frequency is
warranted in future research.
The fHbC monitoring was also limited to the
anterior frontal region covering the frontal pole, one
of the brain areas shown to be affected by TMS treat-
ment.
11
Other brain areas should be assessed to fur-
ther understand the relation between CBF and
treatment efficacy.
As for the NIRS methods, continuous-wave spec-
troscopy was used in the present study as it has been
frequently applied to clinical research.
19
Other NIRS
methods, including time-resolved and frequency-
domain spectroscopy, will be informative in future
research because absolute CBF is available.
31
Other
brain signals, including those detected by electroen-
cephalography and functional magnetic resonance
imaging, will be interesting to assess the change in
activity during TMS as these techniques have higher
spatial resolution.
ACKNOWLEDGMENTS
The authors sincerely thank Dr Masanari Itokawa,
Dr Makoto Arai of the Schizophrenia Research Pro-
ject at the Tokyo Metropolitan Institute of Medical
Table 1. Demographic, near-infrared spectroscopy, and MADRS data in fHbC increase and decrease groups
fHbC increase fHbC decrease
Number (men, women) 9 (7, 2) 6 (4, 2) NS†
OxyHb index response during TMS (start) 2.23 1.74 0.93 1.79 NS
OxyHb index response during TMS (end) 2.98 1.26 −1.27 0.86 P< 0.001
OxyHb index response difference (end –start) 0.75 0.96 −2.20 1.48 P< 0.001
Age (years) 43.6 8.5 48.2 13.9 NS
Onset age (years) 37.9 7.7 39.8 12.7 NS
Duration of MDD (years) 5.7 4.2 8.3 4.7 NS
Number of episodes 1.2 0.7 1.2 0.4 NS
Motor threshold level 1.22 0.20 1.30 0.14 NS
Antidepressant (mg, fluvoxamine-equivalent) 113.2 93.6 54.2 64.1 NS
Antianxiety drug (mg, diazepam-equivalent) 5.0 4.3 7.3 9.1 NS
MADRS at the start of treatment 20.2 6.5 29.8 6.6 P= 0.015
MADRS at the end of treatment 6.0 3.4 16.5 8.7 P= 0.006
MADRS reduction rate (%) 69.9 16.1 43.8 25.9 P= 0.030
Data are presented as mean SD.
P-values are shown in the right column when the data are significantly different (t-test).
†Number of men and women was not statistically different (Fisher’s test).
fHbC, frontal hemoglobin concentration; MADRS, Montgomery–Åsberg Depression Rating Scale; MDD, major depressive
disorder; NS, not statistically different (t-test); oxyHb, oxygenated hemoglobin; TMS, transcranial magnetic stimulation.
©2018 The Authors
Psychiatry and Clinical Neurosciences ©2018 Japanese Society of Psychiatry and Neurology
608 T. Shinba et al.Psychiatry and Clinical Neurosciences 2018; 72: 602–610
Science, Dr Yoko Hoshi of the Medical Photonics
Center at Hamamatsu University School of Medi-
cine, and Ms Kaori Watanabe, Mr Hiroshi Shiga, and
Mr Akihiro Ono of Atworking K.K. for their continu-
ing support of this study. The authors also deeply
thank Dr Mark A. Demitrack of Neuronetics Inc. for
helping us to improve the manuscript.
DISCLOSURE STATEMENT
The authors have no conflict of interest regarding
this study. This study was conducted under the regu-
lar clinical work and no special funding was used.
AUTHOR CONTRIBUTIONS
T.S. and N.K. designed the study conception.
MADRS was scored by H.M. Data acquisition was
conducted by T.S., S.M., H.M., and Y.O. T.S., N.K.,
and S.M. analyzed and interpreted the data. Drafting
of the manuscript was done by T.S.
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