Journal of Psychiatric Research 103 (2018) 5–9

Contents lists available at ScienceDirect

Journal of Psychiatric Research

journal homepage: www.elsevier.com/locate/jpsychires

The effect of transcranial direct current stimulation on psychotic symptoms T

of schizophrenia is associated with oxy-hemoglobin concentrations in the
brain as measured by near-infrared spectroscopy: A pilot study
Zui Naritaa,∗, Takamasa Nodaa, Shiori Setoyamaa, Kazuki Sueyoshib, Takuma Inagawaa,
Tomiki Sumiyoshib
a
Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
b
Department of Clinical Epidemiology, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan

A R T I C LE I N FO A B S T R A C T

Keywords: Transcranial direct current stimulation (tDCS) has been shown to be effective in treating some of the symptoms
Psychosis of schizophrenia. In the current study, we sought to determine whether oxy-hemoglobin ([oxy-Hb]), measured
tDCS by near-infrared spectroscopy (NIRS), is associated with effects of transcranial direct current stimulation (tDCS)
NIRS on psychotic symptoms of schizophrenia. Twenty-six patients underwent tDCS (2 mA × 20 min) two times per
Biomarker
day for five consecutive days. The anodal electrode was placed over the left dorsolateral prefrontal cortex while
Positive symptoms
Negative symptoms
the cathodal electrode was placed over the right supraorbital region. One month after the last administration of
tDCS, positive, but not negative symptoms, evaluated by the Positive and Negative Syndrome Scale (PANSS),
were significantly improved. At baseline, regional [oxy-Hb] concentrations in the brain were measured by a 52-
channel NIRS instrument. Significant negative correlation was demonstrated between [oxy-Hb] concentrations
of left temporoparietal regions throughout verbal fluency tasks vs. changes of PANSS Positive and Negative
subscale scores. This is the first study to demonstrate the correlation between the response of neural activity to
cognitive tasks at baseline and the ability of tDCS to improve positive and negative psychotic symptoms. Our
observations suggest that NIRS provides a marker to predict the response to treatment with tDCS in schizo-
phrenia.

1. Introduction
Schizophrenia is a psychiatric disorder characterized by psychotic
symptoms, mood symptoms, and cognitive impairments (Kremen et al.,
2010; Kurtz, 2005; Micallef et al., 2006). Although its pathogenesis has
not been fully elucidated, several types of intervention, such as anti-
psychotic treatments and electroconvulsive therapy, have been used.
However, they are not always effective and some symptoms often re-
main treatment-resistant (Englisch and Zink, 2012), indicating a need
for the development of novel therapeutics.
Neuromodulation is defined as alterations of neural activity with
targeted delivery of a stimulus to the brain. Methods of neuromodula-
tion include non-invasive approaches, e.g. transcranial magnetic sti-
mulation, as well as invasive (implanted) devices, e.g. spinal cord sti-
mulation and deep brain stimulation. Among them, transcranial direct
current stimulation (tDCS) is feasible and safe, using weak and direct
electrical current to the brain through electrodes (Yokoi et al., 2017;
Yokoi and Sumiyoshi, 2015). tDCS changes cortical excitability
(Schretlen et al., 2014; Stagg and Nitsche, 2011), and has been sug-
gested to modulate cortico-subcortical/cortico-cortical pathways
(Lorenz et al., 2003; Stagg et al., 2013).
In schizophrenia, connectivity in the frontoparietal and inter-
hemispheric networks is decreased (Baker et al., 2014; Guo et al., 2014;
Hoptman et al., 2012), providing a rationale for beneficial effects of
tDCS on some of the symptoms of the illness, particularly, psychotic
symptoms. For example, as Yokoi et al. (2017) reviewed, most of the
studies to investigate the benefits of tDCS in the treatment of schizo-
phrenia have focused on psychotic symptoms, such as positive and
negative symptoms (Brunelin et al., 2012; Gomes et al., 2015; Mondino
et al., 2016; Palm et al., 2016; Yokoi et al., 2017). Also, we have re-
ported the beneficial effects of tDCS on psychotic symptoms in patients
with schizophrenia (Narita et al., 2017). Overall, psychotic symptoms
of schizophrenia have been suggested to be alleviated by tDCS.
Since there is little knowledge on objective methods to predict
whether an intervention will be successful, search for objective indices,
such as biomarkers, is desirable (Ferrarelli, 2013). Near-infrared

∗
Corresponding author. Department of Psychiatry, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo, 1878551 Japan.
E-mail address: zuinarita@ncnp.go.jp (Z. Narita).

https://doi.org/10.1016/j.jpsychires.2018.05.004
Received 9 January 2018; Received in revised form 29 March 2018; Accepted 5 May 2018
0022-3956/ © 2018 Elsevier Ltd. All rights reserved.
Z. Narita et al. Journal of Psychiatric Research 103 (2018) 5–9

spectroscopy (NIRS) is a non-invasive tool to evaluate brain function 2.1. Participants

which offers several advantages; it is easy to set up, requires minimal
constrains, and does not occupy a large space (Pu et al., 2014). NIRS Inpatients and outpatients at National Center Hospital, National
estimates oxy-hemoglobin ([oxy-Hb]) and deoxy-hemoglobin ([doxy- Center of Neurology and Psychiatry were enrolled. Participants were
Hb]) concentrations, which reflect changes of regional cerebral blood recruited by referrals of psychiatrists, according to inclusion/exclusion
volume (Sato et al., 2013). Several studies have evaluated the re- criteria, as follows;
lationship between brain activities, measured by NIRS, and symptoms Inclusion criteria:
of schizophrenia. Thus, Chou et al. (2014) et al. reported that longer
duration of untreated psychosis is associated with decreased cortical 1) Meeting DSM-5 criteria for schizophrenia
activities over the fronto-temporal regions (Chou et al., 2014). In ad- 2) Being 20 through 60 years old
dition, Noda et al. (2017) et al. found an aberrant re-increase in [oxy- 3) Being able to sign and give consent
Hb] concentrations in prefrontal and temporal regions of patients with
schizophrenia performing verbal fluency tasks, and concluded that Exclusion criteria:
NIRS may provide a potential biomarker of working memory deficits in
chronic schizophrenia (Noda et al., 2017). Furthermore, Lee et al. 1) Alcohol or substance disorder
(2008) et al. observed that increased frontal activity was correlated 2) Traumatic brain injury
with accuracy of working memory in patients with schizophrenia. 3) Epilepsy
Taken together, NIRS may provide a measure of brain functions based
on regional blood flows, as in the case with functional magnetic re-
2.2. tDCS
sonance imaging (fMRI) (Lee et al., 2008).
Although previous trials demonstrated the relationship between
Soterix Medical 1 × 1 Transcranial Direct Current Low-Intensity
cortical activity measured by NIRS and symptoms of schizophrenia
Stimulator Model 1300A was used. For each session, the tDCS montage
(Chou et al., 2014; Lee et al., 2008; Noda et al., 2017), no study has
comprised placement of the anode over the left dorsolateral prefrontal
been attempted to determine whether neural activity of specific re-
cortex (DLPFC) and the cathode over the right supraorbital area (cor-
gions, measured by NIRS would predict clinical benefits of tDCS. Con-
responding to F3 and FP2, according to the International 10–20 elec-
sidering that longer duration of untreated psychosis is associated with
troencephalography system), as previously described (Boggio et al.,
decreased cortical activities of the frontotemporal regions (Chou et al.,
2008; Narita et al., 2017). Rubber electrodes were inserted in 35-cm2
2014), we hypothesized that neural activity of some brain areas, e.g.
saline-soaked sponges and fixed with headband. We applied direct
temporal regions, would be related to effects of tDCS on psychosis. In
current of 2 mA for 20 min for each session. Participants underwent ten
the current study, we sought to determine whether [oxy-Hb] con-
tDCS sessions (twice per day for five consecutive days). tDCS was
centrations in specific brain regions measured by NIRS at baseline are
performed approximately at 10 a.m. and 2 p.m (Narita et al., 2017).
correlated with change of psychotic symptoms treated with tDCS in
tDCS was administered by trained psychiatrists. In order to improve
patients with schizophrenia. The dataset used in this study is over-
adherence, we provided all patients and their study partners with costs
lapped with that in our previous study (Narita et al., 2017). Data from
of transportation, and reminded and rescheduled all visits if necessary.
26 patients (who underwent NIRS measurement) out of the full dataset
Criteria for discontinuing interventions were as below:
comprising of 28 subjects were used for analyses.
1) In case patients withdraw informed consent to participate
2) In case severe adverse effects are observed
2. Materials and methods
3) In case patients fail to undergo three consecutive sessions of tDCS

This study was carried out in accordance with the latest version of
Declaration of Helsinki, and was approved by Ethical Committee of
National Center of Neurology and Psychiatry, Tokyo, Japan. Informed
consent of the participants was obtained after the nature of the proce-
dures had been fully explained.
2.3. Outcome measures
2.3.1. NIRS
Hemoglobin concentrations throughout verbal fluency tasks were
measured by a 52-channel NIRS instrument (ETG-4000; Hitachi
Medical Co., Tokyo, Japan), as previously reported (Noda et al., 2017).

Fig. 1. Measurement points of 52 channels for near-infrared spectroscopy (NIRS). The 52 measuring positions are labeled from ch1 to ch52, i.e. from the right-
posterior to the left-posterior regions.

6
Z. Narita et al. Journal of Psychiatric Research 103 (2018) 5–9

Probe attachments were thermos plastic 3 × 11 shells set with 52 Enrollment E

Exclusion criteria
channels. The lowest probe was set along the FP1-FP2 (according to the 1)
1 Alcohol or substance disorder
Inclusion criteria 2) TraumaƟc brain injury
International 10–20 electroencephalography system) line. The distance 3) Epilepsy
1) MeeƟng DSM-5 criteria for schizophrenia
between pairs of source and detector probe was set to 3.0 cm. Fig. 1 2) Being 20 through 60 years old
shows measurement points of 52 channels for NIRS. 3) Being able to sign and give consent
The rate of data sampling was 0.1 s (s). The obtained data were
Baseline assessment
evaluated using integral mode, in which the pre-task baseline was de- NIRS, PANSS
termined as the mean over a 10-s period just prior to the task period,
and the post-task baseline was determined as the last 5-s post-task tDCS
period. Linear fitting was applied to the data between these baselines. Anode on F3 and cathode on FP2
2 mA x 20 min
The moving average method using a 5-s window width was applied to Twice daily over 5 days (10 sessions )
remove short-term motion artifacts. Since all artifacts could not be re-
moved in this way, we applied automatic rejection of data with artifacts
separately for each channel. According to the aforementioned mea-
Follow-up assessment:
surement parameters for integral mode, the waveforms of hemoglobin one month aŌer the end
changes were acquired from each subject in all 52 channels. In this of treatment
study, we chose [oxy-Hb] as an indicator rather than [doxy-Hb], be- PANSS

cause [oxy-Hb] better reflects cortical activity, and reveals stronger

correlations with blood-oxygenation level-dependent signals measured
with fMRI (Sato et al., 2013).
Data analysis
Verbal fluency tasks were adopted as the frontal activation task. The
tasks consisted of a 30-s pre-task baseline period, a 60-s task period Fig. 2. Flowchart of the study schedule.
consisting of three 20-s blocks, and a 70-s post-task baseline period.
During the task period, participants were instructed to produce as many
Table 1
words as possible beginning with a particular syllable. The initial syl-
Clinical characteristics of patients (n = 26).
lables were changed every 20 s during the 60-s task period. The com-
binations of three initial syllables were changed across each of the Variables Mean ± SDa or Number of subjects
sessions. The number of words correctly generated by the patients was
Inpatient/outpatient 20/6
assessed as each subject's performance score on the tasks. In the pre- Male/female 15/11
task and post-task baseline periods, the subjects were asked to repeat a Age, year 40.5 ± 10.0
sequence of syllables (‘/a/, /i/, /u/, /e/, /o/’). The test-retest effect was Age at onset, year 23.0 ± 6.0
unlikely, as the interval between the test and re-test has been suggested Duration of present illness, year 17.6 ± 10.1
Chlorpromazine equivalent dose of 870.8 ± 605.2
not to influence the measurement of [oxy-Hb] concentrations
antipsychotics (mg/day)
(Watanabe et al., 2003). Duration of education, year 13.7 ± 1.7
Premorbid IQ 99.6 ± 11.7
2.3.2. Psychosis Global Assessment of Functioning scores 38.5 ± 7.0
PANSSbscores
Psychosis was measured by the Positive and Negative Syndrome
Positive syndrome 15.0 ± 5.3
Scale (PANSS), commonly used for evaluation of psychotic symptoms of Negative syndrome 14.3 ± 7.3
schizophrenia (Kay et al., 1988). The PANSS is a structured interview, General psychopathology 31.2 ± 7.8
consisting of Positive, Negative, and General psychopathology sub-
a
scales (with scores ranging from 7 to 49, from 7 to 49, and from 16 to SD, Standard Deviation.
b
112, respectively), whose scores are regarded as continuous variables. PANSS, Positive and Negative Syndrome Scale.
The higher scores represent more severe psychotic symptoms.
The study schedule is summarized in Fig. 2. chlorpromazine, levomepromazine (two for each), perospirone, blo-
nanserin, zotepine, and sulpiride (one for each). No medication was
2.4. Statistical analysis modified during the study period. Subtle adverse effects, such as
itching, were noted in some participants. No severe side effect was
Statistical analysis was conducted using STATA 14, created by observed throughout the trial.
StataCorp in Texas, USA. We performed a per protocol approach for The mean and standard deviation of PANSS Positive, Negative, and
subjects who underwent NIRS at baseline. Pearson's product moment General Psychopathology subscales scores one month after the proce-
correlation coefficient was used for the relationship between [oxy-Hb] dures were 12.9 (4.6), 12.7 (5.9), and 27.8 (7.9), respectively. The
of each channel vs. changes from baseline of PANSS subscale scores. mean and standard deviation of changes of PANSS Positive, Negative,
Multiple testing corrections were carried out by means of false recovery and General Psychopathology subscales scores were −2.2 (5.2), −1.6
rate (FDR) estimation (Noble, 2009; Singh and Dan, 2006). (5.4), and −3.4 (8.7), respectively. Scores of the Positive subscale, but
not Negative and General Psychopathology subscales were significantly
3. Results decreased by tDCS administration (t = 2.10; p = 0.046, t = 1.53;
p = 0.137, and t = 1.99; p = 0.057, respectively).
Twenty-six patients underwent NIRS, while two subjects declined Significant negative correlations were demonstrated between [oxy-
the measurement. Demographic features of patients are shown in Hb] concentrations at ch10, ch23, ch24, and ch34 vs. the change of
Table 1. Data of patients who underwent NIRS were used for analysis. PANSS Positive subscale scores. Also, significant negative correlations
The mean and standard deviation of premorbid IQ assessed by the Ja- were observed between [oxy-Hb] levels at ch10, ch21, ch23, ch24, and
panese Adult Reading Test (Fukue et al., 2013) was 99.6 (11.7). The ch26 vs. the change of PANSS Negative subscale scores. After multiple
mean and standard deviation of the Global Assessment of Functioning testing corrections, significance persisted between [oxy-Hb] con-
(Hall, 1995) was 38.5 (7.0). Antipsychotic drugs taken by participants centrations at ch10 vs. changes of PANSS Positive and Negative sub-
were as follows; risperidone (eight patients), paliperidone, quetiapine, scale scores (r = −0.61; p < 0.001, and r = −0.63; p < 0.001, re-
aripiprazole (seven for each), olanzapine (five), haloperidol (three), spectively; Fig. 3 and Fig. 4). No significant correlation was noted

7
Z. Narita et al. Journal of Psychiatric Research 103 (2018) 5–9

anode over F3 and the cathode over FP2 (Smith et al., 2015). Taken
10

together, the positioning of electrodes may affect the ability of tDCS to

alleviate psychotic symptoms, which requires further trials.
The current study suggests that a greater response of neural activity
in left temporoparietal regions measured by NIRS is associated with
0

better treatment outcomes with tDCS. Cortical activities in the fronto-

temporal regions estimated by NIRS have been suggested to be influ-
enced by duration of untreated psychosis in schizophrenia (Chou et al.,
2014). Also, tDCS has been shown to increase activities of the medial
-10

frontal cortex during working memory tasks, as demonstrated by fMRI

(Orlov et al., 2017). These previous findings may be consistent with the
potential utility of NIRS for the prediction of effects of tDCS on psy-
-20

chotic symptoms, as observed here. Also, our observations may support

-.1 0 .1 .2 .3
a concept that NIRS may provide a valid method to assess brain func-
[oxy-Hb] of ch10 tions based on blood flow, similar to fMRI (Lee et al., 2008).
Change of PANSS Positive subscale scores Fitted values The mechanisms by which brain activities, measured by NIRS, are
associated with the ability of tDCS should be considered. In a controlled
study, schizophrenia patients with auditory-verbal hallucinations
Fig. 3. Correlation between [oxy-Hb] of ch10 vs. change of PANSS Positive showed reduced functional connectivity within left temporoparietal
subscale scores.
junction compared with healthy control subjects (Vercammen et al.,
2010). In the present study, activities of left temporoparietal regions
were correlated with change of psychotic symptoms after treatment
10

with tDCS. These findings may suggest associations of left tempor-

oparietal regions with the putative mechanisms by which psychotic
5

symptoms are generated.

tDCS has been suggested to alter cortical excitability (Schretlen
et al., 2014; Stagg and Nitsche, 2011; Sumiyoshi and Higuchi, 2013),
0

and modulate corticosubcortical/corticocortical pathways (Lorenz

et al., 2003; Stagg et al., 2013), as mentioned above. However, there is
-5

little information about which part of the brain is actually stimulated by

tDCS. In the current study, the anodal electrode was placed over the
-10

DLPFC, which is close to left temporoparietal region. Thus, direct cur-

rent flows into the DLPFC may regulate the left temporoparietal neural
-15

activity. Additional methods to evaluate cortical activities, such as

-.1 0 .1 .2
[oxy-Hb] of ch10
Change of PANSS Negative subscale scores Fitted values
Fig. 4. Correlation between [oxy-Hb] of ch10 vs. change of PANSS Negative
subscale scores.
between [oxy-Hb] of any channels vs. change of PANSS General psy-
chopathology subscale scores (data not shown).
4. Discussion
To our knowledge, this is the first study to demonstrate the corre-
lation between baseline [oxy-Hb] of ch10 placed on left temporopar-
ietal regions, measured by NIRS, and the ability of tDCS to improve
positive and negative psychotic symptoms in patients with schizo-
phrenia.
In the present study, negative symptoms were not significantly af-
fected by tDCS. This may have been caused by the low PANSS negative
subscale scores at baseline (Table 1), i.e. “floor effects.” Several studies
conducted by other groups have examined the ability of tDCS to im-
prove psychotic symptoms in patients with schizophrenia. In contrast to
the results of the current study, Brunelin et al. (2012) et al. found
significant improvement in negative symptoms. These investigators
placed the anodal electrode over a point midway between F3 and FP1
and the cathodal electrode over a point midway between T3 and P3
(Brunelin et al., 2012). Also, Palm et al. (2016) et al. demonstrated
significant mitigation in negative symptoms. These authors placed the
anode over the F3 and the cathode over F4 (Palm et al., 2016). On the
other hand, Smith et al. (2015) et al. did not find significant effects on
either positive or negative symptoms. These investigators placed the
.3 fMRI, are warranted to obtain further information on this issue, and
confirm our observations by means of NIRS.
The limitations of this study should be considered. Participants were
recruited irrespective of whether their symptoms were refractory to
antipsychotic treatments or not. However, this may not have compro-
mised the validity of the current study, since no medication was
changed during the study period. On the other hand, the small sample
size of this study may raise caution in generalizing the present results to
the population. Moreover, the lack of sham control condition suggests
that the natural history of illness might have affected the results.
Further study with a control group is warranted.
5. Conclusions
The results of the present study indicate correlation between ac-
tivity in left temporoparietal cortical regions and the ability of tDCS to
treat psychotic symptoms in patients with schizophrenia. Our ob-
servations suggest that NIRS provides a biomarker of the utility of tDCS
in the treatment of schizophrenia.
Funding sources
This study was funded by Kakenhi (No. 17K10321) from Japan
Society for the Promotion of Science and Intramural Research Grants
(27-1, 27-6-2, 29-1) for Neurological and Psychiatric Disorders,
National Center of Neurology and Psychiatry.
Author contributions
TS designed the study and wrote the protocol. TI, TS, and ZN ad-
ministered tDCS. ZN managed the literature searches, undertook the
statistical analysis, and wrote the first draft of the manuscript. KS

8
Z. Narita et al.
conducted clinical assessments. All authors made substantial contribu-
tion, drafted the manuscript, and approved the final manuscript.
Conflicts of interest
The authors declare no conflict of interest in this study.
Acknowledgements
The authors thank Dr. Yuma Yokoi, Dr. Satoru Ikezawa, Dr.
Harumasa Takano, Dr. Mitsutoshi Okazaki, and Dr. Kazuyuki
Nakagome for fruitful discussions. Dr. Haruka Matsuda, Dr. Naonori
Yasuma, Dr. Aiichiro Nakajima, Dr. Takaaki Nakayama, Dr. Yusuke
Toguchi, and Dr. Naoki Yoshimura are gracefully appreciated for the
recruitment of participants.
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