Brain Stimulation 13 (2020) 840e849

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Brain Stimulation
journal homepage: http://www.journals.elsevier.com/brain-stimulation

A randomized, double blind, sham-controlled trial of repetitive

transcranial magnetic stimulation (rTMS) in the treatment of negative
symptoms in schizophrenia
Nand Kumar d, *, Sreenivas Vishnubhatla a, Ashima Nehra Wadhawan b, Sujata Minhas c,
Prashant Gupta c
a
Department of Bio Statistics, AIIMS, Delhi, India
b
Cardio Neuro Centre, AIIMS, Delhi, India
c
Department of Psychiatry AIIMS, Delhi, India
d
All India Institute of Medical Sciences, Delhi, India

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

Article history: Background: Research has implicated hypofrontality in the pathogenesis of Negative symptoms of
Received 17 July 2019 schizophrenia.These symptoms are often resistant to treatment. Repetitive Transcranial Magnetic
Received in revised form Stimulation (rTMS) has been shown to reverse this hypofrontality. Higher frequency rTMS has shown
13 February 2020
better promise, but so far there has been very little research in this area.
Accepted 17 February 2020
Objective: We aimed to evaluate the efficacy of high-frequency (20 Hz) unilateral rTMS over the left
Available online 29 February 2020
Dorso-Lateral Pre-frontal Cortex (DLPFC) in the improvement of Negative symptoms in Schizophrenia.
Methods:100 patients of schizophrenia with predominantly negative symptoms, were enrolled for this
Keywords:
Schizophrenia
randomized, sham-controlled, double-blind trial.Each participant received 20 sessions of rTMS at 20 Hz
Negative symptoms frequency and 100% motor threshold, via either the active or the sham coil, over 4 weeks. A total of 2000
rTMS pulses were imparted in 10 trains per session. Negative symptoms were assessed with the SANS and
Repetitive transcranial magnetic PANSS. CDSS was used to rule out depressive symptoms. Assessments were carried out at baseline, post-
stimulation intervention, and 1-month, 2-months, 3-months and 4-months follow ups.
Results: The improvement in the negative symptoms (Anhedonia, Alogia, Avolition, Attention impair-
ment) in active group was statistically significant at 0.01 and 0.05 (p-value) as compared to sham group.
Conclusions: These results suggest that high-frequency rTMS may lead to improvement in negative
symptoms of schizophrenia. It may be worth considering its use as an adjunct to pharmacological
treatment of negative symptoms.
© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction indicated that pre-frontal brain dysfunction, especially in the

Negative symptoms in schizophrenia are a core feature of the
disease and contribute to a substantial burden associated with the
illness [1]. They include affective flattening or apathy, alogia, avo-
lition or amotivation, anhedonia, impaired attention and social
withdrawal [2]. Despite the substantial research on schizophrenia
over the years, the treatment for negative symptoms remains
elusive. Unlike the positive symptoms, they are often resistant to
antipsychotic drugs and psychological treatments [1]. Research has
* Corresponding author.
E-mail address: nandkm2001@gmail.com (N. Kumar).
dorso-lateral pre-frontal cortex (DLPFC) may be involved in the
aetiology of negative symptoms of schizophrenia [3,4]. Neuro-
imaging studies have shown hypometabolism and hypoperfusion
of pre-frontal regions in patients suffering from negative symptoms
[5]. Studies have suggested that this hypofrontality is more pro-
nounced on the left side [6e8].
Repetitive transcranial magnetic stimulation (rTMS) is a non-
invasive brain stimulation technique which has been shown to be
useful in the treatment of several psychiatric and neuro-psychiatric
disorders, including depression, PTSD, migraine, etc. [9e11]. More
recently, some authors have used it for the treatment of negative
symptoms as well, with varying outcomes [12e15]. It has been
hypothesized that rTMS may lead to reversal of hypofrontality

https://doi.org/10.1016/j.brs.2020.02.016
1935-861X/© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/
).
 N. Kumar et al. / Brain Stimulation 13 (2020) 840e849
which is seen in the brains of patients having negative symptoms
[5,16]. Most of the studies till date have evaluated the effects of
10 Hz pulses, in shorter treatment protocols which deliver up to
20,000 pulses to the brain [15,17e20]. But, higher frequency
treatments over longer times and higher number of total magnetic
pulses administered have tended to show better improvements in
research [18,21,22].
Literature on effects of rTMS on negative symptoms of schizo-
phrenia is composed mainly of the studies with very small sample
sizes and have inadequate power to detect inter-group differences
[15,18,20]. Moreover, methodological rigour has been a problem in
a number of these studies. E.g., the number of randomized, double-
blind, sham-controlled trials has been rather limited, the sham
rTMS controls in a number of these studies may themselves induce
some voltage in the brain, and the different approach to their
administration, as compared to the active treatment may affect the
blinding. Further, the time durations for which the patients in these
studies have been followed up is rather less, mostly up to one
month. Hence, little is known about the sustainability of the effects
of rTMS in negative symptoms.
Hence, given the need for an effective treatment of negative
symptoms of schizophrenia and the need to explore potential role
for rTMS in this using robust study designs, we aim to evaluate the
efficacy of 20 sessions of high-frequency (20 Hz) unilateral rTMS
intervention over the left DLPFC in the improvement of negative
symptoms in schizophrenia and compare it to sham controls, in a
randomized, double-blind trial.
Methods
Study Design:The study was conceptualized as a randomized
sham-controlled double-blind trial.
The study was conducted at the All Indian Institute of Medical
Sciences (AIIMS), New Delhi which has dedicated rTMS unit with a
fully functioning rTMS lab since 2009. Along with this, we have
weekly running TMS clinic.
Sample size calculation: Barr and colleagues (2012) evaluated
the efficacy of 20 Hz RTMS on negative symptoms of schizophrenia
against sham controls in a double-blind RCT [12]. This study yielded
a mean SANS total score of 31.67 ± 13.94 in the sham group post-
intervention. Anticipating 8 units of difference in SANS total score
post-intervention between the groups with a combined SD of 13.97,
alpha error of 5% and power of 80%, the estimated sample size was
34 per group. Our study included a sample of 50 per group ac-
counting for about 30% losses in follow up.
Randomization Procedure:For Randomization of enrolled pa-
tients, 100 sequentially numbered opaque envelopes (with either
‘sham’ or ‘active’ written on it) were prepared as per a computer-
generated random sequence by the Biostatistics Department of
AIIMS, New Delhi. Only two rTMS technicians had access to them.
As per the random sequence they would allot a number to the
randomized patient and provide the intervention as mentioned on
the card inside.
The subjects were blinded regarding the treatment being given,
also the rater was blinded for the allocation, only the rTMS trained
Technician who administered rTMS were aware of the allocation
from the time of randomization to the time of data analysis. A
trained doctor, unrelated to the research project, was present at all
times during the intervention to tackle any emergent conditions.
Patients who were right-handed, clinically diagnosed as having
schizophrenia as per ICD-10 criteria for at least one year and
receiving psychiatric treatment at the psychiatry outpatient
department of AIIMS, New Delhi, been on stable doses of medicines
(if receiving) for the last 4 weeks, but continued to have significant
negative symptoms, i.e., score
15 on N scale of Positive and
841
Negative Syndrome Scale (PANSS), with willingness to give
informed consent were only included in the study. We did not
include patients who had received rTMS treatment in the past for a
similar condition. Patients with Co morbid ICD-10 Axis I diagnosis,
or Axis II Personality Disorder or who qualify any other exclusion
criteria common to every TMS protocol were excluded.
rTMS protocol: We used the Magstim Rapid2 and Magstim
Rapid2 plus machine for this study. For intervention group, rTMS
Magstim’s 70 mm figure-of-8 Double Rapid2 Air Cooled Coil (P/N
3910-00 S/NO 728) was used, while for sham group, Magstim’s
sham coil (P/N 3950-00 S/NO105) was used. The coils were iden-
tical in external appearance which ensured that the patients
remained blind to the intervention.
After clinical assessment and before starting the rTMS inter-
vention, motor threshold of all the patients was determined fol-
lowed by the localization of stimulation site. Left dorso-lateral
prefrontal cortex (DLPFC) was taken as the site for stimulation.
We defined the site of stimulation as a point, 5.5 cm anterior and
then 0.5 cm lateral from the point where optimum stimulation of
the right abductor pollicis brevis muscle was observed on stimu-
lation of cortical representation of left cerebral cortex. Same pro-
cedure was followed for both groups of patients.
After marking site of stimulation and eliciting motor threshold,
following stimulation parameters to left DLPFC were used. The
study subjects were administered 20 sessions of high frequency
rTMS per day (5 consecutive sessions per week for 4 weeks) at
20 Hz frequency, 100% motor threshold (MT), for 10 s with inter-
train time interval ranging from 90 s to 120 s (as calculated auto-
matically by the TMS machine for in built safety measures)
depending on the protocol intensity, total of 2000 pulses imparted
in 10 trains. Both sham and active group patients received the same
stimulation parameters. Each session lasted for approximately
30 min.
Assessment: The assessments were carried out by a trained
psychologist appointed for the project. The following instruments
were used in assessment:
Mini International Neuropsychiatric Interview (MINI) version
5.0.0 [23] Positive and Negative Syndrome Scale (PANSS) [24,25].
Scale for Assessing Negative Symptoms in schizophrenia (SANS)
[2,26].
Clinical Global Impressions scale-severity index (CGI-S) [27]
Calgary Depression Scale for Schizophrenia (CDSS) [28,29].
Procedure: Patients who were receiving treatment for schizo-
phrenia and stable on their medications for at least 4 weeks, but
who continued to have substantial negative symptoms, were
referred by their respective clinicians to our research team for
participation in the study. Those who fulfilled the inclusion criteria
and agreed to provide a written informed consent were random-
ized to either of the study arms. In case a patient lacked the capacity
to consent, their legal guardians were invited to provide consent.
After baseline assessment on the abovementioned instruments,
rTMS intervention was provided as per mentioned protocol. Same
assessments were also carried out at the completion of the inter-
vention (completion of 20 sessions of rTMS) and monthly follow-
ups for four months subsequently.
Analysis: Data was analysed using Stata version 14.2 (StataCorp.
2015). Descriptive analysis was done for socio-demographic data
(Table 1). Two-sample t-test with equal variances and Chi-square
test were used to compare the two groups at baseline. Signifi-
cance value was set at 0.05. We performed an Intention to Treat
(ITT) analysis, i.e., all individuals, who were randomized to exper-
imental arms at the baseline, were included in the analysis irre-
spective of whether they continued with the study protocol or
dropped out. Missing values were imputed as per last observation
carried forward. Generalized Estimating Equations (GEE) 30 were
842 N. Kumar et al. / Brain Stimulation 13 (2020) 840e849

Table 1
Baseline socio-demographic and clinical characteristics of the sample population.

Active rTMS arm (n ¼ 50) Sham rTMS arm (n ¼ 50) p

Age in years, (mean ± SD) 32.4 ± 9.20 30.8 ± 9.34 0.38

Sex, n(%) 0.84

Male 29 (58.0) 28 (56.0)
Female 21 (42.0) 22 (44.0)

Marital status, n(%) 0.67

Never married 23 (46.0) 28 (56.0)
Currently married 19 (38.0) 18 (36.0)
Others 8 (16.0) 4 (8.0)

Education, n(%) 0.98

Intermediate 12 (24.0) 14 (28.0)
Graduate 9 (18.0) 10 (20.0)
Matric 9 (18.0) 9 (18.0)
Middle 9 (18.0) 9 (18.0)
Others 11 (22.0) 8 (8.0)

Employment status, n(%) 0.56

Employed 6 (12.0) 8 (16.0)
Unemployed 44 (88.0) 42 (84.0)

Occupation, n(%) 0.97

Not known 27 (54.0) 26 (52.0)
Home maker 6 (12.0) 9 (18.0)
Student 6 (12.0) 5 (10.0)
Skilled/unskilled 9 (18.0) 8 (16.0)
Others 2 (4.0) 2 (4.0)

Religion, n(%) 0.53

Hindu 46 (92.0) 47 (94.0)
Others 4 (8.0) 3 (6.0)

Residential Area, n(%) 0.22

Delhi 18 (36.0) 24 (48.0)
Outside Delhi 32 (64.0) 26 (52.0)

Duration of illness, in months (mean ± SD) 125.7 ± 76.43 101.5 ± 84.67 0.13

Family History of psychotic illness in 1st degree relative,n(%) 0.71

Yes 17 (34.0) 15 (30.6)
No 33 (66.0) 34 (69.4)

PANSS (mean ± SD)

Total 65.66 ± 8.43 67.02 ± 10.07 0.49
Positive 9.68 ± 2.44 9.94 ± 2.70 0.62
Negative 24.34 ± 4.32 24.9 ± 5.01 0.55
General 31.64 ± 5.01 32.18 ± 5.66 0.61

SANS (mean ± SD)

Total 60.66 ± 11.75 61.46 ± 13.69 0.74
Affective flattening 15.76 ± 6.57 17.76 ± 6.01 0.12
Alogia 11.3 ± 3.26 11.06 ± 3.61 0.73
Anhedonia 16.62 ± 2.42 16.42 ± 2.80 0.70
Attention impairment 6.7 ± 3.23 5.76 ± 3.44 0.16
Avolition 10.22 ± 2.82 10.66 ± 2.92 0.45
CGI-S (mean ± SD) 4.62 ± 0.70 4.52 ± 0.74 0.49

Antipsychotic drugs, n(%) 0.33

Risperidone 15 (30.0) 18 (36.0)

Olanzapine 8 (16.0) 12 (24.0)
Others (Amisulpiride, Clozapine, Quetiapine, Aripiprazole, No antipsychotic) 14 (28.0) 7 (14.0)
Combinations of two or more antipsychotic drugs 13 (26.0) 13 (26.0)

Anticholinergic drugs (Trihexyphenidyl),n(%) 0.42

Yes 23 (46.0) 27 (54.0)
No 27 (54.0) 23 (46.0)

Sedative/Hypnotic drugs (Clonazepam, Lorazepam), n(%) 0.37

Yes 5 (10.0) 8 (16.0)
No 45 (90.0) 42 (84.0)

Antidepressant drugs (Fluoxetine, Escitalopram, Sertraline), n(%) 0.13

Yes 13 (26.0) 7 (14.0)
No 37 (74.0) 43 (86.0)
 N. Kumar et al. / Brain Stimulation 13 (2020) 840e849 843

used to compare the outcome measures between the two groups
over time from pre-intervention to 4-months follow-up
assessment.
Ethics: An ethical approval of the study was taken from the
Institute Ethics Committee of AIIMS, New Delhi. The trial protocol
was registered with the Clinical Trials Registry- India (CTRI)
athttp://ctri.nic.in/Clinicaltrials/login.php with the number CTRI/
2019/05/019099.
Results
A total of 497 patients were screened for inclusion, and 100 of
them were randomized to active treatment arm (n ¼ 50) or sham
treatment arm (n ¼ 50) (Fig. 1). An attrition rate of 8% (n ¼ 4) in the
active rTMS arm and 6% (n ¼ 3) in the sham treatment arm was
seen during the intervention. This further increased to 32% in active
and 38% in sham groups. The number of dropouts in the two groups
were statistically similar (c2 ¼ 0.396, p ¼ .53).
Demographic and clinical characteristics
Table 1 shows the baseline demographic and clinical charac-
teristics of the participants. No significant differences were found
between the active and the sham treatment groups in demographic
characteristics at the baseline. Also, clinical variables (illness
duration, family history, medication use and scores on PANSS& its

Fig. 1. CONSORT flow diagram depicting the flow of participants through the study.
844 N. Kumar et al. / Brain Stimulation 13 (2020) 840e849

subscales, SANS& its subscales, CGI-S and CDSS) were statistically
similar between the two groups at baseline.
rTMS safety and tolerability
One patient in the active treatment group developed a partial
seizure during treatment in the 5th session after which the inter-
vention was discontinued. Another patient in the active arm had
aggravation of positive psychotic symptoms, and her intervention
had to be stopped after 6 sessions. Other than these two events,
both active intervention and sham were well tolerated.
Outcome measures
Negative symptoms of schizophrenia: The total SANS score
reduced significantly after the intervention in both the active
(60.6 ± 11.75 to 43.9 ± 12.67, p < .01) as well as sham (61.5 ± 13.69
to 50.5 ± 14.11, p < .01) rTMS arms on paired sample t-test. Though
the baseline total SANS scores were statistically similar in both the
groups, the post-intervention scores were significantly lesser
among the subjects who received active rTMS as compared to those
who received sham (Table 2). Among the SANS sub-domains, the
difference in post-intervention scores between active and sham
groups was statistically significant in affective flattening and avo-
lition domains, but not others. Statistically significant differences
were seen in the change in SANS domain scores (pre-intervention
vs post intervention) between active and sham groups in anhe-
donia, alogia and attention impairment domains. During the four
months follow up of the study participants, the initial reduction in
SANS total and domain scores seemed to be maintained (Fig. 2). The
change in scores from post intervention to 4-month follow up was
not statistically different between the two groups, except in
anhedonia domain. Statistically significant difference in the scores
on anhedonia, alogia, avolition, attention impairment was seen at
the end of study (Pre-interventionto 4 months follow-up).
The results from PANSS negative scale painted a similar picture.
The scores were statistically similar at the baseline, but a significant
difference was seen between the groups after the intervention,
with active rTMS group having lower mean score (Table 3). The
drop in scores was significantly more in the active rTMS group after
the intervention. This difference was maintained throughout the
follow-up duration, whereby the change in scores from post-
intervention to the end of 4-months follow-up was not signifi-
cantly different between the groups.
The PANSS positive scale did not show any statistically signifi-
cant difference between active and sham groups either at the
baseline, after the intervention or through the follow-up period
(Table 3& Fig. 3). Though the total PANSS scores and the general
psychopathology scale scores or the change in these scores did not
show difference between the two groups immediately after the
intervention, there was a significant difference between the groups
during the follow-ups.
Depressive symptoms: Since depression was already ruled out
among the participants during screening, the CDSS scores were
negligible at baseline. The two groups of participants did not differ
in terms of depressive symptoms at any time points of measure-
ment (Table 4).

Table 2
Comparison of SANS scores between the two study groups across the assessment time points.

Pre- Post- 1 month 2 months 3 months 4 months Reduction (95% CI)

Intervention intervention follow up follow up follow up follow up
Pre-intervention to Post-intervention to 4 Pre-intervention to 4
post-intervention months follow-up months follow-up

N
Sham 50 50 50 50 50 50
Active 50 50 50 50 50 50

SANS total
Sham 61.5 ± 13.69 50.5 ± 14.11 48.3 ± 16.33 45.7 ± 18.13 44.6 ± 17.81 43.7 ± 18.46 11.0 (8.25, 13.67) 6.8 (3.26, 10.26) 17.7 (13.40, 22.04)
Active 60.6 ± 11.75 43.9 ± 12.67 38.9 ± 13.73 36.6 ± 14.72 35.2 ± 14.14 33.8 ± 15.79 16.6 (13.86, 19.42) 10.2 (7.75, 12.65) 26.8 (22.79, 30.89)
p 0.73 0.02 <0.01 <0.01 <0.01 <0.01 <0.01 0.12 <0.01

SANS affective flattening

Sham 17.8 ± 6.01 12.7 ± 6.82 11.9 ± 6.54 11.3 ± 6.86 10.8 ± 6.68 10.6 ± 6.83 5.1 (3.10, 6.12) 2.1 (0.64, 3.64) 7.2 (5.52, 8.88)
Active 15.8 ± 6.57 10.3 ± 5.91 8.8 ± 5.93 7.9 ± 5.84 7.4 ± 5.36 7.2 ± 5.97 5.5 (4.31, 6.61) 3.1 (2.25, 3.99) 8.6 (7.06, 10.10)
p 0.12 0.05 0.01 <0.01 <0.01 <0.01 0.62 0.27 0.24

SANS anhedonia
Sham 16.4 ± 2.80 15.2 ± 3.62 14.6 ± 3.42 14.1 ± 3.94 14.0 ± 3.91 13.8 ± 4.24 1.2 (0.53, 1.87) 1.4 (0.74, 2.06) 2.6 (1.64, 3.56)
Active 16.6 ± 2.42 14.3 ± 3.27 12.9 ± 3.60 12.4 ± 3.93 12.1 ± 4.16 11.6 ± 4.63 2.3 (1.71, 2.97) 2.7 (1.75, 3.61) 5.0 (3.88, 6.16)
p 0.70 0.18 0.02 0.04 0.02 0.01 0.02 0.03 <0.01

SANS alogia
Sham 11.1 ± 3.61 8.8 ± 4.16 8.3 ± 4.51 7.7 ± 4.89 7.5 ± 5.13 7.4 ± 4.87 2.3 (1.51, 3.02) 1.4 (0.27, 2.53) 3.7 (2.37, 4.95)
Active 11.3 ± 3.26 7.2 ± 4.33 6.3 ± 4.38 6.0 ± 4.50 5.6 ± 4.33 5.3 ± 4.60 4.1 (3.05, 5.11) 1.9 (1.13, 2.71) 6.0 (4.85, 7.15)
p 0.73 0.07 0.03 0.08 0.06 0.03 <0.01 0.46 <0.01

SANS avolition
Sham 10.7 ± 2.92 8.9 ± 2.83 8.6 ± 3.20 8.1 ± 3.58 8.0 ± 3.29 7.9 ± 3.18 1.7 (1.15, 2.33) 1.0 (0.35, 1.73) 2.8 (1.98, 3.58)
Active 10.2 ± 2.82 7.9 ± 2.28 6.9 ± 2.45 6.5 ± 2.90 6.4 ± 2.84 6.2 ± 3.15 2.3 (1.65, 2.99) 1.7 (0.94, 2.50) 4.0 (3.09, 4.99)
p 0.44 0.05 <0.01 0.02 <0.01 <0.01 0.21 0.20 0.05

SANS attention impairment

Sham 5.8 ± 3.44 4.9 ± 3.19 4.9 ± 3.18 4.5 ± 3.27 4.3 ± 3.47 4.1 ± 3.46 0.9 (0.24, 1.56) 0.8 (0.18, 1.38) 1.7(0.97, 2.39)
Active 6.7 ± 3.23 4.3 ± 3.46 4.1 ± 3.10 3.8 ± 3.88 3.7 ± 2.96 3.6 ± 3.00 2.4 (1.74, 3.14) 0.7 (0.03, 1.33) 3.1(2.29, 3.95)
p 0.16 0.37 0.18 0.25 0.34 0.44 <0.01 0.82 0.01
 N. Kumar et al. / Brain Stimulation 13 (2020) 840e849 845

Fig. 2. Comparison of SANS scores at baseline, post-intervention and follow-ups between the two study groups.
*Average difference in scores between the active and the sham rTMS groups, over all time points (pre-intervention, post intervention i. e after 20 sessions of rTMS, subsequent
assessments for 4 consecutive months post intervention).

Clinical Global Impression (CGI): The mean CGI severity index completion of intervention, as exemplified by the significant dif-
(CGI-S) score was similar between the active and sham participants ference between the change in scores from pre-to post intervention
at the baseline, but a significantly higher reduction in this score was between the two groups, and no such difference from post-
seen among the active group participants after the intervention intervention to 4 months follow-up.
(Table 4). It appeared to follow the patterns of SANS total and PANSS
negative scale, whereby the change in scores seemed to be main-
Discussion
tained over time, i.e., significant (or tending to be significant) dif-
ference between the groups after the intervention and at each
We examined the effects of 20 sessions of 20 Hz rTMS over left
follow-up (Fig. 4). This difference seemed to primarily stem from
DLPFC in the treatment of negative symptoms in schizophrenia
the reduction in illness severity (CGI-S score) immediately on
among patients who were continuing treatment as usual and found
846 N. Kumar et al. / Brain Stimulation 13 (2020) 840e849

Table 3
Comparison of PANSS scores between the two study groups across the assessment time points.

Pre- Post- 1 month 2 months 3 months 4 months Reduction in scores (95% CI)
Intervention intervention follow up follow up follow up follow up
Pre-intervention to Post-intervention to 4 Pre-intervention to 4
post-intervention months follow-up months follow-up

N
Sham 50 50 50 50 50 50
Active 50 50 50 50 50 50

PANSS total
Sham 67.0 ± 10.97 57.5 ± 9.94 56.7 ± 9.97 55.5 ± 11.69 55.0 ± 12.13 55.2 ± 11.44 9.5 (7.26, 11.82) 2.3 (0.05, 4.47) 11.8 (8.95, 14.65)
Active 65.7 ± 8.43 54.1 ± 10.50 50.9 ± 10.10 50.4 ± 10.38 49.1 ± 10.39 48.4 ± 10.76 11.6 (9.47, 13.65) 5.7 (4.03, 7.45) 17.3 (14.65, 19.95)
P 0.48 0.10 <0.01 0.02 0.01 <0.01 0.20 0.02 <0.01

PANSS positive scale

Sham 9.9 ± 2.70 8.7 ± 2.12 8.6 ± 2.01 8.7 ± 2.26 8.7 ± 2.28 8.9 ± 2.41 1.2 (0.65, 1.83) 0.2 (0.72, 0.36) 1.1 (0.47, 1.65)
Active 9.7 ± 2.44 8.5 ± 1.85 8.3 ± 1.79 8.5 ± 2.31 8.3 ± 1.96 8.3 ± 2.09 1.2 (0.74, 1.61) 0.2 (0.2, 0.56) 1.4 (0.76, 1.97)
P 0.62 0.62 0.38 0.76 0.40 0.22 0.87 0.29 0.48

PANSS negative scale

Sham 24.9 ± 5.01 20.8 ± 4.89 20.1 ± 5.44 19.4 ± 5.66 19.3 ± 6.09 19.3 ± 5.92 4.1 (3.09, 5.07) 1.5 (0.31, 2.77) 5.6 (4.07, 7.18)
Active 24.3 ± 4.32 18.5 ± 5.40 17.0 ± 5.23 16.8 ± 5.18 16.2 ± 4.89 15.7 ± 4.93 5.9 (4.92, 6.80) 2.7 (1.86, 3.62) 8.6 (7.40, 9.80)
P 0.55 0.03 <0.01 0.02 <0.01 <0.01 0.01 0.12 <0.01

PANSS general scale

Sham 32.2 ± 5.65 27.9 ± 5.23 27.9 ± 4.79 27.4 ± 5.67 27.1 ± 5.66 27.1 ± 5.20 4.2 (3.10, 5.34) 0.9 (0.06, 1.85) 5.1 (3.75, 6.49)
Active 31.6 ± 5.01 27.1 ± 5.46 25.6 ± 5.15 25.2 ± 5.31 24.6 ± 5.49 24.3 ± 5.57 4.5 (3.38, 5.66) 2.8 (1.91, 3.73) 7.3 (5.93, 8.75)
p 0.62 0.43 0.02 0.05 0.03 0.01 0.71 <0.01 0.03

favourable effects of rTMS intervention. We used a novel protocol in
which each participant received a total of 2000 pulses (in 10 trains)
in one session, at 100% motor threshold and inter-train interval
between 90 and 120 s. Significant differences were seen in our
study, in negative symptoms, as measured by PANSS negative
symptom scale and SANS, between the active and sham treatment
groups after the rTMS intervention. Ours is one of the largest
published sample size studies, evaluating any rTMS interventions
for negative symptoms of schizophrenia, available till date, and
hence is adequately powered to detect small differences.
Previous studies have used rather small samples; maximum of
23 participants in the 20 Hz active intervention group [22]. Further,
we could find only four RCTs (published in English language) which
assessed the effect of 20 Hz pulses on negative symptoms
[12,21,22,31]. There are suggestions from the literature that rTMS
interventions with frequencies greater than 10 Hz might lead to
better improvement in negative symptoms [18]. Our results provide
further validation to these findings.
Novak and colleagues (2006) administered 20 Hz, total 20,000
pulses unilaterally [31], while Barr and colleagues (2012) admin-
istered 20 Hz, 15,000 pulses to each hemisphere [12]. Both failed to
find any significant improvement in negative symptoms. On the
other hand, Zhao et al. (2014) and Rabany et al. (2014) administered
a total of 30,000 and 33,600 at 20 Hz pulses, respectively, and both
reported at least some statistically significant improvements in the
negative symptoms. We administered a total of 40,000 pulses
unilaterally (highest reported till date) to each patient over 20
sessions, and found significant reductions in negative symptoms.
This possibly indicates towards a potential critical number of pulses
beyond which the rTMS treatment becomes effective and warrants
further investigation. Similar increase in efficacy with number of
pulses has been observed in studies on depression [32,33].
It should be noted that the participants who received sham
rTMS also had statistically significant improvements after the
intervention. We used a specially designed sham coil which ensures
that no magnetic pulses are delivered to the patients who receive
this intervention. One may speculate a possible placebo-effect in
sucha situation, whereby the mere setting of rTMS application
showed some improvement among the subjects. Nevertheless, a
clear statistically significant advantage in the improvement in
negative symptoms was seen among participants randomized to
active group as compared to the control group.
Though our results yielded significant beneficial effects of rTMS
in negative symptoms along with corresponding changes in CGI
severity index, the overall change in negative symptoms was only
modest. The difference in SANS total score (sham ¼ 50.5 ± 14.11 vs
active ¼ 43.9 ± 12.67) and PANSS negative symptom scale score
(sham ¼ 20.82 ± 4.89 vs rTMS ¼ 18.48 ± 5.40) was approximately 7
points and 2 points, respectively, post-intervention. Hence, the
translation of the statistical improvement to clinical improvement
needs to be done with caution, and potentially invites further
research on this issue.
The importance of the results of our study is re-iterated by the
fact that we followed our patients for a substantially long duration.
But, given the long duration of follow up, the attrition rate in our
study was substantial. One-third (33/100) of the sample had
dropped out towards the end. The primary reason for most of the
drop outs was logistic difficulty in commuting to the centre.
Transport or monetary assistance may have helped in reducing the
drop outs. The number of drop-outs did not differ significantly
between the two arms. In our review, we came across a single study
which had a follow-up period comparable to ours. Dlabac-Delange
and colleagues (2015) found sustained improvement in SANS
scores over a period of 3 months with 10 Hz, total of 30000 pulses
to each hemisphere [13]. Similarly, the favourable effects of rTMS in
our study also seemed to be sustained over 4 months of follow-up
after the intervention. It remains to be seen in future research that
how long such beneficial effects may be sustained and whether
there is any role for booster sessions. An important advantage in
our study was the use of sham coil. Majority of the studies use the
intervention coil as sham by tilting it to 90  [12,13,31]. This method
has been found to induce at least some voltage in the brain
[34],whereas, a sham coil is devoid of this effect. Only Prikryl and
colleagues have used a sham coil in evaluation of efficacy for
 N. Kumar et al. / Brain Stimulation 13 (2020) 840e849 847

Fig. 3. Comparison of PANSS scores at baseline, post-intervention and follow-ups between the two study groups.
*Average difference in scores between the active and the sham rTMS groups, over all time points (pre-intervention, post intervention i. e after 20 sessions of rTMS, subsequent
assessments for 4 consecutive months post intervention).

negative symptoms previously [35]. Moreover, the sham coil in our
study was identical to the active coil in appearance and the same
stimulation parameters were used in the sham as the active coil.
This helped in ensuring more stringent patient blinding. The
blinding was further strengthened by the use of Sequentially
Numbered Opaque Sealed Envelopes (SNOSE), which were carefully
handled.
Depression is a common confounder for negative symptoms of
schizophrenia due to their overlapping conditions. Moreover,
depression is known to respond to rTMS interventions over left
DLPFC. Hence, we made an efforts to control for this confounder by

Table 4
Comparison of CGI-S and CDSS scores between the two study groups across the assessment time points.

Pre- Post- 1 month 2 months 3 months 4 months Reduction$ (95% CI)

Intervention intervention follow up follow up follow up follow up
Pre-intervention to Post-intervention to 4 Pre-intervention to 4
post-intervention months follow-up months follow-up

N
Sham 50 50 50 50 50 50
Active 50 50 50 50 50 50

CGI-S
Sham 4.5 ± 0.73 4.2 ± 0.68 3.9 ± 0.65 3.9 ± 0.76 3.9 ± 0.77 3.8 ± 0.79 0.3 (0.17, 0.43) 0.4 (0.20, 0.57) 0.7 (0.44, 0.91)
Active p- 4.6 ± 0.69 3.9 ± 0.70 3.7 ± 0.84 3.6 ± 0.92 3.4 ± 0.86 3.4 ± 0.90 0.7 (0.52, 0.92) 0.5 (0.36, 0.68) 1.2 (0.97, 1.51)
value 0.49 0.02 0.07 0.08 <0.01 <0.01 <0.01 0.27 <0.01

CDSS
Sham 0.3 ± 1.05 0.12 ± 0.72 0.22 ± 0.91 0.12 ± 0.44 0.24 ± 0.98 0.26 ± 0.97 0.2 (0.01, 0.37) 0.1 (0.42, 0.14) 0.04 (0.3, 0.4)
Active p- 0.3 ± 0.74 0.12 ± 0.44 0.1 ± 0.36 0.02 ± 0.14 0.12 ± 0.59 0.02 ± 0.14 0.2 (0.00, 0.36) 0.1 (0.01, 0.22) 0.3 (0.1, 0.5)
value 1 1 0.39 0.13 0.46 0.09 1 0.13 0.24
848 N. Kumar et al. / Brain Stimulation 13 (2020) 840e849
Fig. 4. Comparison of CGI-S scores at baseline, post-intervention and follow-ups be-
tween the two study groups.
*Average difference in scores between the active and the sham rTMS groups, over all
time points (pre-intervention, post intervention i. e after 20 sessions of rTMS, subse-
quent assessments for 4 consecutive months post intervention).
screening to exclude the subjects having depression. Moreover, the
CDSS, which is a scale for measuring depressive symptoms specif-
ically in people having schizophrenia, was used to measure the
severity of depressive symptoms at baseline and to evaluate
changes if any through follow-ups. Both the groups had statistically
similar CDSS scores at baseline, and no significant changes were
seen at any time points during the study.
A major limitation of our study was that we located the DLPFC
by manual measurements over the scalp. Even though the “5 cm
rule” has been a standard practice, studies have shown that neuro
navigational techniques are more accurate in localizing the stim-
ulation site [36]. Also, our study participants continued their
respective usual pharmacological interventions during the study
period as prescribed by their clinicians. One may argue that this
might lead to some confounding of the outcomes. But, we did not
find any difference in the medications administered to the partic-
ipants of active or sham group at the baseline. Moreover, we
included only those patients who were receiving stable doses of
medicines for at least one month, without any recent dose or
medication changes. Hence, the chances of medicines being a
confounder are low. Continuation of treatment as usual is in
keeping with the ethical guidelines as rTMS is not yet a proven
exclusive treatment modality for schizophrenia.
We did not take an upper limit cut-off for PANSS positive scale
scores. This was done to make the study inclusions more repre-
sentative of the real-world conditions. Nevertheless, since our
sample included only the patients who were already on stable
treatment, the incidence of positive symptoms in our study was
quite low. The maximum PANSS positive scale score in our study
sample was 16.
Conclusion
Our study showed benefits of high frequency (20 Hz) rTMS at
100% motor threshold with 2000 pulses per session administered
through 10 trains over left DLPFC for 20 sessions over 4 weeks for
patients suffering from schizophrenia with predominant Negative
symptoms. This study adds to the existing literature with its robust
design and large sample size despite few limitations and paves the
path for future research regarding administration of high frequency
rTMS for regular clinical treatment of Negative symptoms in
schizophrenia with adequate safety measures.
Declaration of competing interest
The authors declare that they have no conflict of Interest.
Acknowledgement
The study is fully funded by Department of science and Tech-
nology under CSRI Initiative (vide grant No DST No:SR/CSRI/48/
2013(G). I sincerely acknowledge the contribution of technical staff
of the Neuromodulation lab for mental health for their assistance in
completing this project.
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