Psychiatry Research 320 (2023) 115033

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Effectiveness of accelerated intermittent theta burst stimulation for social

cognition and negative symptoms among individuals with schizophrenia: A
randomized controlled trial
Ying Jin †, *, Jie Tong †, Ying Huang, Dianhong Shi, Na Zhu, Minghuan Zhu, Minjia Liu,
Haijun Liu, Xirong Sun *
Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University, Shanghai, China

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Social cognitive and negative symptoms impairment may increase the risk of mental disability in
Intermittent theta burst stimulation individuals with schizophrenia. However, randomized controlled studies on the effectiveness of accelerated
iTBS intermittent theta burst stimulation (iTBS) for social cognition and negative symptoms in individuals with
Schizophrenia
schizophrenia are very limited.
Social cognition
Negative symptoms
Methods: A total of 125 individuals with schizophrenia were recruited, 66 of whom were randomly divided into
an active iTBS group (n=34) and sham iTBS group (n=32) by stratified sampling. Participants received either
active iTBS or sham iTBS targeting the left dorsolateral prefrontal cortex (DLPFC) 20 sessions for 4 weeks under
navigation. The Facial Emotion Recognition Test (FERT), Hinting Task (HT), and Positive and Negative Syn­
drome Scale (PANSS) were measured at baseline, 2 weeks, and 4 weeks. The trial protocol was registered with
the Chinese Clinical Trial Registry (ChiCTR2100051984).
Results: Sixty patients (90.90%) completed the intervention and the 4-week follow-up, including 29 women
(43.94%) and 37 men (56.06%) with a mean (SD) age of 47.53 (10.17) years. The primary outcomes showed
FERT scores (week 2; 0.27 [95% CI, 0.09 to 0.45]; P< .01; ES 0.14) (week 4; 0.63 [95% CI, 0.45 to 0.80]; P<
.001; ES 0.47) and HT scores (week 2; 1.00 [95% CI, -0.02 to 1.98]; P< .05; ES 0.67) (week 4; 2.13 [95% CI, 1.21
to 3.06]; P< .001; ES 0.27) in the active iTBS group were significantly different from those in the sham iTBS
group at 2 and 4 weeks of follow-up. The secondary outcome showed that the negative symptom score (-3.43
[95% CI, -4.85 to -2.01]; P< .001; ES 0.29) of the active iTBS group was significantly different from that of the
sham iTBS group at the 4th week of follow-up.
Conclusions: Accelerated iTBS can effectively ameliorate the social cognition and negative symptoms of in­
dividuals with schizophrenia. These results suggest that accelerated iTBS may be a safe and effective neuro­
modulation technique to improve the overall functional recovery of individuals with schizophrenia, and has a
good clinical application prospect.

1. Background include positive, negative, and cognitive symptoms (Sommer et al.,

2022). Most studies have demonstrated the effectiveness of antipsy­
Schizophrenia is a leading cause of mental disability and is charac­ chotics in alleviating the positive symptoms of schizophrenia, but
terized by impairments in multiple functional domains (Abplanalp et al., treatment of the negative and cognitive symptoms is limited (Huhn
2022). The 2019 Global Burden of Disease Study reported that the et al., 2019). Compared with positive symptoms, negative and cognitive
number of individuals with schizophrenia cases has increased to 23.6 symptoms have a greater impact on the quality of life and social func­
million, contributing 12.2% of the global disability-adjusted life years tioning of individuals with schizophrenia, and are also the main reasons
(DALYs) (2022). The psychopathological dimensions of schizophrenia for the chronic duration of illness (He et al., 2022).

* Corresponding authors.
E-mail addresses: [email protected] (Y. Jin), [email protected] (X. Sun).
†
Ying Jin and Jie Tong contributed equally to this work.

https://doi.org/10.1016/j.psychres.2022.115033
Received 22 October 2022; Received in revised form 19 December 2022; Accepted 24 December 2022
Available online 25 December 2022
0165-1781/© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Y. Jin et al. Psychiatry Research 320 (2023) 115033

Evidence indicates that in cognitive symptoms of schizophrenia, 2. Methods

social cognition plays an important key role in patients’ social func­
tioning and interpersonal interactions, which is the direction of the 2.1. Study design
latest research (Green et al., 2019; van Hooren et al., 2008). Social
cognition refers to psychological activities during social interactions, The study was a randomized, double-blind, controlled clinical trial. It
which involve perceiving, interpreting and generating reactions to the was based on the Neuroscience Laboratory of Shanghai Pudong Mental
intentions, tendencies and behaviours of others (Green et al., 2008), Health Center, School of Medicine, Tongji University. The sample size of
including emotional processing, theory of mind, social perception, and the study was calculated by sample size power analysis software (PASS
attribution bias (Pinkham et al., 2014). Although social cognition and version 21.0.3 [NCSS LLC, Utah, USA]). Based on our preliminary
non-social cognition share some overlapping cognitive processes, experiment, we set the significance level as 0.05, the power value as 0.8,
indeed, social cognitive impairment has a more-negative effect on daily the standard deviation as 1.36, and a two-sided test was needed. The
functioning than does non-social cognitive impairment (Green et al., samples were divided into two groups: the active iTBS and sham iTBS
2015). Furthermore, emotion recognition and theory of mind are the groups, with at least 23 participants assigned to each arm. Considering
two most important domains of social cognition in schizophrenia. (Tan that participants may be unable to drop out or complete the test for
et al., 2018). The former involves identifying, managing, understanding, special reasons, we set a 20% loss rate and ultimately determined a
and interpreting emotions, while the latter involves understanding and sample size of 30 people in each group. The study protocol was regis­
predicting others’ beliefs, intentions, and behaviours (Lim et al., 2021b). tered with the Chinese Clinical Trial Registry (ChiCTR2100051984).
These dysfunctions are particularly associated with difficulties in con­
flict resolution ability, interpersonal relationships, social interactions 2.2. Participants
(Green et al., 2012).
However, there are limited studies on intervention for social cogni­ All participants were recruited from the Shanghai Pudong Mental
tion and negative symptoms in schizophrenia. Psychopharmacological Health Center, School of Medicine, Tongji University, from November 1,
studies suggest that there are different opinions on the use of antipsy­ 2020, to June 30, 2021. The inclusion criteria were as follows: (1) in­
chotics for the improvement of negative symptoms, and the effectiveness dividuals who met the DSM-5 (Roehr, 2013) diagnostic criteria for
for social cognition may be even less promising (Kucharska-Pietura and schizophrenia; (2) individuals aged between 18 years and 65 years; (3)
Mortimer, 2013; Na et al., 2015). Simultaneously, the interaction of individuals with a course of disease ≥ 5 years; (4) individuals who were
antipsychotics with various neurotransmitters in the brain may lead to right-handed; (5) individuals who were treated with a stable dose of
sedation, agitation, compulsion, tremor and other adverse drug re­ olanzapine for at least 6 months before the iTBS intervention and until
actions (Skokou et al., 2022). Although psychosocial interventions may the follow-up was completed; (6) individuals who were able to coop­
be a feasible way to improve social cognition and negative symptoms, erate with treatment and complete various assessments independently;
they require substantial time and presents objective difficulties in their (7) individuals who were able to express themselves through spoken or
promotion (Solmi et al., 2022a; Wang et al., 2013). Therefore, it is of written language; and (8) participants with signed informed consent
great clinical value to explore simple and effective interventions to forms for participation in the study. The exclusion criteria were as fol­
improve social cognition and negative symptoms in individuals with lows: (1) patients who met the DSM-5 (Roehr, 2013) diagnostic criteria
schizophrenia (Solmi et al., 2022b). for brain organic mental disorder, dementia, or intellectual disability;
Noninvasive brain stimulation (NIBS) can induce neuronal action (2) patients with severe brain trauma, neurological disorders, or phys­
potentials by physically regulating the brain, or modulates spontaneous ical illness; (3) history of metal implantation in the body; (4) patients
neuronal activity by a tonic depolarization or hyperpolarization, which with severe visual, hearing or language impairments; (5) patients who
is helpful to improve negative symptoms, depressive symptoms, or received treatment with iTBS, rTMS, or MECT within 3 months; (6)
cognitive impairment. (Chen et al., 2020; Huhn et al., 2019). Due to its patients with changed or combined use of other antipsychotics or drug
noninvasive characteristics, NIBS has gradually attracted attention in dosage adjustments during the observation period; (7) patients with a
the clinical treatment and research of mental diseases (Lefaucheur et al., history of vertigo, syncope, epilepsy, or alcohol or drug dependence; and
2014). At present, repetitive transcranial magnetic stimulation (rTMS) (8) participants or guardians did not sign the study informed consent
in NIBS has gotten the most traction in psychiatry as a technique, while form and those who dropped out.
intermittent theta burst stimulation (iTBS) is a more novel form of rTMS
(Chu et al., 2021). ITBS is a new form of NIBS, that is characterized by 2.3. Randomization
the delivery of 600 pulses within 3 minutes (Di Lazzaro et al., 2011). It
produces an increase in motor cortex excitability in a short time, and its The subjects were sorted and numbered according to the time of
excitatory effect may be superior to that of rTMS (Blumberger et al., enrolment. A researcher who did not participate in the assessments or
2018). Some studies show that prefrontal rTMS may help to improve stimulation randomly sampled the numbers through SPSS 26.0 software
negative symptoms in individuals with schizophrenia (Freitas et al., (SPSS, Inc., Chicago, IL, USA) and divided them into the active iTBS
2009; Shi et al., 2014). Wobrock et al. (2015) believed that active 10-Hz group and the sham iTBS group at a ratio of 1:1. After the subjects were
rTMS was not superior compared with sham rTMS in improving negative enrolled in the group, they were assigned a ranking number according to
symptoms. Additionally, iTBS can increase the executive function of enrolment time. Finally, they were assigned to the corresponding groups
patients with medication-resistant depression (Cheng et al., 2016), according to the results of prior random sampling. Neither the partici­
alleviate the decline on cognitive and memory abilities, and improve pants nor the investigators were aware of the groupings except for
working memory performance (Debarnot et al., 2015; Hoy et al., 2016). randomization and stimulation.
Most studies of major depressive disorder (MDD) or autism spectrum
disorder (ASD) have proven that iTBS is a safe and effective neuro­ 2.4. Accelerated intermittent theta burst stimulation (Accelerated iTBS)
regulatory technique (Chung et al., 2015; Demirtas-Tatlidede et al.,
2010). Accelerated iTBS was performed using a Brain Ultimate M-100
We attempted to explore the efficacy of accelerated iTBS for social transcranial magnetic stimulator (Brain Ultimate, Atlanta, USA) with a
cognition and negative symptoms in a randomized controlled trial based 70-mm air-cooled butterfly coil. The accelerated iTBS parameters were
on a sample of individuals with chronic schizophrenia. If this hypothesis as follows: 3 pulses, 50 Hz bursts, 2 s on and 8 s off; 600 pulses per
can be confirmed, it will provide insights for the use of iTBS in the field session; total duration of 3 min 9 s, and a resting motor threshold (RMT)
of clinical neuroregulation for schizophrenia. intensity of 120% (Blumberger et al., 2018). Considering that high-dose

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Y. Jin et al. Psychiatry Research 320 (2023) 115033

TBS may cause patient discomfort (Williams et al., 2018), we applied as an operationalized, standardized measure of schizophrenia that pro­
three iTBS rounds per treatment day and separated by 15 minutes (total: vides a balanced representation of positive and negative symptoms and
1800 pulses/day). Simultaneously, using the TMS Navigation System gauges their relationship to one another and to psychopathology (Lim
(Brain Ultimate, Atlanta, USA) to accurately locate the coil, the coil was et al., 2021a). The 30-item PANSS constitutes four scales measuring
placed with the Visor 2.0 and tangential to the skull with the handle positive and negative symptoms, general psychopathology, and their
pointing in the posterolateral direction. The stimulation target was differences. The Chinese version of the PANSS provides better reliability
located in the left dorsolateral prefrontal cortex (DLPFC), which may be and validity; and Cronbach’s α coefficient is 0.80, and the remeasuring
an effective target for individuals with schizophrenia (Kumar et al., reliability is 0.89 (Si et al., 2004). The scale is scored on a 7-point Likert
2020). Treatment was performed in a sitting or semirecumbent position. scale, and the higher the score, the more severe the psychopathology in
Treatment was performed once a day, 5 times per week, for 4 weeks, the dimension.
yielding a total of 20 sessions. All instruments and parameters were
standardized and adjusted by the manufacturer. During treatment, 3.4. Procedure
subjects were required to wear noise-cancelling earplugs and remove all
objects sensitive to magnetic fields, such as watches, cell phones, All the enrolled participants underwent social cognition and psy­
jewellery, and metal dentures. chopathology assessments at baseline, 2 weeks, and 4 weeks. Under the
guidance of the experimenter, the participants completed the FERT and
2.5. Blinding strategy HT according to the instructions on the computer, and completed the
PANSS assessment in a quiet room, and checked the completion of each
To maintain study blinding, this study used a Brain Ultimate sham item. The evaluator has a master’s degree in psychiatry and is a regis­
butterfly coil (P/N 3950-00 S/NO105). The system provides the sensa­ tered clinical psychological scale surveyor in China. To ensure consis­
tion of TBS without enough magnetic energy to reach the cortex. The tency and blinding, only one consistently-trained evaluator was
system has been used in numerous TBS trials and includes specific coil involved, and the assignment of active and sham TBS was unknown.
windings to optimize the blinding experience. It is also visually indis­ After the last follow-up, the subjects and the psychological evaluator
tinguishable from active coils to minimize accidental unblinding. To filled in the blinding questionnaire, including three choices: active iTBS,
ensure consistency and blindness, all subjects and psychological asses­ sham iTBS or "Don`t know".
sors are blind. Only one professionally licenced TBS therapist knew
about the grouping and provided the intervention throughout the study, 3.5. Statistical analysis
and only one transcranial magnetic stimulator and navigator were used.
Data analysis was conducted using SAS software (version 9.4 SAS
3. Measures Institute, Inc). We performed normality tests on all data by Kolmogorov-
Smirnov normality analysis, using the mean (SD) to statistically describe
3.1. Facial emotion recognition test (FERT) normal continuous data. The t test was applied for evaluation between
two groups. A nonparametric Mann-Whitney U test was used for data
The FERT is an assessment of a person’s ability to recognize and that did not meet the median (IQR). For classified data, the frequency
discern the facial emotions of others, and is an important research area (percentage) was used for statistical descriptions, and the χ2 test was
in social cognition (Yalcin-Siedentopf et al., 2014). Huang et al. created used for intergroup comparisons. The Fisher exact probability method
a Chinese localized facial expression picture test system based on the was used for data with al theoretical frequency that was too small. The
Facial Action Coding System (FACS) by Ekman (Polli et al., 2012). The analysis was performed in the intention-to-treat population, defined as
Cronbach’s α coefficient is 0.77, and the remeasuring reliability is 0.81 all patients randomly assigned into a treatment group who started at
(Y et al., 2020). The test consists of 42 facial emotion photographs, least one treatment session. A linear mixed model regression test was
which show seven basic emotions (anger, disgust, fear, sadness, surprise, used to evaluate the effect size of the FERT, HT, and PANSS. Effect sizes
happiness, and neutral), and subjects are asked to indicate the emotion are described as Cohen’s d. Differences were statistically significant at P
and intensity in each photograph. The outcome of the FERT is the ac­ < .05.
curacy of emotion category recognition, with 1 point for correct answer
and 0 points for incorrect answers. Higher scores indicate better emotion 3.6. Ethics statement
judgment.
The protocol for this research was approved by the Research Ethics
3.2. Hinting task (HT) Committee of the Shanghai Pudong New Area Mental Health Center and
Tongji University School of Medicine (No: PDJWLL2020027). All pro­
The HT is a linguistic measure of theory of mind and an important cedures were performed in accordance with the ethical standards of the
indicator of social cognition (Corcoran et al., 1995). It evaluates a responsible committee on human experimentation (institutional and
subject’s ability to infer the real intentions behind indirect speech ut­ national) and the Helsinki Declaration of 1975, as revised in 2008. Both
terances or hints. The task consists of 10 essays presenting an interaction participants and guardians provided written informed consent for
between two characters, and the participant is asked to say the intention participation in this study.
of the character dropping the hint. If the participant’s first answer is
correct, they receive a score of 2 points. If the participant gives the 4. Results
correct response when prompted with paraphrasing of the hint, a score
of one is given. Failure to infer true intent receives a score of zero. The 4.1. Recruitment
Cronbach’s α coefficient is 0.62 and the remeasuring reliability is 0.64
(Lindgren et al., 2018). Total scores range from 0 to 20, with higher Of the 125 participants who met the diagnostic criteria, 59 were
scores indicating better theory of mind performance (Mallawaarachchi ineligible for participation based on the inclusion and exclusion criteria
et al., 2019). (Fig. 1). Nine participants were excluded because of an age over 65
years, 7 were excluded because of a disease duration less than 5 years,
3.3. Positive and negative syndrome scale (PANSS) 13 were excluded because of the use of other antipsychotic medications,
and 8 were excluded because of medication adjustments within 6
The PANSS scale was proposed by Kay et al. (1987). It was conceived months. Three participants who received rTMS within one month and 1

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Y. Jin et al. Psychiatry Research 320 (2023) 115033

Fig. 1. Study flowchart for enrolment, allocation, follow-up, and analysis.

who received MECT were excluded. Of the 66 enrolled participants, 2 correctly. Jame’s blinding index (BI) is 0.683 (95% CI: 0.593 to 0.772),
were uncomfortable with stimulation, 1 withdrew due to their guardian, which was greater than 0.5 to determine the overall success of the
1 was excluded due to the use of other antipsychotics, 1 was unable to implementation of blindness.
complete the psychobehavioural assessment, and 1 had other serious
diseases during the follow-up period. Ultimately, 30 participants were 4.3. Social cognition
included in each of the active and sham iTBS groups and completed the
entire research process. Table 2 and Fig. 2 show the comparison of the main outcomes of
social cognition between groups at the baseline, 2-week, and 4-week
follow-ups. There was no significant difference in FERT and HT be­
4.2. Participant characteristics
tween the active-iTBS group and the sham-iTBS group at baseline (P>
.05). The main outcomes of social cognition showed that the FERT scores
The demographic characteristics of the participants from the active
(week 2; 0.27 [95% CI, 0.09 to 0.45]; P< .01; ES 0.14; Fig. 2A) (week 4;
iTBS, sham iTBS, and total sample groups in terms of age, sex, education
0.63 [95% CI, 0.45 to 0.80]; P< .001; ES 0.47) and HT scores (week 2;
level, marital status, employment status, course of disease, family his­
1.00 [95% CI, -0.02 to 1.98]; P< .05; ES 0.67; Fig. 2C) (week 4; 2.13
tory of mental illness, and olanzapine use are shown in Table 1. Among
[95% CI, 1.21 to 3.06]; P< .001; ES 0.27) of the two groups were
the 66 participants, the average age was 47.53±10.17 years, and the
significantly different at the 2-week and 4-week follow-ups. On the FERT
proportion of females was 41.67%. The average education level of the
subscale, there was a significant difference between the two groups at
participants was 7.27±2.33 years, and most of them were married
the 2-week follow-up only for the identification of fear (P< .05; Fig. 2B)
(60.00%). Fifty-six percent of the participants were unemployed, and
and surprise (P< .01). At the 4-week follow-up, the active iTBS group
the average course of disease was 8.62±4.09 years. It is noteworthy that
had higher scores than the sham iTBS group for the identification of
36.67% of the patients had a family history of mental illness, and the
anger, fear, sadness, surprise and happiness, and the difference was
average maintenance dose of olanzapine was 11.98±2.69 mg/d. There
statistically significant (P< .001).
were no significant differences in the demographics between the active
and sham iTBS groups (p> .05). At the end of follow-up, only 32% of
subjects and 41% of evaluators could guess the intervention assignment

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Y. Jin et al. Psychiatry Research 320 (2023) 115033

Table 1
Demographic characteristics of the included participants.

Effect
Characteristic Total Active Sham t / χ2 P

sizeb

0.13

0.02

0.29

0.01
0.47
0.22
0.01
0.21
0.27
0.22
0.24
0.01
0.27
sample iTBS iTBS valuea
(n¼66) (n¼34) (n¼32)

-0.23 (-1.93 to 1.46)

-0.07 (-0.63 to 0.49)

0.03 (-0.20 to 0.27)

0.49 (-0.74 to 1.73)

Age, mean (SD). Y 47.53 47.60 47.47 0.05a .960

0.63 (0.45 to 0.80)

1.00 (0.51 to 1.49)

1.13 (0.55 to 1.72)

0.67 (0.38 to 0.96)
0.93 (0.47 to 1.39)
0.70 (0.38 to 1.02)

2.13 (1.21 to 3.06)

(10.17) (9.46) (10.99)

-2.47 (-5.83 to

-3.43 (-4.85 to
Sex, No. (%) 0.62b .432

Differencea
Male 37 18 19

(95% CI)
(56.06) (52.94) (59.37)

-1.10)

-2.01)
Female 29 16 13
(43.94) (47.06) (40.63)
Education, mean (SD). 7.27 7.53 7.00 0.89a .379
y (2.33) (2.36) (2.30)

4.07 (0.36)
2.77 (1.07)
2.83 (1.12)
3.17 (1.29)
5.20 (0.71)
4.03 (1.00)
4.77 (0.63)
5.70 (0.47)
Sham iTBS
Marital status, No. (%) 2.89b .236

(n=30)

(1.93)

(5.09)

(2.10)

(2.36)

(3.61)
13.13

64.77

12.30

23.13

29.33
Single 16 9 (26.47) 7 (21.86)
(24.24)
Married 38 17 21
(57.58) (50.00) (65.63)

Active iTBS

4.70 (0.32)
3.77 (0.82)
2.77 (1.04)
4.30 (0.95)
5.87 (0.35)
3.93 (0.79)
5.47 (0.63)
5.50 (0.57)
Divorced or 12 8 (23.53) 4 (12.51)

Week 4

(n=30)
widowhood (18.18)

(1.64)

(3.98)

(2.40)

(3.09)

(2.91)
15.27

61.30

12.50

19.70

29.10
Employment, No. (%) 1.09b .297
Yes 29 14 15
(43.94) (41.18) (46.87)
No 37 20 17
(56.06) (58.82) (53.13)

Effect
sizeb

0.30

0.00

0.62

0.01
0.14
0.25
0.01
0.07
0.04
0.11
0.03
0.03
0.67
Course of disease, 8.62 8.83 8.40 0.41a .685
mean (SD). y (4.09) (3.95) (4.29)
Family history of 1.15b .284

-0.07 (-0.60 to 0.46)

-1.63 (-4.08 to 0.82)

-1.50 (-3.03 to 0.03)

-0.20 (-1.85 to 1.45)

0.35 (-0.99 to 1.69)
0.27 (-0.17 to 0.71)

0.50 (-0.01 to 0.99)

0.27 (-0.08 to 0.61)

0.23 (-0.15 to 0.62)

0.17 (-0.11 to 0.44)
1.00 (-0.02 to 1.98)
0.27 (0.09 to 0.45)

0.53 (0.14 to 0.93)

mental illness, No.
(%)
Yes 24 10 14 Differencea
(36.36) (29.41) (43.75) (95% CI)
No 42 24 18
(63.64) (70.59) (56.25)

Abbreviations: FERT, Facial emotion recognition test; HT, Hinting Task; PANSS, Positive and negative syndrome scale..
Olanzapine dose, 11.98 11.91 12.07 -0.43a .670
mean (SD), mg/d (2.69) (2.45) (3.00)
3.98 (0.33)
2.73 (0.91)
2.73 (1.02)
3.10 (0.96)
5.17 (0.65)
3.93 (0.79)
4.70 (0.84)
5.50 (0.57)
Sham iTBS

a
Two-sample t-test.
(n=31)

(1.91)

(4.91)

(2.11)

(2.60)

(3.38)
13.07

65.57

12.57

23.33

29.67
b
Chi-squared test.
Comparison of social cognitive and psychiatric symptoms effects between the active and sham iTBS groups.

4.4. Negative symptoms

Active iTBS

4.25 (0.36)
3.00 (0.79)
2.67 (1.03)
3.60 (0.97)
5.43 (0.68)
4.47 (0.73)
4.93 (0.64)
5.67 (0.48)
Week 2

(n=32)

(1.89)

(4.56)

(3.38)

(3.27)

(2.99)
14.07

63.93

12.30

21.83

29.47
Table 2 and Fig. 2 show the comparison of psychopathology symp­
toms between groups at the baseline, 2-week, and 4-week follow-ups.
There was no significant difference in PANSS, between the active-iTBS
group and the sham-iTBS group at baseline (P> .05). The PANSS score
Effect

(-2.47 [95% CI, -5.83 to -1.10]; P< .01; ES 0.13; Fig. 2D) and negative
sizeb

0.96

0.92

0.90

0.91
0.10
0.88
0.91
0.82
0.74
0.80
0.88
0.71
0.83

symptom score (-3.43 [95% CI, -4.85 to -2.01]; P< .001; ES 0.29; Fig. 2F)
of the active iTBS group were significantly different from those in the -0.10 (-1.91 to 1.71)
-0.16 (-0.36 to 0.03)

-0.03 (-0.68 to 0.62)

-0.67 (-0.65 to 0.52)
-0.07 (-0.47 to 0.34)
-0.07 (0.27 to -0.60)
-0.03 (-0.49 to 0.43)
-0.07 (-0.43 to 0.29)
-1.33 (-1.37 to 1.10)

0.07 (-2.57 to 2.70)

0.07 (-1.33 to 1.47)

0.10 (-1.55 to 1.75)

0.03 (-0.42 to 0.49)

control group at the 4th week of follow-up. However, there was no

significant difference between the two groups in the positive symptoms
Differencea

and general psychopathology subscale scores at the 2-week and 4-week Differences differences between active and sham iTBS groups.
(95% CI)

follow-ups (P> .05). Effect sizes are listed as Cohen d; df = 124 for all analysis.

4.5. Secondary analysis

3.66 (0.37)
2.70 (0.88)
2.67 (1.37)
3.03 (1.33)
5.10 (0.80)
3.77 (1.19)
4.60 (0.85)
5.40 (0.72)
Sham iTBS

Table 3 shows the differences of social cognition and psychopa­

(n=32)

(2.50)

(5.25)

(2.44)

(2.95)

(3.62)
12.63

65.97

12.70

23.47

29.80

thology symptoms within the groups at the 2-week and 4-week follow-
ups compared with baseline. At the 4-week follow-up, the active iTBS
group had a mean increase of points in the FERT scores (-0.76 [95% CI,
Active iTBS

3.49 (0.38)
2.73 (0.91)
2.63 (1.13)
2.97 (0.89)
5.03 (0.76)
3.70 (0.83)
4.57 (0.93)
5.33 (0.66)

-0.95 to -0.56]; P< .001) and HT scores (-1.57 [95% CI, -2.65 to -0.49];
Baseline

(n=34)

(2.27)

(4.94)

(2.95)

(3.41)

(3.38)

P= .01) from baseline. In the FERT subgroup, there was a statistically

12.50

66.03

12.77

23.57

29.70

significant difference in the scores of fear (P= .01), sadness (P= .04),
surprise (P< .001), and neutral (P= .03) factors. The FERT scores (-1.20
[95% CI, -1.38 to -1.02]; P< .001), HT scores (-2.77 [95% CI, -3.79 to
Variable, mean (SD)

Negative syndromes

-1.74]; P< .001), PANSS scores (4.73 [95% CI, 2.42 to 7.05]; P= .001),
Positive syndromes

psychopathology

and negative symptom scores (3.87 [95% CI, 2.19 to 5.55]; P= .001)
were significantly different from baseline after 4-week follow-up in the
Happiness

active iTBS group, and only disgust factor in FERT subgroup showed no
Surprise
Sadness

General
Neutral
Disgust

PANSS
Table 2

Anger
FERT

statistical difference (P> .05). In the sham iTBS group, only FERT scores
Fear

HT,

were significantly different from baseline at the 2-week and 4-week

b
a

5
Y. Jin et al. Psychiatry Research 320 (2023) 115033

Fig. 2. Differences in social cognition, psychiatric symptoms, and adverse events between active and sham iTBS groups.
A, Advancement in FERT score, B, Radar chart of FERT basic emotion difference between active and sham iTBS groups in different periods; C, Advancement in HT
score; D, Improvement in PANSS score; E No significant difference in positive symptom score; F, Improvement in negative symptom score; G, No significant difference
in general psychopathology score; H, Dot plot of the percentage of adverse events.
Abbreviations: FERT, Facial emotion recognition test; HT, Hinting task; PANSS, Positive and negative syndrome scale.
* p< .05, ** p< .01, *** p< .001.

follow-ups (P< .05). 5. Discussion

4.6. Adverse events We used the FERT, HT, and PANSS in a randomized, double-blind,
and sham-controlled trial to explore the effectiveness of accelerated
During the study, 15 (50%) participants in the active iTBS group and iTBS on social cognition and negative symptoms in individuals with
3 (10%) participants in the sham iTBS group reported one or more schizophrenia. To our knowledge, this is the first randomized controlled
adverse events. Numb-headedness had the highest incidence of the study to simultaneously focus on the use of accelerated iTBS for social
adverse events, reported by 10 (33%) participants in the active iTBS cognition and negative symptoms in individuals with schizophrenia,
group and 3 (37.5%) participants in the sham iTBS group. However, no which is an original research direction. We demonstrated that acceler­
serious adverse events, such as seizure or syncope, occured. The inci­ ated iTBS administration in the left DLPFC significantly improved
dence of adverse reaction records is shown in Fig. 2H. negative symptoms in individuals with schizophrenia, but there were no
significant changes in positive symptoms or general psychopathology.

6
Y. Jin et al. Psychiatry Research 320 (2023) 115033

Table 3
Comparison of social cognitive and psychiatric symptoms effects in active and sham iTBS groups from baseline.
Variable Difference from week 2 and baseline P-valuea P- Difference from week 4 and baseline P-valuea P-valueb
(95% CI) valueb (95% CI)

Active iTBS Sham iTBS Active iTBS Sham iTBS

(n¼32) (n¼31) (n¼30) (n¼30)

FERT -0.76 -0.95 to -0.56) -0.32 (-0.50 to 0.14) < .001*** .01* -1.20 (-1.38 to -1.02) -0.41 (-0.60 to -0.22) < .001*** < .001***
Anger -0.27 (-0.71 to 0.17) -0.03 (-0.49 to 0.43) .23 .89 -1.03 (-1.48 to -0.59) -0.07 (-0.57 to 0.44) < .001*** .79
Disgust -0.03 (-0.59 to 0.59) -0.07 (-0.69 to 0.56) .91 .83 -0.13 (-0.69 to 0.43) -0.17 (-0.81 to 0.48) .64 .61
Fear -0.63 (–1.11 to -0.15) -0.10 (-0.54 to 0.34) .01* .82 -1.33 (-1.81 to -0.86) -0.17 (-0.55 to 0.22) < .001*** .39
Sadness -0.40 (-0.77 to -0.03) -0.07 (-0.44 to 0.31) .04* .73 -0.83 (-1.14 to -0.53) -0.27 (-0.84 to 0.30) < .001*** .35
Surprise -0.77 (-1.17 to -0.36) -0.17 (-0.69 to 0.36) < .001*** .53 -1.27 (-1.68 to -0.85) -0.27 (-0.84 to 0.30) < .001*** .35
Happiness -0.37 (-0.78 to 0.05) -0.10 (-0.54 to 0.34) .08 .65 -0.90 (-1.31 to -0.49) -0.17 (-0.55 to 0.22) < .001*** .39
Neutral -0.33 (-0.63 to -0.04) -0.10 (-0.44 to 0.24) .03* .56 -0.40 (-0.69 to -0.11) 0.16 (-0.62 to 0.02 .01* .06
HT, -1.57 (-2.65 to -0.49) -0.43 (-1.58 to 0.72) .01* .45 -2.77 (-3.79 to -1.74) -0.50 (-1.65 to 0.65) < .001*** .39
PANSS 2.10 (-0.36 to 4.56) 0.40 (-2.23 to 3.03) .09 .76 4.73 (2.42 to 7.05) 1.20 (-1.47 to 3.87) .001** .37
Positive syndromes 0.13 (-1.34 to 1.61) 0.13 (-1.05 to 1.31) .86 .82 0.27 (-1.13 to 1.66) 0.40 (-0.78 to 1.58) .70 .50
Negative syndromes 1.73 (0.01 to 3.46) 0.13 (-1.30 to 1.57) .49 .85 3.87 (2.19 to 5.55) 0.33 (-1.05 to 1.71) .001** .63
General psychopathology 0.23 (-1.42 to 1.88) 0.13 (-1.68 to 1.94) .78 .88 0.60 (-1.03 to 2.23) 0.47 (-1.40 to 2.34) .46 .62

Abbreviations: FERT, Facial emotion recognition test; HT, Hinting Task; PANSS, Positive and negative syndrome scale.
a
Differences from baseline in active iTBS Group.
b
Differences from baseline in sham iTBS Group.
*
p< .05.
**
p< .01.
***
p< .001.

Our results are consistent with the study by Zhao et al., which evaluated et al. (2017) used rTMS to intervene in the left DLPFC of patients with
the therapeutic effects of four different intensities of rTMS and iTBS in depression, which could accelerate the emotional cognitive process.
individuals with schizophrenia, effective only for negative symptoms Rassovsky et al. (2015) found that patients with schizophrenia under­
and not for positive symptoms (Zhao et al., 2014). Some recent studies going tDCS on the DLPFC showed significant improvement in facial
supported that left DLPFC significantly decreased negative symptoms emotion recognition. Nitsche et al. (2012) conducted tDCS on the left
severity among individuals with schizophrenia compared with sham DLPFC of healthy subjects, revealing that the perception of positive
iTBS (Bation et al., 2021; Wang et al., 2020). Neurochemical and neu­ emotions was improved. Therefore, we hypothesized that the reason for
roimaging studies have reported that negative symptoms are associated the improvement in emotional processing and theory of mind might be
with decreased frontal or prefrontal metabolism and dopamine function related to the iTBS on the left DLPFC.
(Galderisi et al., 2015). ITBS ameliorates negative symptoms by stimu­ However, the neurobiological hypothesis suggests that iTBS can in­
lating the left DLPFC, increasing metabolism in this area, promoting fluence the magnitude of long-term potentiation (LTP), which has much
dopamine release, and increasing regional blood flow to the resting in common with long-term memory and is one of the main molecular
brain (Bulteau et al., 2022). This hypothesis supports our finding that mechanisms of learning and memory (Feng et al., 2023). Opie et al.
the longitudinal difference in negative symptoms at the 4-week (Sergi et al., 2007) found that iTBS can enhance the neural regeneration
follow-up is more significant than that at the 2-week follow-up, which response, which is also the basis of learning and memory. Interestingly,
means that the duration of brain stimulation may be proportional to the our study found that iTBS seems to have very limited improvement in
amount of dopamine released. disgust emotion recognition. There are few studies on emotion recog­
Furthermore, our results show that the improvement in emotional nition and intensity, which cannot truely explain the neurobiological
processing and theory of mind in the positive iTBS group was more basis and can only confirm the positive role of emotion recognition and
significant than that in the control group, which indicates that iTBS can intensity in interpersonal communication (Wang et al., 2013). More­
enhance the social cognitive function of individuals with schizophrenia. over, no serious adverse events such as syncope or seizure occurred
To date, iTBS research on facial emotion recognition and theory of mind during the entire treatment period, and only complaints of headache,
in individuals with schizophrenia is relatively limited. Wolwer et al. needle-tingling, numb-headedness, and dizziness were reported. These
found that high-frequency (10 Hz) rTMS on the left DLPFC improved results are consistent with most studies, which confirm that iTBS is a safe
impaired facial emotion recognition in individuals with schizophrenia and well-tolerated neuromodulation technique with good clinical
(Wölwer et al., 2014). Dumitru et al. administered iTBS on the left application prospects (Demirtas-Tatlidede et al., 2010).
DLPFC to 28 healthy subjects and found a positive effect on facial
emotion recognition (Dumitru et al., 2020). Tong et al. (2021) suggested
that high-frequency rTMS could significantly improve the performance 5.1. Limitations
on a theory of mind and executive function, improving self-other
discrimination and the ability to regulate self-other representation. We also note several limitations. First, this study was been greatly
These results are generally consistent with our findings and confirm the limited with respect to expanding the number of participants and the
effectiveness of noninvasive neuromodulation techniques for social follow-up period due to the COVID-19 pandemic, and the follow-up was
cognition. limited to 4 weeks. Second, considering the possible inconsistent attri­
The mechanism of the positive effects of iTBS on social cognition butes of social perception and attribution bias, our study only used
remains unclear. The neuropsychological hypothesis suggests that the emotional processing and theory of mind as social cognitive assessment
frontal lobe may play an important role in promoting social cognition factors. Third, we did not extend serum pro-brain derived neurotrophic
(Lee et al., 2004), and the limited activation of the prefrontal cortex may factor concentration (BDNF) or brain imaging tests such as functional
be at the core of facial emotion recognition disorders (Li et al., 2010), magnetic resonance imaging (fMRI) to explore the neuropathological
leading to reduced theory of mind-related responses in the medial su­ mechanisms by which accelerated iTBS improves social cognition and
perior prefrontal temporal neural network (Park et al., 2011). Lantrip negative symptoms. Future studies should investigate the long-term ef­
fects of accelerated iTBS intervention duration and stimulation intensity

7
Y. Jin et al. Psychiatry Research 320 (2023) 115033

on social cognition and negative symptoms in individuals with chronic theta burst stimulation (iTBS) versus 10 Hz high-frequency repetitive transcranial
magnetic stimulation (rTMS) to alleviate treatment-resistant unipolar depression: a
schizophrenia. These results provide an evidence-based foundation for
randomized controlled trial (THETA-DEP). Brain Stimul. 15 (3), 870–880. https://
the clinical application of accelerated iTBS in physical therapy for pa­ doi.org/10.1016/j.brs.2022.05.011.
tients with schizophrenia. Chen, J.J., Zeng, B.S., Wu, C.N., Stubbs, B., Carvalho, A.F., Brunoni, A.R., Su, K.P., Tu, Y.
K., Wu, Y.C., Chen, T.Y., Lin, P.Y., Liang, C.S., Hsu, C.W., Hsu, S.P., Kuo, H.C.,
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org/10.1016/j.neurobiolaging.2015.05.001.
Demirtas-Tatlidede, A., Freitas, C., Cromer, J.R., Safar, L., Ongur, D., Stone, W.S.,
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Freitas, C., Fregni, F., Pascual-Leone, A., 2009. Meta-analysis of the effects of repetitive
transcranial magnetic stimulation (rTMS) on negative and positive symptoms in
The authors declare no conflict of interest. schizophrenia. Schizophr. Res. 108 (1-3), 11–24. https://doi.org/10.1016/j.
schres.2008.11.027.
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