The effects of high-frequency repetitive transcranial magnetic stimulation on negative symptoms in schizophrenia patients: A systemic review and meta-analysis

Boxing Wang; Xinyue Zhu; Ling Chen; Shuyun Liu; Chengshi Wang

doi:10.1371/journal.pone.0337847

. 2025 Dec 11;20(12):e0337847. doi: 10.1371/journal.pone.0337847

The effects of high-frequency repetitive transcranial magnetic stimulation on negative symptoms in schizophrenia patients: A systemic review and meta-analysis

Boxing Wang ^1,^#, Xinyue Zhu ^2,^#, Ling Chen ³, Shuyun Liu ^4,^*, Chengshi Wang ^5,^*

Editor: Sandra Carvalho⁶

PMCID: PMC12697975 PMID: 41379812

Abstract

Objective

The research on high-frequency repetitive transcranial magnetic stimulation (rTMS) is very ambiguous, particularly the variability in treatment parameters and the need for standardized protocols, and its effectiveness have hardly been provided conclusive evidence. This systematic review and meta-analysis aimed to determine the effects of high-frequency rTMS on negative symptoms in schizophrenia patients.

Methods

Six databases (PubMed, Embase, Web of Science, SinoMed, PsycINFO and MEDLINE) were searched from inception to March 2024. Relevant data were extracted and analysed by two independent investigators using Cochrane RevMan software (version 5.3) and R software (version 4.3.1).

Results

A total of 17 Randomized Controlled Trials (RCTs) were included in the current meta-analysis. Compared with control treatment, active rTMS showed advantage in treating negative symptoms of schizophrenia [standardized mean difference (SMD): −0.22, 95% confidence interval (CI): −0.38, −0.05, P = 0.009; I² = 9%]. Subgroup analysis revealed that rTMS with a total treatment course of more than 15 sessions [SMD: −0.31 (95% CI: −0.49, −0.13), P = 0.0007; I²= 0%], active rTMS with a frequency of 20 Hz [SMD: −0.40 (95% CI: −0.67, −0.13), P = 0.004; I² = 0%], and active rTMS targeting the dorsolateral prefrontal cortex (DLPFC) [SMD: −0.25 (95% CI: −0.40, −0.09), P = 0.003; I² = 0%] were significantly effective in terms of reducing negative symptoms.

Conclusions

The effect of rTMS on negative symptoms is influenced by rTMS parameters. We suggest that researchers should focus on changing the frequency, location and length of treatment to improve negative symptoms of schizophrenia.

Introduction

Schizophrenia is a serious mental disorder that affects approximately 1% of the global population [1]. The diagnosis of schizophrenia is typically based on clinical evaluations. The disorder is characterized by several positive symptoms, such as hallucinations and delusions, as well as negative symptoms, such as a lack of emotion, decreased joy or motivation, delayed speech, social withdrawal, and difficulty initiating and sustaining activities [2]. Furthermore, individuals with schizophrenia also suffer from other cognitive deficits, including impairments in working memory, executive function, and processing speed [3,4].

Negative symptoms are one of the core features of schizophrenia and are associated with long-term morbidity and poor functional outcomes. Recent clinical studies have suggested that up to 60% of patients may exhibit prominent negative symptoms that necessitate treatment [5–7]. However, antipsychotic treatments, such as antipsychotic drugs with dopamine D2 antagonists or partial D2 agonists, are not optimal methods [8–10]. While these drugs may be effective for treating some positive symptoms, they often fail to address negative symptoms and can lead to side effects such as weight gain and metabolic syndrome [11,12]. Furthermore, the clinical diagnosis of negative symptoms is challenging because schizophrenia patients may not recognize the impact of negative symptoms and are unlikely to report them [13].

In recent years, several studies have demonstrated that high-frequency rTMS have effect on reducing negative symptoms in schizophrenia patients [14–16]. Furthermore, several meta-analyses and reviews have also provided evidence supporting the use of high-frequency rTMS for treating these symptoms [17–20]. However, the frequency, location and sessions of high-frequency rTMS remain controversial [18,19,21–22]. Recently, high-frequency rTMS also has therapeutic implications for depression [23,24], but studies have suggested that rTMS may not have a significant benefit on positive symptoms of schizophrenia [25,26]. Therefore, we conducted this systematic review and meta-analysis to assess the effectiveness of high-frequency rTMS for reducing negative symptoms among schizophrenia patients, and to assess the effectiveness for depression and positive symptoms of schizophrenia.

Materials and methods

Registration and protocol

This systematic review and meta-analysis were registered in the International Prospective Register of Systematic Review (PROSPERO) trial registry (CRD42023450243) [27]. Ethical approval and patient consent were not required as all the analyses were based on previously published studies.

Search strategy and selection criteria

The systematic search was conducted on the electronic database including PubMed, EMBASE, Web of Science, SinoMed, PsycINFO and MEDLINE database for articles published from inception to July, 2023 with the following keywords: “rTMS”, “repetitive transcranial magnetic stimulation”, “Schizophrenia”, “high-frequency” and “Negative Symptoms”. The reference lists of retrieved studies and relevant reviews were hand-searched, and the process mentioned above was repeatedly performed for ensuring that all eligible studies were included.

Inclusion criteria are presented as follows: (1) study design is randomized controlled trial (RCT); (2) the frequency was > 1 Hz rTMS; (3) patients diagnosed with schizophrenia or schizoaffective disorder diagnosed according to standardized criteria such as Diagnostic and Statistical Manual of Mental Disorders (DSM), International Statistical Classification of Diseases and Related Health Problems (ICD) or MiniInternational Neuropsychiatric Interview. The severity of negative symptoms with schizophrenia were assessed with PANSS [28,29] and the SANS [30]. The severity of positive symptoms with schizophrenia PANSS, and depression with Schizophrenia were assessed with the Calgary Depression Scale (CDSS) [31]; (4) without comminating other psychiatric diseases.

Data extraction

The data were extracted by two individuals independently: (1) author, title, journal, publication year and study design; (2) the PANSS, the SANS and the CDSS rating scale values; (3) demographic and clinical characteristics were also extracted including (age, age of onset, duration of illness, gender distribution, antipsychotic medication, rTMS condition, frequency of treatment, follow up time and outcome measurements). In case of missing data, we tried to contact the author to obtain the data. Alternatively, we performed subgroup analyses based on different data to ensure stability of the results.

Outcome measures

The primary outcome was the efficacy of high-frequency rTMS group versus control group on negative symptoms in patients diagnosed with schizophrenia. PANSS or SANS were consistently used as outcomes measurement. Severity of negative symptoms is positively correlated with level of score. The secondary outcomes were narrative analysis of the results from articles not included in the primary analysis, PANSS positive, and CDSS were used to evaluate the synergistic effect of high-frequency rTMS.

Quality assessment and risk of bias

The Cochrane risk of bias was used by two investigators independently and with the differences resolved by discussion with all authors. The domain-based evaluation recommended by the Cochrane Handbook for Systematic Reviews of Intervention were used to address the following domains: bias arising from the randomisation process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome and bias in selection of the reported result [32]. Fig 1b and 1c were made by using Review Manager Software Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).

Statistical analysis

Cochrane RevMan software (version 5.3) and R software (version 4.3.1) were used to conduct the statistical analysis. Given the anticipated heterogeneity in global data, a random-effects model was employed to analyse. Cohen’s d standardized mean differences (SMD) were computed to calculate the random-effect meta-analysis with inverse variance weighting. In this meta-analysis, 95% confidence intervals (CIs) were calculated for categorical and continuous outcomes, significance level was set as P < 0.05. Heterogeneity among studies was determined using the I² test, with a P-value less than 0.1 and an I² – value over 50%, suggesting the presence of significant study heterogeneity. Sensitivity analysis was performed for evaluating the influence of a single study on the overall estimate by omitting one study. Publication bias of the primary outcome was evaluated using Funnel plots and Egger’s test. Subgroup analyses were performed to assess potential confounding effects of heterogeneity. Four subgroup analyses were also conducted for further investigation: (1) applied 15 continues stimulation sessions or more 15 stimulation sessions; (2) the frequency of rTMS was 10 Hz; (3) the frequency of rTMS was 20 Hz; (4) the location of stimulate was DLPFC. The difference between groups was assessed using a P-value, with a threshold of P < 0.05 indicating a statistical significance.

Results

Literature search

A systematic search was performed according to the PRISMA flow diagram. A total of 59 articles were identified after reviewing the literature, and 17 studies were ultimately included. The reasons for exclusion were as follows: two studies focused on the efficacy of high-frequency rTMS for preventing cognition, two studies lacked endpoint results, four studies used drug combinations, two studies investigated the relationship between smoking and high-frequency rTMS, and several other studies focused on different topics (auditory verbal hallucinations, low-frequency rTMS, and mechanical repetitive transcranial magnetic stimulation). Fig 1a shows the PRISMA flow chart for the study selection process. The characteristics of the included RCTs are summarized in Table 1. Seventeen double-blind RCTs (n = 911) were included. Xiu et al 2020 [33] contain 10 Hz and 20 Hz as treatment. Thirteen RCTs involved stimulation in the DLPFC, and the frequency of treatment was five sessions a week. Twelve RCTs had more than 15 sessions in total. When the frequency of rTMS ranged from 5 Hz to 20 Hz, eight and six studies had frequencies of 10 Hz and 20 Hz, respectively. Other details are presented in Table 2.

Table 1. Characteristics of included studies.

No.	Author	Year	rTMS Group			Control Group
No.	Author	Year	Number	Age	AP ^c dosage, chlorpromazine equivalents (mg)	Number	Age	AP † dosage, chlorpromazine equivalents (mg)
1	Barr et al.	2012	13	40.46 (12.21)	388.89(328.86)	12	47.92(12.78)	813.49(560.15)
2	Du et al.	2022	20	45.9(10.0)	323.5(193.1)	18	45.1(10.4)	341.7(168.7)
3	Fitzgerald et al.	2008	10	37.2 (10.4)	not reported	10	33.2 (9.8)	not reported
4	Garg et al.	2016	20	32.40 (8.44)	388(110)	20	30.75 (7.90)	363(129)
5	Holi et al.	2004	11	38.5(10.2)	1168	11	34.8(9.8)	1309
6	Kumar et al.	2020	50	32.4 (9.20)	not reported	50	30.8(9.34)	not reported
7	Liu et al.	2017	20	30.75(3.9)	not reported	20	31.60(3.7)	not reported
8	Li et al.	2017	25	50. 32 (7. 88)	378. 64 (194. 10)	25	50. 24 (9. 58)	385.56 (169.74)
9	Li et al.	2018	20	41.58(6.34)	not reported	21	40.63(6.2)	not reported
10	Quan et al.	2015	78	46.87(7.87)	411.78(194.19)	39	46.87(9.07)	438.46(189.58)
11	Singh et al.	2020	15	33.3 (9.8)	not reported	15	29.8 (5.7)	not reported
12	Wen et al.	2021	26	41.4(7.5)	435.8(302.6)	26	38.8(9.1)	467.1(267.6)
13	Wobrock et al.	2015	62	36.2 (10.5)	572 (435)	64	34.9(9.1)	597 (486)
14	Xiu et al. ^a	2020	40	50.7(9.0)	416.9(257.6)	40	54.7 (6.4)	416.9(257.6)
15	Xiu et al. ^b	2020	40	52.0(10.1)	422.3(231.7)	40	54.7 (6.4)	416.9(257.6)
16	Prikryl et al.	2013	23	31.60(8.04)	282.96(231.38)	17	33.94(9.98)	387.19(272.51)
17	Huang et al.	2018	30	37.43(10.96)	not reported	30	38.00(8.56)	not reported
18	Lin et al.	2018	30	38.9(3.6)	not reported	30	39.2(3.3)	not reported

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AP: Antipsychotic; ^a10 Hz as treatment; ^b20Hz as treatment; ^c Some studies did not calculate the chlorpromazine equivalents which is marked with a hyphen in the table;

Table 2. Stimulation parameters.

Author	Year	Target	Stimulation (Hz)	Density	Sessions	Frequency(day/week)
Barr et al.	2012	DLPFC	20	90%	20	5
Du et al.	2022	DLPFC	10	110%	20	5
Fitzgerald et al.	2008	PFC	10	110%	15	5
Garg et al.	2016	Cerebellum	5/6/7 Hz	100%	10	5
Holi et al.	2004	DLPFC	10	100%	20	5
Kumar et al.	2020	DLPFC	20	100%	20	5
Liu et al.	2017	DLPFC	20	not reported	24	5
Li et al.	2017	DLPFC	10	100%	20	5
Li et al.	2018	DLPFC	20	100%	40	5
Quan et al.	2015	DLPFC	10	80%	20	5
Singh et al.	2020	DLPFC	20	100%	20	5
Wen et al.	2021	DLPFC	10	110%	20	5
Wobrock et al.	2015	DLPFC	10	110%	15	5
Xiu et al. ^a	2020	DLPFC	10	110%	40	5
Xiu et al. ^b	2020	DLPFC	20	110%	40	5
Prikryl et al.	2013	DLPFC	10	110%	15	5
Huang et al.	2018	DLPFC	15	100%	40	5
Lin et al.	2018	DLPFC	15	100%	40	5

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PFC: bilateral prefrontal cortex; DLPFC: dorsolateral prefrontal cortex; ^a10 Hz as treatment; ^b20Hz as treatment;

Quality assessment

Fourteen RCTs (14/18, 77.78%) reported an adequate method of random sequence generation. Other risk of bias domains was rated as “unclear” in all RCTs (18/18, 100%). Based on the Cochrane risk of bias tool, the overall quality of the outcomes ranged from “low risk” (63/108, 58.33%) to “high risk” (45/108, 41.67%). The risk of bias graph and risk of bias summary are shown in Fig 1.

Negative symptoms

The primary outcome of this study was the effect of high-frequency rTMS versus control-assisted rTMS on negative symptoms in patients with schizophrenia. The 15 RCTs in our meta-analysis that included PANSS-negative scores suggested that high-frequency rTMS is beneficial for treating negative symptoms in schizophrenia patients. Additionally, 10 studies including SANS scores found a stronger effect than the studies using PANSS scores. The PANSS was used to assess negative symptoms, and two frequencies (10 Hz and 20 Hz) were adopted by Xiu et al. PANSS-negative and SANS scores were used as endpoints after the end of treatment. Standardized mean differences were calculated, and the random effects model was used to analyse the primary outcomes.

Significant differences were found (SMD = −0.31; 95% CI = −0.49 – −0.14; P < 0.05) (Fig 2) between the high-frequency rTMS group and the control group. A total of 791 participants were included in the analysis, and the endpoint was PANSS-negative scores. There was significant heterogeneity among the studies (I²= 32%, P = 0.11). We analysed SANS as an endpoint; the results showed significant differences (SMD = −0.99; 95% CI = −1.64 to −0.33; P < 0.05) (Fig 3), with significant heterogeneity among the studies (I²= 91%, P < 0.05).

Subgroup analysis

Standardized mean differences were also calculated, and the random effects model was used to analyse the primary outcomes in Table 3.

Table 3. Subgroup and secondary outcomes.

Variables	Studies (subjects)	SMDs (95%CI)	I² (%)	P-value
Subgroup
More than 15 sessions	12 (635)	-0.40 [-0.57, -0.24]	NA	<0.05
10 Hz group	8 (480)	-0.26 [-0.49, -0.02]	33	<0.05
20 Hz group	6 (301)	-0.48 [-0.71, -0.25]	NA	<0.05
DLPFC group	13 (761)	-0.34 [-0.52, -0.17]	25	<0.05
Secondary outcomes
Positive symptom	14 (801)	-0.02 [-0.16, 0.13]	NA	0.81
CDSS	6 (361)	-0.09 [-0.30, 0.13]	NA	0.43

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Abbreviations: CI: confidence interval; SMDs: Standard mean differences; DLPFC: dorsolateral prefrontal cortex; CDSS: Calgary Depression Scale for Schizophrenia; Table: Lists key information about each study, including: authors of the study, number of participants in each study, effect size (SMD): effect size and its 95% CI for each study, weight (%): weight of each study in the meta-analysis.

We performed subgroup analysis to determine whether 15 sessions or more led to significant differences. The twelve included studies were carefully read. PANSS-negative scores were used to compare the efficacy of active versus control rTMS. In total, 605 participants were included in this subgroup analysis. The significant effects were reported (SMD = −0.40; 95% CI = −0.57 – −0.24; P < 0.05), and there was no significant heterogeneity among the studies (I²= 7%, P = 0.38) (Fig 4a).

Another subgroup analysis was conducted to investigate the effect of the frequency of rTMS. We found that 20 Hz (Fig 4c) (SMD = −0.48; 95% CI = −0.71 – −0.25; P < 0.05) had a stronger effect than 10 Hz (Fig 4b) (SMD = −0.26; 95% CI = −0.49 – −0.02; P < 0.05). We found significant heterogeneity among the studies using 10 Hz (I²= 33%, P = 0.17) and no significant heterogeneity among the studies using 20 Hz (I²= 0%, P = 0.65).

An additional subgroup analysis was performed to determine the effect of the location of the stimulation which is the most place that DLPFC. Thirteen studies were included in this subgroup analysis, and significant differences were observed (Fig 4d) (SMD = −0.34; 95% CI = −0.52 – −0.17; P < 0.05). There was low heterogeneity among the studies (I²= 25%, P = 0.19).

Secondary outcomes

Positive symptoms.

The PANSS is widely used as a clinical assessment tool for evaluating the severity of symptoms in individuals with schizophrenia. Fourteen studies reported this secondary outcome; no significant effects (Fig 4e) (SMD = −0.02; 95% CI = −0.16–0.13; P = 0.81) were found, and there was no significant heterogeneity among the studies (I²= 2%, P = 0.43).

Calgary Depression Scale for Schizophrenia.

The CDSS is a rating scale used to assess depression in individuals with schizophrenia. It was developed specifically to measure depressive symptoms that may be present alongside the core symptoms of schizophrenia. The results of meta-analysis did not reveal any statistically significant differences (Fig 4f) (SMD = −0.09; 95% CI = −0.30–0.13; P = 0.43).

Sensitivity analysis

Sensitivity analysis is one of the most common statistical methods and is used mainly to evaluate the robustness and reliability of combined meta-analysis results. No statistically significant differences were found (Fig 5) (SMD = −0.31; 95% CI = −0.49–0.14; P = 0.11).

Publication bias

Initially, the funnel plot showed no asymmetry (Fig 6). Egger’s regression test was performed to quantify the possible amount of bias, and the result was nonsignificant (P = 0.9605). Taken together, these complementary analyses indicate the absence of publication bias in this meta-analysis.

Discussion

We conducted a meta-analysis of 17 randomized controlled trials that examined the use of high-frequency rTMS to treat negative symptoms in patients with schizophrenia. Among these studies, 15 included PANSS-negative scores, and 1 included only SANS scores. The SANS is a reliable scale for assessing negative symptoms in patients with schizophrenia [34]. The PANSS-negative scores suggested that high-frequency rTMS is beneficial for treating negative symptoms in schizophrenia patients. Additionally, 10 studies including SANS scores found a stronger effect than the studies using PANSS scores. Although the PANSS and SANS are widely used, their differences may result in variations in baseline data, different frequencies used in the experiments, and different stimulation locations. The PANSS is a more comprehensive assessment tool that covers both positive and negative symptoms as well as general psychopathology, while the SANS focuses exclusively on negative symptoms. Both scales can be used depending on the needs of research or clinical practice, and they are sometimes used in conjunction to obtain a more complete symptom assessment [35]. In the articles we included, the procedures were consistent with the experimental group except for the orientation of the coils or the dummy coils. To further explore the effect of stimulation frequency on negative symptoms in schizophrenia patients, we conducted two subgroup analyses: one with a 10-Hz stimulation frequency (eight studies) and another with a 20-Hz stimulation frequency (six studies) [19]. Surprisingly, the studies using a 10-Hz frequency showed significant effects (P < 0.05), but the studies using a 20-Hz frequency showed stronger effects (P < 0.05). We found that although the effect size of the 20 Hz treatment (−0.40 [−0.67, −0.13]) was greater than that of the treatment of 10 Hz (−0.18 [−0.37, 0.01]), there was an overlap of the two confidence intervals, suggesting that the difference between the two groups may not be statistically significant. Numerous studies have recommended that more than three weeks of treatment may be necessary to achieve more significant effects, which means that 15 sessions or more could yield effective outcomes [36]. Most studies recommend a treatment frequency of five times per week, and the duration of treatment increases with the number of treatments. In the 12 studies with treatment durations longer than three weeks, we observed only slight improvements, which demonstrated that an increase in duration did not result in stronger effects. The safety and tolerability of rTMS at the time of treatment have also been validated in previous studies. [12]

The DLPFC is considered an effective stimulation location [37] and a common target for noninvasive brain stimulation in the treatment of schizophrenia [38,39]. It is closely connected to schizophrenia-spectrum disorders [40,41], negative symptoms and impairments in higher cognitive functions are associated with dysfunction in the DLPFC [42]. We found that 13 studies stimulating DLPFC targeting had significant results. After excluding the study that targeted the cerebellum, the effect size significantly increased, further confirming that the DLPFC is a relevant stimulation target for schizophrenia. While exploring factors associated with negative symptoms in patients with schizophrenia, we found that most studies also reported PANSS-positive and CDSS scores. We found that high-frequency rTMS did not significantly affect these two outcomes’ measures (P = 0.81, P = 0.43).

The 17 studies included in this analysis had mild heterogeneity, which can be attributed to several factors. First, there was a significant difference in the survival time between baseline and the endpoint, ranging from 14 to 56 days. Second, patients had different baseline characteristics at enrolment. Finally, there were significant differences in the stimulation targets, stimulation parameters (such as intensity, pulse number, and control procedures), and evaluation principles used in different studies, thus highlighting the need to standardize rTMS protocols in the treatment of negative symptoms among patients with schizophrenia.

Admittedly, our meta-analysis has several limitations. First, the heterogeneity of the baseline data, including age, sex, methods, specifications of the equipment, stimulation threshold and staging of illness, may have introduced bias in our results. Garg et al. found a more significant improvement in the control intervention group by targeting the cerebellum, suggesting that the DLPFC may be an important target for schizophrenia-spectrum disorders [43,44]. Second, the scoring system used herein is more subjective than the other scoring systems, which could introduce bias into the results. Finally, regarding schizophrenia patients with negative symptoms, among the results, we did not find that patients with positive symptoms and depression could benefit from the treatment course of rTMS, which may be further emphasized by the specific efficacy of rTMS on negative symptoms, however, our treatment group was not very abundant, so such results need to be proven by further studies. Therefore, further standardization and uniformity of the procedures must be established between each study. Finally, the missing negative and unpublished data in the original studies may have led to publication bias and skewed our conclusions. Thus, we suggest that robust RCTs with large sample sizes and a standard protocol should be performed in the future to obtain more accurate data and verify our results.

Conclusions

In conclusion, our systematic meta-analysis provides evidence that the efficacy of high-frequency rTMS on negative symptoms are associate with rTMS parameters. We recommend a frequency of 20 Hz, more than 15 treatment sessions may benefit in the DLPFC. However, further large-scale randomized controlled trials, specific measurement scales for assessing negative symptoms in schizophrenia, standardized rTMS treatment protocols, and consistent outcome measures are needed to confirm the efficacy of rTMS in treating negative symptoms in schizophrenia patients.

Practitioner Points

Schizophrenia with negative symptoms need to benefit from non-pharmacological treatment modalities.
The location and frequency of high-frequency repetitive transcranial magnetic stimulation, as well as the scale scored, may affect the treatment effect.
High-frequency repetitive transcranial magnetic stimulation may benefit patients with schizophrenia who have significant negative symptoms as well as positive and depressive symptoms.

Supporting information

S1 Checklist. PRISMA 2020 Checklist.

(DOCX)

pone.0337847.s001.docx^{(41.1KB, docx)}

S1 Table

(DOCX)

pone.0337847.s002.docx^{(31.1KB, docx)}

S2 Table

(DOCX)

pone.0337847.s003.docx^{(25KB, docx)}

Abbreviations

rTMS: repetitive Transcranial Magnetic Stimulation
RCTs: Randomized Clinical Trials
PANSS: Positive and Negative Syndrome Scale
SMD: Standardized mean Difference
CI: Confidence Interval
DLPFC: Dorsolateral Prefrontal Cortex
DSM: Diagnostic and Statistical Manual of Mental Disorders
ICD: International Statistical Classification of Diseases and Related Health Problems
CDSS: Calgary Depression Scale for Schizophrenia
SANS: Scale for the Assessment of Negative Symptoms.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0337847.r001

Decision Letter 0

Giuseppe Lanza

5 Nov 2024

Dear Dr. wang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

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2. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

https://www.sciencedirect.com/science/article/pii/S0022395621005409?via%3Dihub

https://doi.org/10.3389/fendo.2022.1098325

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

3. As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following:

A numbered table of all studies identified in the literature search, including those that were excluded from the analyses.

For every excluded study, the table should list the reason(s) for exclusion.

If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: The manuscript investigated the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in patients with schizophrenia through a systematic review and meta-analysis. The manuscript is well-structured, and the experimental design is innovative and rigorous. However, there are still some areas that need further improvement.

1.Objective Section: What specific aspect of rTMS research is considered limited?

2.Abbreviations Section: Should the format of upper and lower case letters be standardized?

3.Introduction Section, Paragraph 3, Sentence 4: There is no mention of comorbid depression in schizophrenia. Why is the significance of rTMS in treating depression specifically emphasized?

4.Should full terms be provided for technical abbreviations when they first appear in the text?

5.Should the use of capitalization for technical terms be standardized throughout the manuscript?

6.Literature Search Section, Sentence 4: Why is the registration number (CRD42023450243) included after “the study selection process”?

7.Subgroup Analysis Section, Paragraph 4: What specific locations are being referred to in terms of differences in “the location of the stimulation”?

8.Discussion Section, Paragraph 1, Sentence 4: What specific effect is indicated to be stronger in studies using SANS scores compared to those using PANSS scores?

9.Discussion Section, Paragraph 1, Sentence 5: What is the specific relationship between differences in baseline data, frequencies, and stimulation locations and the PANSS and SANS scales?

10.Discussion Section, Paragraph 2, Sentence 2: How can the repeated use of “and” be optimized to improve the logical flow of the sentence?

Reviewer #2: This study reports a systematic review and meta-analysis of rTMS effects on schizophrenia patients, however, a report table presenting the key details for each study, including number of rTMS sessions, stimulation localization in scalp, rTMS stimulation frequency, and mean outcomes for PANSS and SANS (metrics that are discussed in the manuscript) is missing.

Some information currently reported in the Discussion should be moved to the Methods section, specifically details such as the number of studies included in each analysis. Additionally, there is a general lack of clarity regarding the statistical methods applied and the number of studies included in each analysis.

The primary outcome of this study suggests that rTMS improves the negative symptoms of schizophrenia. However, this finding is neither novel nor uniquely revealed by this review and meta-analysis. This information does not add substantial value to the field. Instead, what may contribute more meaningfully is the subgroup comparison conducted subsequently. Again, there is limited clarity on the studies included, their number, and the statistical methods used here. The potentially interesting aspect of this study could lie in the comparison of study characteristics, but the reported diagrams do not compare same indexes of different stimulation characteristics.

There is no description of the statistical analysis between frequencies, no reporting of frequencies per article, no statistical report on differences between session numbers, and no rationale provided for the inclusion criteria for requiring studies with 10 or more rTMS sessions.

Overall, there is a potential impact in the topic and results, however this study does not appear to analyze comparisons that could offer unique insights into the scientific literature—data that could only be derived from a meta-analysis. The study needs to more rigorously present the characteristics of each study and provide a statistically sound comparison of characteristics such as stimulation frequency, number of rTMS sessions, and stimulation location.

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Reviewer #1: No

Reviewer #2: Yes: Arantzazu San Agustin

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PLoS One. 2025 Dec 11;20(12):e0337847. doi: 10.1371/journal.pone.0337847.r002

Author response to Decision Letter 1

3 Apr 2025

Response to reviewers

We thank the reviewers for their insightful comments, and we are pleased that our manuscript received such positive reviews. Reviewers found, however, several points that need further clarification. We have changed our manuscript according to the reviewers’ valid suggestions and please find below our point-by-point response to each reviewer.

Reviewer #1:

1. Objective Section: What specific aspect of rTMS research is considered limited?

Response: We thank the reviewer for the valuable suggestion. We have expanded the "Objective Section" to include a discussion on the limitations of rTMS research, particularly focusing on the variability in treatment parameters and the need for standardized protocols.

2. Abbreviations Section: Should the format of upper and lower case letters be standardized?

Response: We have standardized the format of abbreviations throughout the manuscript, ensuring consistency in the use of upper and lower case letters as per your suggestion.

3. Introduction Section, Paragraph 3, Sentence 4: There is no mention of comorbid depression in schizophrenia. Why is the significance of rTMS in treating depression specifically emphasized?

Response: We thank the reviewer for the valuable suggestion. We have added a discussion on comorbid depression in schizophrenia to highlight its significance and the potential benefits of rTMS in treating both conditions.

4. Should full terms be provided for technical abbreviations when they first appear in the text?

Response: We thank the reviewer for the valuable suggestion. We have provided full terms for technical abbreviations when they first appear in the text, as recommended.

5. Should the use of capitalization for technical terms be standardized throughout the manuscript?

Response: We thank the reviewer for the valuable suggestion. We have reviewed and standardized the capitalization of technical terms throughout the manuscript. The term about “rTMS” is the standardized form which can be seen in this research 10.1001/jamapsychiatry.2024.0026.

6. Literature Search Section, Sentence 4: Why is the registration number (CRD42023450243) included after “the study selection process”?

Response: We thank the reviewer for the valuable suggestion. We originally aim to enhance the transparency and traceability of our research. Now we will delete the registration number (CRD42023450243) in the "Literature Search Section" of the revised manuscript.

7. Subgroup Analysis Section, Paragraph 4: What specific locations are being referred to in terms of differences in “the location of the stimulation”?

Response: We thank the reviewer for the valuable suggestion. In the "Subgroup Analysis Section," we only provide a explanation of what is meant by "the location of the stimulation" and discuss how dorsolateral prefrontal cortex (DLPFC) locations may affect treatment outcomes. Because the studies that used PANSS as the primary outcome did not all use the DLPFC as the stimulation site, we wanted to explore whether this site would have an effect on the results.

8. Discussion Section, Paragraph 1, Sentence 4: What specific effect is indicated to be stronger in studies using SANS scores compared to those using PANSS scores?

Response: We thank the reviewer for the valuable suggestion. We have now clarified the specific effects observed in studies using SANS scores compared to those using PANSS scores. We discuss how the choice of scale can influence the assessment of negative symptoms and the perceived efficacy of rTMS treatment. This comparison highlights the importance of considering the sensitivity and specificity of different assessment tools when interpreting the effects of rTMS on negative symptoms in schizophrenia patients.

9. Discussion Section, Paragraph 1, Sentence 5: What is the specific relationship between differences in baseline data, frequencies, and stimulation locations and the PANSS and SANS scales?

Response: We thank the reviewer for the valuable suggestion. We regret that we were unable to perform a definitive statistical analysis and will continue to investigate solutions in the future. Because we hypothesized that this discrepancy may have occurred as a result of the baseline data from the included studies, more research is needed in the future to explore more appropriate scales.

10. Discussion Section, Paragraph 2, Sentence 2: How can the repeated use of “and” be optimized to improve the logical flow of the sentence?

Response: We thank the reviewer for the valuable suggestion. We have rephrased the sentence to improve the logical flow, avoiding repetitive use of "and" and ensuring the sentence reads smoothly.

Reviewer #2:

This study reports a systematic review and meta-analysis of rTMS effects on schizophrenia patients, however, a report table presenting the key details for each study, including number of rTMS sessions, stimulation localization in scalp, rTMS stimulation frequency, and mean outcomes for PANSS and SANS (metrics that are discussed in the manuscript) is missing.

Response: We thank the reviewer for the valuable suggestion.

(1) We recognize the importance of including a comprehensive reporting form that details the key aspects of each study analyzed. Among our Table 1, we list the number of transcranial magnetic stimulations, stimulation localization, and frequency of transcranial magnetic stimulation, and our supplemental file will also list the mean PANSS and SANS results for each study in the meta-analysis.

(2) We have moved the details regarding the number of studies included in each analysis from the Discussion section to the Methods section to enhance clarity and ensure that all methodological aspects are transparently reported.

(3) To address the lack of clarity regarding the statistical methods applied, we have provided a more detailed description of the statistical tests used and the number of studies included in each analysis in the Methods section.

(4) We understand the need to provide a more nuanced comparison of study characteristics. In our manuscript, we made detailed comparisons of study characteristics and ensured that the reported graphs compared indices for different stimulus characteristics. Based on the subgroup analyses we did, we found that the number of treatments, the frequency of the stimulation, and the location of the stimulation all produced significant differences. However, when we wanted to look for comparative differences between 10 Hz and 20 Hz in high-frequency stimulation, we found that although the effect size of the 20 Hz treatment (-0.40 [-0.67, -0.13]) was greater than that of the treatment of 10 Hz (-0.18 [-0.37, 0.01]), there was an overlap of the two confidence intervals, suggesting that the difference between the two groups may not be statistically significant.

(5) We have revised the inclusive criterion for including studies with 10 or more rTMS sessions.

(6) We have expanded the Discussion section to highlight how our study provides unique insights into the scientific literature, which could only be derived from a meta-analysis. We emphasize the importance of standardized rTMS treatment protocols and consistent outcome measures in future research.

We believe these revisions have significantly strengthened our manuscript and have addressed the concerns raised by your review. We are grateful for the opportunity to improve our work based on your valuable feedback and hope that the revised manuscript meets the standards for publication in your esteemed journal.

Sincerely,

Boxing Wang, Xinyue Zhu, Ling Chen, Liu Shuyun, Chengshi Wang

Attachment

Submitted filename: Response to reviewers.doc

pone.0337847.s004.doc^{(41KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0337847.r003

Decision Letter 1

Giuseppe Lanza

21 Apr 2025

Dear Dr. wang,

Please submit your revised manuscript by Jun 05 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Giuseppe Lanza, M.D., Ph.D.

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: The author has revised the manuscript as requested. The changes are satisfactory, and publication is recommended.

Reviewer #2: Thank you for your kind response to my previous comments. I appreciate the improved clarity in the description of the statistical procedures. However, I noticed that Table 1 appears to be missing from the submission; I could not locate it within the manuscript, and it is not referenced in the figure legends either. Below, I offer additional comments and suggestions that may help further enhance the manuscript:

• Abstract:

o In the opening sentence, please clarify whether the statement “The research on high-frequency repetitive transcranial magnetic stimulation (rTMS) is very little… its effectiveness has hardly been provided conclusive evidence” refers specifically to schizophrenia. Over 700 papers have been published in the past five years on high-frequency TMS in general, so rephrasing may be necessary to avoid misrepresentation.

o Since rTMS is abbreviated in the first sentence, please ensure consistent use of the abbreviation throughout the abstract (e.g. second sentence in the abstract and Practitioner Points section).

o Please write out the full term for RTC before using the abbreviation in the abstract.

• Practitioner Points:

o Consider rephrasing the third practitioner point to improve clarity.

• Stimulation Parameters and Table Reference:

o It would be helpful to specify which figure is referred to as Table 1, particularly regarding the report on TMS number of pulses, stimulation location, and frequency. Currently, Figure 1 is the flowchart, and other figures do not indicate stimulation parameters by paper.

o As the systematic review and meta-analysis of stimulation frequency, brain location, and session count are central to your manuscript (as outlined in the introduction), please clearly indicate this information for each study, similar to how the PANSS results are detailed in Supplementary Table S2.

o Table 1 is cited multiple times throughout the manuscript but appears to be missing. If you are referring to the table in one of the PRISMA 2020 Checklist, would be helpful to have an independent table, titled Table 1, with the stimulation parameters per study.

o Please include a legend for Table 1 under the Figure Legends section (or consider renaming the section to “Table and Figure Legends”).

• Search Strategy:

o On inclusion criteria number 2, could you clarify what is meant by “non-invasive stimulation”? Are there additional types of stimulation reported in the studies besides TMS?

• Data Extraction:

o Please include the stimulation site as part of the extracted data, especially since your findings emphasize the DLPFC. Without this data point, claims regarding the importance of stimulation site may be unsupported.

• Outcome Measures:

o In the penultimate sentence, the phrase “addition effective” may have been intended to read “additional effects.” If so, please revise for clarity.

• Figures:

o In Figure 1, if the manuscript compares rTMS and sham stimulation groups, consider using the term “sham” in the figure for consistency (or vice versa—use “control” in both the figure and text). If control groups include more than sham stimulation, please clarify this.

o For Figure 1 and other figures, it would be helpful if the legends also describe the table components within the figures, not just the forest plots.

• Figures 4a–d:

o These figures appear to present data that overlap with Figure 1. To substantiate the claim that 15 sessions of high-frequency rTMS result in greater improvements in negative symptoms, a direct comparison between studies with ≥15 sessions vs. <15 sessions is necessary, using only active stimulation groups. The same applies to frequency comparisons (e.g., 20 Hz vs. 10 Hz or <20 Hz). Even if these comparisons do not yield statistically significant differences, they remain informative and should be reported in the results section.

o Similarly, to support the claim that DLPFC stimulation is particularly effective, a comparison with other stimulation sites (e.g., DLPFC vs. non-DLPFC) would be beneficial.

o Additionally, comparing outcomes like SANS vs. PANSS-positive and CDSS scores could further underscore the specificity of effects on negative symptoms in schizophrenia. You briefly mention the lack of significant effects on these outcomes in the discussion, but including this analysis in the results could strengthen your conclusions.

• Supplementary Materials:

o An additional Supplementary Table (e.g., S3) detailing stimulation parameters such as intensity, and sham/control procedures could enhance the manuscript’s transparency and utility.

• References:

o In the discussion section, the manuscript cites Garg et al. as reference 44. However, reference 44 currently corresponds to a different paper (Slotema et al.). It appears that Garg et al. may be missing from the reference list. Please review and correct the reference numbering and ensure all citations are included.

In summary, the manuscript presents a valuable and timely synthesis of high-frequency rTMS effects on schizophrenia symptoms. Addressing the points above—especially those related to completeness of results—will substantially strengthen the overall impact and scientific rigor of the paper.

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Reviewer #1: No

Reviewer #2: Yes: Arantzazu San Agustín

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PLoS One. 2025 Dec 11;20(12):e0337847. doi: 10.1371/journal.pone.0337847.r004

Author response to Decision Letter 2

24 May 2025

We thank the reviewers for their insightful comments. We are encouraged by the overall positive evaluation and have revised the manuscript in response to the thoughtful suggestions provided. Below, we provide a detailed point-by-point response to Reviewer #2's comments.

Reviewer #2:

Reviewer#2: Thank you for your kind response to my previous comments. I appreciate the improved clarity in the description of the statistical procedures. However, I noticed that Table 1 appears to be missing from the submission; I could not locate it within the manuscript, and it is not referenced in the figure legends either. Below, I offer additional comments and suggestions that may help further enhance the manuscript:

Abstract:

• In the opening sentence, please clarify whether the statement "The research on high-frequency repetitive transcranial magnetic stimulation(rTMS)is very little. its effectiveness has hardly been provided conclusive evidence" refers specifically to schizophrenia. Over 700 papers have been published in the past five years on high-frequency TMS in general, so rephrasing may be necessary to avoid misrepresentation.

• Since rTMS is abbreviated in the first sentence, please ensure consistent use of the abbreviation throughout the abstract(e.g.second sentence in the abstract and Practitioner Points section).

• Please write out the full form for RTC before using the abbreviation in the abstract.

Response: We thank the reviewer for the valuable suggestion. We clarified the first sentence to emphasize that the focus of the research on repetitive high-frequency transcranial magnetic stimulation (rTMS) is on standardized treatment procedures. We also ensured that the acronym rTMS was used consistently throughout the abstract and expanded the full title before its first use.

Practitioner Points:

• Consider rephrasing the third practitioner point to improve clarity.

Response: We thank the reviewer for the valuable suggestion. The third practitioner point has been rephrased to improve clarity.

“High-frequency repetitive transcranial magnetic stimulation may benefit patients with schizophrenia who have significant negative symptoms as well as positive and depressive symptoms.”

• Stimulation Parameters and Table Reference:

• It would be helpful to specify which figure is referred to as Table 1, particularly regarding the report on TMS number of pulses, stimulation location, and frequency. Currently, Figure 1 is the flowchart, and other figures do not indicate stimulation parameters by paper.

• As the systematic review and meta-analysis of stimulation frequency, brain location, and session count are central to your manuscript (as outlined in the introduction), please clearly indicate this information for each study, similar to how the PANSS results are detailed in Supplementary Table S2.

• Table 1 is cited multiple times throughout the manuscript but appears to be missing. If you are referring to the table in one of the PRISMA 2020 Checklist, would be helpful to have an independent table, titled Table 1, with the stimulation parameters per study.

• Please include a legend for Table 1 under the Figure Legends section(or consider renaming the section to" Table and Figure Legends").

Response: We thank the reviewer for the valuable suggestion. We have clarified which figure corresponds to Table 1, especially regarding TMS pulse count, stimulation location, and frequency. We have included a detailed table with stimulation parameters for each study; this table is referenced throughout the manuscript. We have added a legend for Table 1 under the "Figure Legends" section, which we have renamed to "Table and Figure Legends" for clarity. The charts are added as images in the section above the manuscript references, while the charts in word form are uploaded as a separate file.

• Search Strategy:

• On inclusion criteria number 2,could you clarify what is meant by "non-invasive stimulation"? Are there additional types of stimulation reported in the studies besides TMS?

Response: We thank the reviewer for the valuable suggestion. We have clarified the term "non-invasive stimulation" in the inclusion criteria.

• Data Extraction:

• Please include the stimulation site as part of the extracted data, especially since your findings emphasize the DLPFC. Without this data point, claims regarding the importance of stimulation site may be unsupported.

Response: We thank the reviewer for the valuable suggestion. We have incorporated the stimulation site into our extracted data, as suggested. This information is now clearly included in Table 1, which details the stimulation parameters for all studies analyzed. We believe this addition strengthens our findings regarding the importance of the DLPFC stimulation site.

• Outcome Measures:

• In the penultimate sentence, the phrase "addition effective" may have been intended to read "additional effects." If so, please revise for clarity.

Response: We thank the reviewer for the valuable suggestion. We have revised the penultimate sentence to clarify that "additional effects" may have been intended to read "additional effects" instead of "addition effective."

• Figures:

• In Figure 1,if the manuscript compares rTMS and sham stimulation groups, consider using the term "sham" in the figure for consistency(or vice versa—use "control" in both the figure and text).If control groups include more than sham stimulation, please clarify this.

• For Figure 1 and other figures, it would be helpful if the legends also describe the table components within the figures, not just the forest plots.

Response: We thank the reviewer for the valuable suggestion. We have used the term "control" consistently for the sham stimulation groups. We have updated the legends for Figure 1 and other figures to include descriptions of all table components within the figures, not just the forest plots as the comment. This should provide clearer context and improve the overall understanding of the figures.

Figures 4a-d:

• These figures appear to present data that overlap with Figure 1.To substantiate the claim that 15 sessions of high-frequency rTMS result in greater improvements in negative symptoms, a direct comparison between studies with≥15 sessions vs.<15 sessions is necessary, using only active stimulation groups. The same applies to frequency comparisons (e.g.,20 Hz vs.10 Hz or<20 Hz). Even if these comparisons do not yield statistically significant differences, they remain informative and should be reported in the results section.

• Similarly, to support the claim that DLPFC stimulation is particularly effective, a comparison with other stimulation sites (e.g. ,DLPFC vs. non-DLPFC)would be beneficial.

• Additionally, comparing outcomes like SANS vs. PANSS-positive and CDSS scores could further underscore the specificity of effects on negative symptoms in schizophrenia. You briefly mention the lack of significant effects on these outcomes in the discussion, but including this analysis in the results could strengthen your conclusions.

Response: We thank the reviewer for the valuable suggestion. We would have liked to make such a comparison, but only Xiu et al. included experimental groups at 10 Hz and 20 Hz, and we were unable to compare the results of the other articles due to the different baselines. We would prefer that the future studies be able to perform group experiments with different locations, frequencies, and numbers. Therefore, we hope that future studies will be able to perform group experiments with different locations, frequencies, and numbers to aid in the investigation of the efficacy of rTMS. Regarding PANSS-positive and CDSS scores, among the results, we did not find that patients with positive symptoms and depression could benefit from the treatment course of rTMS, which may be further emphasized by the specific efficacy of rTMS on negative symptoms, however, our treatment group was not very abundant, so such results need to be proven by further studies.

We do not emphasize the specific effect of rTMS on negative symptoms, but are more concerned with its broad therapeutic effect, because most schizophrenic patients tend to have a variety of symptom presentations, so we did not compare the results of SANS, PANSS-positive, and CDSS scores.

• Supplementary Materials:

• An additional Supplementary Table(e.g.,S3)detailing stimulation parameters such as intensity, and sham/control procedures could enhance the manuscript’s transparency and utility.

Response: We thank the reviewer for the valuable suggestion. To improve the transparency and usefulness of the manuscript, we read the included articles in detail, summarized the treatment procedures in the control group, and added appropriate explanations in the discussion. “In the articles we included, the procedures were consistent with the experimental group except for the orientation of the coils or the dummy coils.”

• References:

• In the discussion section, the manuscript cites Garg et al.as reference 44, however, reference 44 currently corresponds to a different paper (Slotema et al.). It appears that Garg et al. may be missing from the reference list. Please review and correct the reference numbering and ensure all citations are included.

In summary, the manuscript presents a valuable and timely synthesis of high frequency rTMS effects on schizophrenia symptoms. Addressing the points above, especially those related to completeness of results—will substantially strengthen the overall impact and scientific rigor of the paper.

Response: Sorry for the careless mistake. We have reviewed and corrected the reference accordingly, we have ensured all citations are included and the reference list is complete

Attachment

Submitted filename: Response to reviewer.docx

pone.0337847.s005.docx^{(22.3KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0337847.r005

Decision Letter 2

Giuseppe Lanza

12 Jun 2025

PONE-D-24-33430R2

The effects of high-frequency repetitive transcranial magnetic stimulation on negative symptoms in schizophrenia patients: A systemic review and meta-analysis

PLOS ONE

Dear Dr. wang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

Specifically: please see comments below.

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.

Kind regards,

Giuseppe Lanza, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

Although the authors' revision, major flaws still persisted in the revised version. According to the reviewer's comments, these cannot be addressed with another round of revision; unfortunately, therefore, the manuscript cannot be further processed.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #2: Partly

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3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #2: No

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4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #2: No

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: Yes

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Reviewer #2: Dear Authors,

Thank you for your responses to the reviewers' comments. However, several concerns have been answered but not adequately addressed in the revised manuscript:

In the data extraction section, the stimulation location is still not included, despite being a critical element to support one of the main findings of the study.

In the outcome measures, a typographical error was identified, but your response indicates a misunderstanding of the issue. As a result, the sentence was only partially corrected, and the typo remains in the manuscript (i.e., "effective" is still used instead of "effect").

The main concern is that the manuscript’s primary conclusion highlights the benefits of a 20 Hz stimulation frequency, more than 15 sessions, and DLPFC targeting, even though these factors are not compared to alternative conditions. The subgroup analyses remain redundant with the main analyses and do not provide additional insights. In this form, the manuscript loses scientific value, as its main result simply reiterates what is already known from individual studies—that rTMS is beneficial for the negative symptoms of schizophrenia—without contributing any novel findings.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #2: No

**********

- - - - -

For journal use only: PONEDEC3

PLoS One. 2025 Dec 11;20(12):e0337847. doi: 10.1371/journal.pone.0337847.r006

Author response to Decision Letter 3

18 Jul 2025

Response to academic editor

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: We thank the reviewer for the valuable suggestion. We have modified the format as required to meet the formatting requirements of your publication.

2. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

https://www.sciencedirect.com/science/article/pii/S0022395621005409?via%3Dihub

https://doi.org/10.3389/fendo.2022.1098325

Response: We thank the reviewer for the valuable suggestion. We have consulted and carefully read both articles and have cited them in the appropriate places and ensured that the citations are sound and reasonable.

3. As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following:

A numbered table of all studies identified in the literature search, including those that were excluded from the analyses.

For every excluded study, the table should list the reason(s) for exclusion.

If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed.

A table of all data extracted from the primary research sources for the systematic review and/or meta-analysis. The table must include the following information for each study:

Name of data extractors and date of data extraction

Confirmation that the study was eligible to be included in the review.

All data extracted from each study for the reported systematic review and/or meta-analysis that would be needed to replicate your analyses.

An explanation of how missing data were handled.

Response: We thank the reviewer for the valuable suggestion. We have made a table containing all the literature, also labeled with the reasons for exclusion. There are no unpublished articles in our references. We completed a table containing the data involved in our meta-analysis, the names of the dataminers, and the corresponding already labeled. All data was obtained from the article's table. We used the Cochrane Randomized Trial Risk of Bias tool, and it is presented in Figure 1. In the manuscript “Data Extraction”, we explain the handling for missing data.

We trust that these revisions will meet your expectations and enhance the quality and transparency of our research. We look forward to any further feedback you may have and appreciate your support of our work.

Yours sincerely,

Boxing Wang, Xinyue Zhu, Ling Chen, Liu Shuyun, Chengshi Wang

Response to reviewers

2025.4