Effects of bilateral repetitive transcranial magnetic stimulation on prospective memory in patients with schizophrenia: A double‐blind randomized controlled clinical trial

Fen Xue; Xin‐Fu Wang; Fan‐Ni Kong; Tian‐Lu Yin; Yu‐Hong Wang; Li‐Da Shi; Xiao‐Wen Liu; Hui‐Jing Yu; Li‐Jun Liu; Ping Zhu; Xiao‐Xue Qi; Xue‐Jing Xu; Hong‐Pu Hu; Su‐Xia Li

doi:10.1002/npr2.12397

. 2023 Dec 6;44(1):97–108. doi: 10.1002/npr2.12397

Effects of bilateral repetitive transcranial magnetic stimulation on prospective memory in patients with schizophrenia: A double‐blind randomized controlled clinical trial

Fen Xue ¹, Xin‐Fu Wang ², Fan‐Ni Kong ³, Tian‐Lu Yin ⁴, Yu‐Hong Wang ², Li‐Da Shi ², Xiao‐Wen Liu ², Hui‐Jing Yu ², Li‐Jun Liu ², Ping Zhu ¹, Xiao‐Xue Qi ¹, Xue‐Jing Xu ⁵, Hong‐Pu Hu ^4,^✉, Su‐Xia Li ^3,^✉

PMCID: PMC10932802 PMID: 38053478

Abstract

Aims

To investigate effects of repetitive transcranial magnetic stimulation (rTMS) on the prospective memory (PM) in patients with schizophrenia (SCZ).

Methods

Fifty of 71 patients completed this double‐blind placebo‐controlled randomized trial and compared with 18 healthy controls' (HCs) PM outcomes. Bilateral 20 Hz rTMS to the dorsolateral prefrontal cortex at 90% RMT administered 5 weekdays for 4 weeks for a total of 20 treatments. The Positive and Negative Symptom Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), and PM test were assessed before and after treatment.

Results

Both Event‐based PM (EBPM) and Time‐based PM (TBPM) scores at baseline were significantly lower in patients with SCZ than that in HCs. After rTMS treatments, the scores of EBPM in patients with SCZ was significantly improved and had no differences from that in HCs, while the scores of TBPM did not improved. The negative symptom scores on PANSS and the scores of almost all subscales and total scores of SANS were significantly improved in both groups.

Conclusions

Our findings indicated that bilateral high‐frequency rTMS treatment can alleviate EBPM but not TBPM in patients with SCZ, as well as improve the negative symptoms. Significance: Our results provide one therapeutic option for PM in patients with SCZ.

Keywords: cognitive function, dorsolateral prefrontal cortex, event‐based prospective memory, negative symptoms, positive symptoms, prefrontal cortex, prospective memory, rTMS, schizophrenia, time‐based prospective memory

This is the first study to investigate the effect of long‐term rTMS on PM impairment in patients with schizophrenia. We observed a positive result with active rTMS on EBPM, but not on TBPM, compared to sham stimulation. Our results provide one therapeutic option for PM in patients with SCZ.

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1. INTRODUCTION

Schizophrenia (SCZ) is a group of difficult‐to‐treat mental disorders with unknown etiology. ¹ , ² Clinical symptoms mainly include positive symptoms (delusions, hallucinations, thought disorder, abnormal behavior, etc.), negative symptoms (anhedonia, apathy, social withdrawal, etc.), and the impairment of cognitive function. ¹ , ³ , ⁴ SCZ is associated with mild‐to‐moderate impairment in several cognitive domains, including attention, language, executive functions, and memory. Most people with SCZ have extensive memory impairment and this damage involves all parts of the memory system. ¹ , ⁵

Prospective memory (PM), the ability to remember to perform future activities, is a fundamental requirement for independent living. ⁶ Prospective information can be retrieved via different modalities. The first one associates prospective retrieval to a given event that acts as a cue, defined as event‐based PM (EBPM); the second one implies that prospective retrieval of information occurs at a specific time or within a determined temporal interval, defined as time‐based PM (TBPM). PM has been a hot topic in the field of memory research. It has the characteristics of delay, mosaicism and self‐excited extraction. ⁷ Studies have pointed out that patients with SCZ have PM impairment. ⁶ , ⁸ PM deficits have been consistently confirmed in both chronic ¹ , ⁶ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ and first‐episode schizophrenia. ⁸ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ The result of non‐psychotic first‐degree relatives of patients with schizophrenia show similar but attenuated PM impairments compared to patients suggesting that PM deficits may be an endophenotype of the illness. ⁸ , ²⁰ Previous studies showed that both the left and right DLPFC is involved in PM, ²¹ , ²² , ²³ , ²⁴ and an fMRI study of prospective memory in healthy individuals revealed that both EBPM and TBPM activated the posterior frontal and parietal cortices, and deactivated the medial rostral prefrontal cortex. ²⁵ The prefrontal cortex involvement in PM deficits was observed in individuals with schizophrenia and schizotypal features. ¹³ , ²⁶ , ²⁷

At present, the treatment of schizophrenia is mainly clinically based on drug therapy, including the first‐generation antipsychotics and the second‐generation antipsychotics. But patients with SCZ often experience symptoms which fail to fully respond to antipsychotic medication. ²⁸ , ²⁹ These drugs are mainly useful for positive symptoms of SCZ but have poor response to negative symptoms and cognitive impairment in patients with SCZ. ²⁹ At the same time, drug therapy is often accompanied by a large number of side effects, such as extrapyramidal side effects, weight gain, metabolic disturbance, etc. ³⁰ This will undoubtedly need to find new treatments. ²⁸ Currently, treatment for PM is more to take a variety of mental rehabilitation training, such as psychological intervention, training life skills, social skills training. ³¹ However, these psychiatric rehabilitation exercises do not fundamentally improve the PM impairment in patients with schizophrenia.

Repetitive transcranial magnetic stimulation (rTMS) is increasingly being investigated as a potential treatment for a number of psychiatric disorders, including schizophrenia. rTMS is a relatively safe and non‐invasive method ³² that uses alternating magnetic fields to induce an electric current in the underlying brain tissue. It stimulates specific parts of the brain extracranially to achieve therapeutic effects by altering the activity of neurons in the cerebral cortex, the plasticity of cortical cells, and the release of neurotransmitters in the brain. ³³ Some studies have reported that rTMS is effective in the treatment of auditory hallucinations, negative symptoms, and cognitive impairment in schizophrenia. ³⁴ , ³⁵ , ³⁶ , ³⁷ To date, numerous studies have investigated the effects of rTMS on cognition in human subjects ³⁸ , ³⁹ , ⁴⁰ and several systematic reviews have tried to illuminate the effects of rTMS on cognitive profiles. ⁴¹ , ⁴² , ⁴³ However, despite the increased clinical use of rTMS worldwide, it remains unclear whether rTMS has the effect of improving cognitive function in patients with SCZ, ⁴⁴ although a recent meta‐analysis indicated that High‐frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) with a total pulses <30 000 stimulation could significantly improve working memory in SCZs for an extended period of time. ⁴⁵ Also, a recent study reported that 2 weeks of bilateral DLPFC high‐frequency (20 Hz) rTMS in patients with early phase psychosis improved a standardized cognitive battery. ⁴⁶ However, so far, there is still a lack of studies on the effect of rTMS on PM in patients with schizophrenia. ⁴⁷

Based on the above existing studies, we hypothesized that high‐frequency rTMS therapy, especially in the bilateral DLPFC, could improve not only negative symptoms but also PM in patients with schizophrenia. This study used a randomized, placebo‐controlled, double‐blind and healthy control (HC) design to explore the efficacy and safety of rTMS for PM in patients with schizophrenia.

2. METHODS AND MATERIALS

2.1. Study design

This study was a double‐blind, randomized placebo‐controlled and HC study (patients, n = 50; HC, n = 18) conducted at Rong Jun Hospital, Baoding, Hebei Province, China. Patients were allocated in a 1:1 ratio to both treatment condition and order of stimulation (i.e., right, followed by left, or left, followed by right) according to a computer‐generated random number sequence. The patients and raters were blind to treatment and order of stimulation conditions. The rTMS treatments were administered by technicians who were not aware of the patients' stimulation conditions. The technicians operated rTMS according to the number of the coil label and of the patient's label. The patients were advised that they would receive either active or the placebo‐controlled sham rTMS; however, the specifics regarding the difference between the stimulations were not described. Repetitive TMS was delivered for 4 weeks, Monday to Friday for a total of 20 treatment sessions. The HC did not receive any treatment. The study conforms to the standards set by the Consolidated Standards of Reporting Trials (CONSORT) consortium.

2.2. Participants

Seventy‐one patients with a diagnosis of schizophrenia, confirmed by the Structured Clinical Interview for DSM‐5, were recruited for this study. All patients were consecutively recruited from Rong Jun Hospital, Baoding, Hebei Province, China. Recruitment occurred between July 2015 and Aug 2019. HCs included 18 physically and mentally healthy volunteers were recruited from the community residents of the city. All subjects provided their written informed consent, and the protocol was approved by the ethics committee of Peking University Health Science Center, Beijing, China (IRB00001052‐15009), and all procedures were carried out with the adequate understanding of the subjects. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. The informed consent process complied the ICMJE guidelines regarding informed consent. All participants were asked to fill in a questionnaire about side effects. Inclusion and exclusion criteria for subjects are shown in the Appendix S1.

2.3. rTMS treatment

A Magstim Rapid® device (MAGSTIM Ltd., Whitland, Wales, UK) and a vacuum‐cooled 70 mm figure of eight Coil (Air Film Coil, Magstim, Whitland, Wales, UK) was utilized in the delivery of rTMS. The participants were seated upright in a comfortable chair during the procedure. The protocol consisted of 30 trains, each lasting for 3 s and with an intertrain interval of 57 s with a total of 1800 pulses per session. Participants were stimulated 30 min per session for bilateral treatment, first the left or right dorsolateral prefrontal cortex (DLPFC) area was stimulated for 15 min. Subsequently, for the following 15 min, the coil position was switched to the right or left DLPFC area. Each participant underwent 20 treatment sessions, one session a day, for four consecutive weeks (workdays only), resulting in the administration of a total of 36 000 pulses. Stimulation intensity was set at 90% of the motor threshold. ⁴⁸ The F3 and F4 location from the EEG 10–20 system was used to target the bilateral DLPFC. ⁴⁹ The same protocol was applied with a sham coil (Sham Air Film Coil, MAGSTIM Ltd., Whitland, Wales, UK) which looks and sounds like an active coil; however, it does not produce active magnetic stimulation in the sham group. None of the participants had received rTMS prior to this study and were not familiar with the differences between sham and active rTMS with regard to its acoustic and tactile artifacts.

2.4. Primary outcomes—PM tasks

The PM assessment paradigm is derived from the standard Chinese version of the PM test designed by Einstein and McDaniel. ⁵⁰ , ⁵¹ The details of this paradigm have been described previously. ⁵² We revised some details according to the actual situation of schizophrenic patients to facilitate the subject's operation. The test was divided into two parts to assess TBPM and EBPM, respectively. Before and after treatment patients were assessed using the PM paradigm by one senior doctor who had been trained in the use of this PM paradigm. The detailed description of the tasks of TBPM and EBPM is provided in the Appendix S1.

2.5. Secondary outcome measures—clinical outcome measure

The two groups of patients lived in the same hospital room conditions, as well as diet and daily activities. HCs were recruited from the local community. Medications that patients were receiving were unchanged during the course of this study. Before and after treatment patients were assessed using the Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) by three senior doctors who had been trained in the use of these scales (one of the doctors also was responsible for quality control in this study). The SANS, comprises 25 items, is grouped into five subscales of withdrawal or emotional poverty, poverty of thought (lack of speech), avolition and apathy (lack of energy, lack of initiative), anhedonia and social withdrawal (loss of interests), and attention. All three doctors were blinded to the type of treatment patients were receiving. Any patients who dropped out during the treatment had their data removed from the final analysis.

2.6. Data analysis

The data that followed a normal distribution were characterized by the mean (SD) for demographic and clinical characteristics. Mean ± SE was used to describe each subscale scores of PANSS and SANS and their total scores and PM scores. Independent t‐tests for continuous variables and Fisher's chi‐square tests for categorical variables were used to assess between‐group differences in baseline demographic and clinical data. The analyses of the efficacy outcomes including PANSS, SANS, TBPM, and EBPM were conducted by using a general linear model for two‐way repeated measures ANOVA with between subjects (treatment: the active rTMS and the sham rTMS) and within subjects (time: baseline, final) factors. One‐way ANOVA was conducted to compare the differences among the outcomes of PM before, after rTMS treatment and HC. The post hoc Bonferroni test was used to correct for multiple comparisons. We applied Pearson's chi‐square test to compare qualitative or categorical variables. A power calculation was based on the primary study endpoint. All statistical analyses were executed using SPSS version 26.0 (IBM, Somers, NY, USA). Significance was defined as a p value <0.05.

3. RESULTS

3.1. Demographics and baseline clinical characteristics of the study population

As shown in Table 1 and Figure 1, the active and sham groups did not differ significantly in demographics or baseline clinical ratings. There was no difference between groups at baseline in age, gender, age of onset, duration of illness, years of education, severity of illness assessed as with the score of EBPM and TBPM, the PANSS, SANS total score and their subscales scores, antipsychotic use, antidepressant agents, lithium, or VPA. Twenty‐one of the 71 patients dropped out of the study. Nine active rTMS group patients and twelve sham rTMS group patients were dropped out of the study with at least one time of treatment. The number of dropouts across the time of measurements was not significantly different between the groups (Pearson chi‐square χ ² = 0.5, df = 1, p = 0.48). There were 15 patients, 8 patients belong to active rTMS group and 7 patients belong to sham rTMS group, could not stand the adverse reactions of TMS. One sham rTMS group patient had intestinal obstruction after 6 sessions of treatment. Four sham rTMS group patients and one active rTMS group patient did not receive treatment according to protocol because of the National Day holiday. The data from these dropouts were not included in the analysis.

TABLE 1.

Demographic and clinical characteristics of the two groups at baseline.

Variable	HC (n = 18)	Active rTMS (n = 26)	Sham rTMS (n = 24)	p
Male (%)	15 (83.33%)	22 (84.62%)	20 (83.33%)	0.99 ^c
Age (mean years, SD)	49.89 (7.04)	45.5 (7.26)	48.67 (7.99)	0.131 ^a
Duration of disease (mean years, SD)		24.88 (7.51)	25.52 (9.82)	0.798 ^b
Age first onset (Mean years, SD)		20.65 (2.35)	21.06 (3.48)	0.432 ^b
Education (mean years, SD)	9.17 (2.36)	9.65 (2.45)	9.46 (2.35)	0.801 ^a
Classic Antipsychotics (%)		0 (0)	0 (0)	ns
Atypical Antipsychotics (%)		26 (100%)	24 (100%)	ns
Lithium or VPA (%)		3 (11.54%)	2 (8.33%)	1.000 ^c
Antidepressant Agents (%)		6 (23.08%)	4 (16.67%)	0.832 ^c
PM
EBPM (mean, SD)	5.44 (1.5)	1.65 (1.72)****	2.04 (2.6)****	<0.0001 ^a
TBPM (mean, SD)	4.33 (1.46)	2.08 (2.13)**	1.67 (2.3)****	<0.0001 ^a
PANSS
Positive items (mean, SD)		12.64 (6.77)	12.35 (6.82)	0.892 ^b
Negative items (mean, SD)		15.23 (7.05)	13.65 (5.61)	0.430 ^b
General items (mean, SD)		25.86 (7.01)	23.8 (4.72)	0.275 ^b
Total score (mean, SD)		53.73 (18.91)	49.8 (14.44)	0.457 ^b
SANS
Emotional poverty (mean, SD)		11.27 (7.39)	11.33 (7.53)	0.975 ^b
Poverty of thought (mean, SD)		5.96 (3.66)	5.46 (3.36)	0.616 ^b
Avolition and apathy (mean, SD)		5.54 (2.75)	4.38 (2.95)	0.155 ^b
Anhedonia or social withdrawal (mean, SD)		8.54 (3.5)	7.38 (3.56)	0.250 ^b
Attention (mean, SD)		3.54 (1.92)	3.25 (1.65)	0.573 ^b
Total (mean, SD)		34.85 (18.07)	31.79 (17.2)	0.544 ^b

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Note: **p < 0.01, ****p < 0.0001, compared with healthy control.

Abbreviations: EBPM, event‐based prospective memory; HC, healthy control; PANSS, Positive and Negative Symptom Scale; PM, prospective memory; rTMS, repetitive transcranial magnetic stimulation; SANS, Scale for the Assessment of Negative Symptoms; TBPM, time‐based prospective memory; VPA, Valproic acid.

^{^a}

One‐way ANOVA.

^{^b}

Independent t‐test.

^{^c}

χ ² test.

Study flowchart. ICF, Informed Consent Form; PANSS, Positive and Negative Symptom Scale; PM, prospective memory; rTMS, repetitive transcranial magnetic stimulation; SANS, Scale for the Assessment of Negative Symptoms.

3.2. Changes in PM

There was no significant main effect of treatment (F _{1, 23} = 1.39, p = 0.25, effect size 0.06), a significant main effect of time (F _{1, 23} = 32.25, p < 0.001, effect size 0.58) on the EBPM, with a significant treatment × time interaction (F _{1, 23} = 10.96, p = 0.003, effect size 0.32). The post hoc Bonferroni test revealed that active rTMS significantly improved EBPM (F _{1, 25} = 32.02, p < 0.001, effect size 0.56). There was no significant main effect of treatment and time (for treatment: F _{1, 23} = 0.32, p = 0.58, effect size 0.014; for time: F _{1, 23} = 1.05, p = 0.32, effect size 0.04, respectively) on the TBPM, without a significant treatment × time interaction (F _{1, 23} = 0.28, p = 0.60, effect size 0.01) (Figure 2A,B). These results indicated that 20 days of active rTMS treatment significantly improved the performance of the EBPM, but not of the TBPM tests. As for the retrospective memory, there was no significant main effect of treatment (F _{1, 23} = 1.08, p = 0.31, effect size 0.05), a significant main effect of time (F _{1, 23} = 16.42, p < 0.001, effect size 0.42) on the retrospective memory in EBPM, also called EBRM, without a significant treatment × time interaction (F _{1, 23} = 0.22, p = 0.64, effect size 0.01). There was no significant main effect of treatment (F _{1, 23} = 1.013, p = 0.33, effect size 0.04), nor a significant main effect of time (F _{1, 23} = 1.63, p = 0.21, effect size 0.07) on the retrospective memory in TBPM, also called TBRM, without a significant treatment × time interaction (F _{1, 23} = 0.55, p = 0.47, effect size 0.02) (Figure S1A,B).

Effects of rTMS on the prospective memory. Active, active rTMS group; EBPM, event‐based prospective memory; HC, healthy control; Sham, sham rTMS group; TBPM, time‐based prospective memory. ^$$$ *p <* 0.001, compared with baseline. ***p <* 0.01, ****p <* 0.001, *****p <* 0.0001, compared with HC.

To test whether there was a difference in PM between patients with schizophrenia before and after treatment of rTMS and HCs, we further compared the PM between patients with schizophrenia before and after rTMS treatment with that of HCs. Before treatment, one‐way ANOVA showed that there was a significant difference in EBPM and TBPM among active, sham and HC groups (EBPM: F _{2, 67} = 21.136, p < 0.0001; TBPM: F _{2, 67} = 9.799, p < 0.0001, respectively), post hoc Bonferroni test revealed that in active and sham rTMS group the scores of EBPM or TBPM were significantly lower than those in HC group (p values <0.0001, except for p = 0.002 for TBPM in active rTMS group; 95% confidence interval for EBPM, active vs sham: −1.799 1.023; HC vs active: 2.263 5.319; HC vs sham: 1.849 4.957, respectively. 95% confidence interval for TBPM, active vs sham: −1.011 1.831; HC vs active: 0.717 3.796; HC vs sham: 1.102 4.232, respectively) (Figure 2C,E). After treatment, one‐way ANOVA showed that there was a significant difference in EBPM and TBPM among active, sham and HC groups (EBPM: F _{2, 67} = 10.824, p < 0.0001; TBPM: F _{2, 67} = 7.81, p = 0.001, respectively), post hoc Bonferroni test revealed that the score of EBPM in active rTMS group had no significant difference compared with HC (p = 0.351, 95% confidence interval, −0.537 2.503), while that in sham rTMS group was lower than that in HC (p < 0.0001, 95% confidence interval, 1.274 4.365); the scores of TBPM in active and sham rTMS group were lower than that in HC (p = 0.006 for active rTMS group, 95% confidence interval, 0.479 3.65; p = 0.001 for sham rTMS group, 95% confidence interval, 0.846 4.071, respectively) (Figure 2D,F).

3.3. Changes in clinical symptomatology

Figure 3 showed that there was no main effect of treatment and time on the PANSS positive items, without a significant treatment × time interaction (for treatment: F _{1, 23} = 0.052, p = 0.82, effect size 0.002; for time: F _{1, 23} = 2.545, p = 0.12, effect size 0.1; for group × time interaction: F _{1, 23} = 0.28, p = 0.6, effect size 0.01). There was no main effect of treatment (F _{1, 23} = 0.07, p = 0.8, effect size 0.003), a significant main effect of time (F _{1, 23} = 20.5, p < 0.001, effect size 0.47) on the PANSS negative items, with a significant treatment × time interaction (F _{1, 23} = 4.36, p = 0.048, effect size 0.16). The post hoc Bonferroni test revealed that both active and sham rTMS significantly improved the PANSS negative items (for active rTMS: F _{1, 25} = 12.66, p = 0.002, effect size 0.34; for sham rTMS: F _{1, 23} = 8.6, p = 0.007, effect size 0.27). As for the general Items and total scores of PANSS, there was no main effect of treatment (for general items: F _{1, 23} = 0.89, p = 0.35, effect size 0.04; for total score: F _{1, 23} = 0.27, p = 0.61, effect size 0.01), a significant main effect of time (for general Items: F _{1, 23} = 14.51, p = 0.001, effect size 0.39; for total score: F _{1, 23} = 19.29, p < 0.001, effect size 0.46), without a significant treatment × time interaction (for general Items: F _{1, 23} = 0.97, p = 0.33, effect size 0.04; for total score: F _{1, 23} = 2.87, p = 0.1, effect size 0.11).

Effects of rTMS on the Positive and Negative Symptom Scale. (A) Positive subscale, (B) Negative subscale, (C) General psychopathological subscale, (D) Total score. Active, active rTMS group; rTMS, repetitive transcranial magnetic stimulation; Sham, sham rTMS group. ***p <* 0.01, compared with baseline. ^### *p <* 0.001, the main effects of time.

We further used the SANS to evaluate the efficacy of rTMS. Figure 4 showed that there was a significant main effect of treatment (F _{1, 23} = 47.39, p < 0.001, effect size 0.67), no main effect of time (F _{1, 23} = 0.51, p = 0.48, effect size 0.02) on the emotional poverty, without a significant treatment × time interaction (F _{1, 23} = 2.29, p = 0.14, effect size 0.09). This result indicated that the treatment significantly improved the emotional poverty. There was a significant main effect of treatment (F _{1, 23} = 32.29, p < 0.001, effect size 0.58), no main effect of time (F _{1, 23} = 0.1, p = 0.75, effect size 0.004) on the poverty of thought, with a significant treatment × time interaction (F _{1, 23} = 4.84, p = 0.038, effect size 0.17). The post hoc Bonferroni test revealed that both active and sham rTMS significantly improved the poverty of thought (for active TMS: F _{1, 25} = 24.08, p < 0.001, effect size 0.49; for sham TMS: F _{1, 23} = 6.41, p = 0.02, effect size 0.22). There was a significant main effect of treatment (F _{1, 23} = 33.87, p < 0.001, effect size 0.6), no main effect of time (F _{1, 23} = 0.5, p = 0.49, effect size 0.02) on the avolition, with a significant group × time interaction (F _{1, 23} = 5.81, p = 0.024, effect size 0.2). The post hoc Bonferroni test revealed that both active and sham rTMS significantly improved the avolition (for active TMS: F _{1, 25} = 27.29, p < 0.001, effect size 0.52; for sham TMS: F _{1, 23} = 12.69, p = 0.002, effect size 0.36). There was a significant main effect of treatment (F _{1, 23} = 15.81, p = 0.001, effect size 0.03), no main effect of time (F _{1, 23} = 0.77, p = 0.39, effect size 0.03) on the anhedonia, without a significant treatment × time interaction (F _{1, 23} = 1.51, p = 0.23, effect size 0.06). This result indicated the treatment significantly improved the anhedonia. There was a significant main effect of treatment (F _{1, 23} = 8.6, p = 0.007, effect size 0.27), no main effect of time (F _{1, 23} = 0.17, p = 0.68, effect size0.007) on the attention, with a significant treatment × time interaction (F _{1, 23} = 4.54, p = 0.04, effect size0.17). The post hoc Bonferroni test revealed that the active rTMS significantly improved the attention (F _{1, 25} = 11.25, p = 0.003, effect size 0.31). While the sham rTMS did not show effect on the attention (F _{1, 23} = 0.46, p = 0.5, effect size 0.02). There was a significant main effect of treatment (F _{1, 23} = 43.09, p < 0.001, effect size 0.65), no main effect of time (F _{1, 23} = 0.18, p = 0.89, effect size 0.001) on the total score of SANS, without a significant treatment × time interaction (F _{1, 23} = 4.075, p = 0.055, effect size 0.15). This result indicated that the treatment significantly improved the total score of SANS.

Effects of rTMS on the Scale for the Assessment of Negative Symptoms. (A) Eomotional poverty subscale, (B) Poverty of thought subscale, (C) Avolition subscale, (D) Anhedonia subscale, (E) Attention subscale, (F) Total score. Active, active rTMS group; rTMS, repetitive transcranial magnetic stimulation; Sham, sham rTMS group. **p <* 0.05, ***p <* 0.01, ****p <* 0.001, compared with baseline. ^&&& *p <* 0.001, the main effects of treatment.

3.4. rTMS safety and tolerability

No serious adverse events occurred. Common reported side effects were twitching of the facial muscles, face pain, eye pain, and scalp painful or numb during rTMS stimulation and transient mild headache after rTMS stimulation. There were 21 participants' dropout from the research. Fifteen of 21 patients, 8 patients belong to active rTMS group and 7 patients belong to sham rTMS group, could not stand the adverse reactions of rTMS. The adverse reactions of these dropouts were summarized into two categories. One kind occurs in the process of stimulation, the other happens after the stimulation. During the rTMS stimulation, four cases felt anxiety, restlessness, back fever, and sweating; three cases had vibratory sensation; three cases felt head or face numbness; two cases had a history of head trauma, that felt the wound shook obviously and the scalp was lifted; one case felt unspeakable misery, brain cramp, pain, dizziness, irritating to eyes, and nose bulge. After the rTMS stimulation, three cases felt unstable walking and weak lower limbs and two cases had sleep disorder.

4. DISCUSSION

In this randomized double‐blind sham‐controlled trial of bilateral high‐frequency rTMS, we found a significant therapeutic benefit of active treatment compared with sham treatment when applied for PM in chronic schizophrenia. We found active rTMS treatment significantly improved EBPM, but not for TBPM. With regarding to the symptoms assessed by PANSS scale, both the active and sham rTMS significantly improved negative symptoms. The negative symptoms were further evaluated by the SANS, and it was found that the active rTMS had a significant improvement on the subscales of SANS, and the sham rTMS also had a significant improvement on the other subscales of SANS except the attention subscale. The rTMS resulted in a meaningful clinical benefit not only in negative symptoms, also in EBPM. The lack of seizure induction is notable given the use of clozapine and other antipsychotic medications in these patients that have been known to lower the seizure threshold.

This is the first study investigating the effect of long‐term rTMS on PM impairment in patients with schizophrenia. Fortunately, we observed a positive result with active rTMS on EBPM, but not on TBPM, compared to sham stimulation. Previous studies revealed that EBPM tasks require the PM task development together with an ongoing activity. ⁵³ Instead, TBPM tasks place higher demand on self‐initiation ⁵⁰ and require time estimation and monitoring. ⁵⁴ , ⁵⁵ TBPM paradigms are considered as more difficult than EBPM ones. ⁵⁰ , ⁵⁶ Previous study showed that TBPM tasks performance need greater activation in frontal brain regions compared with EBPM tasks. ²⁵ The anterior medial frontal lobe and anterior cingulate gyrus, as well as the bilateral superior frontal gyrus, are involved in TBPM evidenced by a positron emission tomography (PET) study ⁵⁷ and PFC is more selectively involved in EBPM, but less in TBPM also evidenced by patients with lesions in the prefrontal cortex. ⁵¹ A most recent activation likelihood estimation meta‐analysis revealed that the brain regions associated with the PM tasks, including right insula and right orbitofrontal cortex, left pre‐supplementary motor area extending to part of anterior cingulate/paracingulate cortex, and posterior cingulate regions. ⁵⁸ The use of rTMS to stimulate DLPFC alone may not be sufficient to improve the impairment of TBPM in patients with schizophrenia. This may partly explain why rTMS stimulation of DLPFC is only effective for EBPM, but not for TBPM.

A recent meta‐analysis reported that there were 17 studies investigated the effects of rTMS on cognition in patients with schizophrenia before April 2018. ⁴⁵ The researched cognitive domains including executive function, processing speed, attention, language function, verbal memory, and working memory. ⁴⁴ , ⁴⁵ From April 2018 to January 2020, additional 4 studies investigated the effects of rTMS on cognition in patients with schizophrenia. ⁴⁶ , ⁵⁹ , ⁶⁰ , ⁶¹ So far, there have been 6 studies on the effects of rTMS on cognition in patients with schizophrenia with a sample size ≥20, one study on the effects of rTMS on cognition in patients with schizophrenia in early phase, ⁴⁶ and one study on the effects of short‐term rTMS on cognition in patients with schizophrenia with smoking behavior. ⁶⁰ A significant efficacy of high‐frequency rTMS on working memory, but not executive function, processing speed, attention, language function, and verbal memory, in SCZs was found compared with sham stimulation. ⁴⁵ Although a recent study ⁴⁶ reported a positive finding on a standardized cognitive battery, such as Brief Assessment of Cognition in Schizophrenia (BACS) Symbol Coding and BACS Semantic and Letter Fluency, in patients with schizophrenia in early phase compared with sham stimulation with smaller sample size (i.e., N < 20). None of these studies had a prospective memory component.

Randomized controlled trials (RCTs) suggested that rTMS is moderately effective in the treatment of auditory hallucinations and negative symptoms of schizophrenia compared with sham rTMS. ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ These studies also reported that duration of illness and stimulation parameters relating to target region, pulse frequency and motor threshold as well as overall treatment duration were significant moderators of efficacy. ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ As the majority of rTMS studies that focused on hallucinations targeted the left temporo‐parietal junction using low pulse frequencies (<10 Hz). ⁶² We did not separately evaluate changes in hallucinations. In terms of positive symptoms, we failed to find any significant therapeutic benefit of active treatment compared with sham. No significant deterioration of positive symptoms was found, although there have been reports of worsening of positive symptoms with rTMS. ⁶² So far, evidence for an effect of TMS on positive symptoms was mixed. ⁶⁶ Further research on effects of TMS on other positive symptoms, such as thought disorder and delusions need to be conducted.

With regarding to negative symptoms, we found a positive result with a moderate size effect of both the active and the sham rTMS. This is in the line with previous published systematic review and meta‐analysis for non‐invasive brain stimulation for negative symptoms in SCZ. ⁶⁷ , ⁶⁸ Although there are some trials yielded mixed results with several negative previous trials. It can be explained by the brief nature of treatment applied in those trials given that the negative symptoms of schizophrenia appear relatively enduring symptoms that seem unlikely to be ameliorated with very short‐term treatment and with relatively weak parameters of the rTMS. It is reported that greater reduction in negative symptoms was associated with using pulse frequency of 20–50 Hz, motor threshold intensity of 110%, trial duration over 3 weeks and treatment site over the left PFC. ⁶² A more recent systematic review and network meta‐analysis for non‐invasive brain stimulation intervention for negative symptoms of schizophrenia also found high frequency of rTMS over the left DLPFC were associated with significantly large improvements in the severity of negative symptoms. ⁶⁹ However, there is also reported that non‐significant trend for a better response when stimulating the left DLPFC or inhibiting the right DLPFC. ⁶⁸ Interestingly, our results suggested that the sham rTMS also significantly improved negative symptoms. We think it may have something to do with the antipsychotics that the patients were taking, which are all second‐generation antipsychotics. Some of these patients also taken a combination of antidepressants or mood stabilizers. The effects of these drugs might be further enhanced in combination with rTMS, although the treatment regimen had been stable for a year prior to the study, and for the duration of the study. Whether this effect really exists needs to be confirmed by further research in the future. Two recent reviews evidenced that the second‐generation anti‐psychotics monotherapy or adjunctive treatment with an antidepressant drug may improve response in patients with schizophrenia who have severe depressive or negative symptoms. ⁷⁰ , ⁷¹ Additionally, we think that the placebo effect of rTMS also plays a role in this phenomenon. Especially with longer and greater number of treatment sessions, the placebo effect can be more by promoting better a doctor–patient relationship.

Notably, the score of attention disorders subscale of SANS improved significantly after active rTMS treatment, while the sham rTMS group did not. Among subscales of SANS, only a differential improvement in attention domain was found. This may be more reflective of the subjects' neurocognitive status rather than a classical negative symptom as per literature. Our data indicated that long‐term, high‐frequency rTMS should be considered to be used for the treatment of neurocognitive status in patients with schizophrenia in the future study.

We noted that the inter‐train interval (ITI; 57 s) in the present study is about double the time, comparing to existing literature (30 s of ITI). ⁷² Whether the acute effect of rTMS would dissipate off quite quickly, especially, only 3 s of 20 Hz stimulation per minute. A previous study indicated that after 1.5 s of 10‐Hz rTMS, the mean amplitude of motor‐evoked potentials (MEPs) increased in stimulated cortex for up to 120 min. ⁷³ Although there are no relevant data reports on 20 Hz rTMS, we speculate that the duration of the mean amplitude of MEPs increase induced by 3 s of 20 Hz rTMS per minute will not be less than 120 min. This needs to be confirmed by a further specialized study in the future.

There is still space for improvement in this study. First of all, the samples used in this study were relatively concentrated in middle‐aged patients and the sample size was relatively small. Although the sample size of this study >20 in each group of patients with SCZ, the effects of rTMS on TBPM may require a larger sample size in the future. The subsequent study should expand the sample size and improve the representativeness of the samples. Secondly, the time of rTMS was relatively short, and the treatment time may be prolonged in the future. Thirdly, the accuracy of positioning has been the bottleneck restricting the development of this technology, the process of rTMS treatment did not use a very fine positioning. Fourth, the lack of information on premorbid cognitive functions makes it impossible to accurately determine the extent of PM impairment in patients and effects of rTMS therapy, despite the availability of HCs for reference. Therefore, whether these findings of this study can be deduced into the practice of schizophrenia treatment still requires further study.

In conclusion, the effectiveness of rTMS for EBPM, not for TBPM, in patients with schizophrenia gained a positive result. Whether rTMS can be as a PM therapy for patients with schizophrenia need to be subject to bigger sample size, more rigorous, rational, and scientific clinical studies. The major target of rTMS in the treatment of negative symptoms and cognitive symptoms of schizophrenia is DLPFC. ⁴⁵ , ⁶⁸ , ⁷⁴ A recent review suggests that rTMS can be applied to symptom‐specific networks through accessible cortical targets, symptoms can be improved through neuromodulation of the network. In the near future, individual‐defined network‐based rTMS therapy may be a novel treatment approach for schizophrenia. ⁷⁵

AUTHOR CONTRIBUTIONS

All authors contributed to the study concept; Su‐Xia Li designed the study; Fen Xue, Xin‐Fu Wang, Fan‐Ni Kong, Yu‐Hong Wang, Li‐Da Shi, Ping Zhu, and Xiao‐Xue Qi collected clinical data and interpretation; Xiao‐Wen Liu, Hui‐Jing Yu, and Li‐Jun Liu performed rTMS and responded for administering medication to patients; Fen Xue, Xin‐Fu Wang, Tian‐Lu Yin, and Su‐Xia Li performed the statistical analysis; Fan‐Ni Kong, Xue‐Jing Xu, and Su‐Xia Li wrote the manuscript; Hong‐Pu Hu and Su‐Xia Li guided the assessment tool application and data exploration, revised the manuscript for important intellectual content. All the authors reviewed and approved the final manuscript.

FUNDING INFORMATION

This work was supported by the National Natural Science Foundation of China (L.S.X., grant numbers 81 871 071), Natural Science Foundation of Beijing Municipal (L.S.X., grant number 7222109), Health Commission of Dongcheng District, Beijing (X.F. with no grant number), and National Clinical Research Centre for Mental Disorder (Peking University Sixth Hospital), the key research project of independent exploration in 2021 (L.S.X., grant number NCRC2021Z03).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

Approval of the research protocol by an Institutional Reviewer Board: This research protocol was approved by the ethics committee of Peking University Health Science Center, Beijing, China (IRB00001052‐15009).

Informed Consent: All subjects provided their written informed consent. The informed consent process complied the ICMJE guidelines regarding informed consent.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.

Supporting information

Appendix S1.

NPR2-44-97-s001.docx^{(31.8KB, docx)}

ACKNOWLEDGMENTS

I would like to thank all the subjects and members of the research team for their dedicated work, as well as the guidance and support given by the experts in this article.

Xue F, Wang X‐F, Kong F‐N, Yin T‐L, Wang Y‐H, Shi L‐D, et al. Effects of bilateral repetitive transcranial magnetic stimulation on prospective memory in patients with schizophrenia: A double‐blind randomized controlled clinical trial. Neuropsychopharmacol Rep. 2024;44:97–108. 10.1002/npr2.12397

Fen Xue, Xin‐Fu Wang, Fan‐Ni Kong and Tian‐Lu Yin equally contributed to this work.

Contributor Information

Hong‐Pu Hu, Email: hu.hongpu@imicams.ac.cn.

Su‐Xia Li, Email: li313@bjmu.edu.cn.

DATA AVAILABILITY STATEMENT

Due to the inherent characteristics of this study, it required the collection of personal information, including dynamic changes in participants' clinical symptoms and dynamic changes in other observational measures. Parts of the study are ongoing and not yet fully concluded. To protect the privacy of the participants, the dataset supporting the findings of the study are still not disclosed in the public domain. In addition, due to the stigma of patients with mental illness, they are worried about their private information being exposed, which may affect the participants' return to society. Owing to these considerations, we refrained from seeking informed consent for the public release of the dataset. The data that support the findings of this study can be accessed through from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Appendix S1.

NPR2-44-97-s001.docx^{(31.8KB, docx)}

Data Availability Statement

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PERMALINK

Effects of bilateral repetitive transcranial magnetic stimulation on prospective memory in patients with schizophrenia: A double‐blind randomized controlled clinical trial

Fen Xue

Xin‐Fu Wang

Fan‐Ni Kong

Tian‐Lu Yin

Yu‐Hong Wang

Li‐Da Shi

Xiao‐Wen Liu

Hui‐Jing Yu

Li‐Jun Liu

Ping Zhu

Xiao‐Xue Qi

Xue‐Jing Xu

Hong‐Pu Hu

Su‐Xia Li

Abstract

Aims

Methods

Results

Conclusions

1. INTRODUCTION

2. METHODS AND MATERIALS

2.1. Study design

2.2. Participants

2.3. rTMS treatment

2.4. Primary outcomes—PM tasks

2.5. Secondary outcome measures—clinical outcome measure

2.6. Data analysis

3. RESULTS

3.1. Demographics and baseline clinical characteristics of the study population

TABLE 1.

FIGURE 1.

3.2. Changes in PM

FIGURE 2.

3.3. Changes in clinical symptomatology

FIGURE 3.

FIGURE 4.

3.4. rTMS safety and tolerability

4. DISCUSSION

AUTHOR CONTRIBUTIONS

FUNDING INFORMATION

CONFLICT OF INTEREST STATEMENT

ETHICS STATEMENT

Supporting information

ACKNOWLEDGMENTS

Contributor Information

DATA AVAILABILITY STATEMENT

REFERENCES

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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