Repetitive transcranial magnetic stimulation guided by event-related potential P300 application in schizophrenia

Abstract

BACKGROUND

Repetitive transcranial magnetic stimulation (rTMS) entered clinical practice in China after 2000, first used in psychiatric surgery, and then in neurology and other disciplines. The First Hospital of Jiaxing introduced TMS in 2015. In practical applications, it has been found that different models of instruments and technical parameters can lead to differences in therapeutic efficacy. Therefore, our hospital selected the Danish TMS instrument, which ranks second in China, to test patients with schizophrenia from March 2021 to July 2021, with a focus on comparing the results at 5 Hz, 10 Hz, and 15 Hz. The testing time is concentrated between 8:30 to 10:30 in the morning. A contingency plan was made for the quality after inspection before testing. Two evaluators independently control the quality of the contingency plan. The data is independently saved and proofread by two evaluators. The purpose of this study is to translate the research results into clinical practice and provide reference basis.

AIM

To investigate the effects of rehabilitation therapy using rTMS on the negative symptoms and event-related potential component of P300 in chronic schizophrenia.

METHODS

One hundred and five patients with chronic schizophrenia were randomly allocated to three groups based on the frequency of rTMS (5, 10, or 15 Hz). The patients underwent five sessions of rTMS per week for 5 weeks. We compared the pre- and post-treatment P300 latency and scores for the Scale for Assessment of Negative Symptoms (SANS).

RESULTS

A significant decrease in SANS score after rTMS was observed in the 10-Hz group (P < 0.05), which was not observed in the 5-Hz and 15-Hz groups. There was a significant increase in P300 amplitude in the 10-Hz group after rTMS treatment (P < 0.05), but there was no significant change in P300 latency (P > 0.05). The improvement of SANS score in the 10-Hz rTMS group was related to patient age and disease course.

CONCLUSION

rTMS at 10 Hz improved negative symptoms and cognitive function in chronic schizophrenia; however, further studies on the mechanism of action are required to validate our observations.

Key Words: Schizophrenia; Repetitive transcranial magnetic stimulation; Negative symptoms; P300; Different frequency

Core Tip: This study investigates the optimal frequency of repetitive transcranial magnetic stimulation (rTMS) in the treatment of schizophrenia and discovers that 10 Hz is superior to 5 Hz and 15 Hz. The innovations of this study consist of designing the experiment in accordance with the Chinese rTMS standard, utilizing the P300 to assess the treatment effect, formulating a detection plan and a quality assurance plan, and adjusting technical parameters. The results demonstrate that the Scale for Assessment of Negative Symptoms score improved in the 10 Hz group, and the P300 wave amplitude presented initial evidence of change. The conclusion is that 10 Hz is appropriate for adult schizophrenia patients, and P300 can serve as an electrophysiological evaluation indicator before and after rTMS treatment.

INTRODUCTION

Schizophrenia is a chronic, early onset mental disorder, associated with poor prognostic outcomes. Relapse rates of 67% have been reported after 1 year of withdrawal of antipsychotic medication therapy[1]. Due to the chronic nature of the illness, patients exhibit negative symptoms, such as emotional indifference, lack of will, impaired social skills and loss of creative labor capacity. The symptoms significantly affect overall quality of life[1]; thus, rehabilitation of chronic schizophrenic patients poses a huge challenge.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique that targets specific regions of the brain by distant neuronal electrical activity, which is induced by high magnetic flux field changes around the external coil of the device. This novel technology of nerve regulation has been applied to schizophrenia[2], depression[3] and other mental illnesses. The effect of TMS on schizophrenia is related to the frequency of stimulation. It is generally believed that low frequency stimulation (< 1.0 Hz) can inhibit excitability, while high frequency stimulation (> 1.0 Hz) can improve excitability of the cerebral cortex[2]. Studies have shown that, compared with pseudostimulation, high frequency rTMS (10 Hz) can improve negative symptoms and cognitive function in patients with chronic schizophrenia[4]. However, the various effects produced by different frequencies of rTMS on chronic schizophrenia patients with negative symptoms and cognitive impairment has not been elucidated. The aim of this study was to compare the rehabilitative effects of different frequencies of rTMS (P300) in chronic schizophrenia patients with negative symptoms and cognitive impairment.

MATERIALS AND METHODS

Study design

Patients with schizophrenia were admitted to the Department of Neurology, Shanghai Mental Health Center from March 2021 to July 2023. Only patients who complied with the diagnostic criteria for schizophrenia in the Chinese Mental Disorders Classification and Diagnostic Criteria Revision 3 were included. The inclusion criteria were as follows: (1) Disease course > 2 years; (2) Age 18-60 years; and (3) Scale for Assessment of Negative Symptoms (SANS) score > 35[5]. Exclusion criteria were: (1) Severe dementia and organic disease; (2) Metal implants; (3) Positive personal and family history of previous traumatic brain injury or epilepsy; (4) Obvious extrapyramidal effects; and (5) Patients who had accepted improved electroconvulsive treatment within 1 month of the study. There were 139 patients who met the screening criteria; among which, six declined to undergo TMS and seven rejected event-related potential data acquisition. A total of 126 patients were included in the study and were allocated to either the 5-Hz, 10-Hz or 15-Hz group according to a random number table. Each group comprised 42 patients with 21 males and 21 females. In the 5-Hz group, average age was 45.2 ± 9.5 years; average education 9.9 ± 4.7 years; disease course 7.2 ± 2.5 years (median 5.1 years); and the drug dose (chlorpromazine equivalent) 260.5 ± 24.3 mg/day. In the 10-Hz group, average age was 44.8 ± 7.9 years; average education 9.6 ± 4.7 years; disease course 9.4 ± 2.2 years (median 7.9 years); and drug dose (chlorpromazine equivalent) 270.5 ± 38.5 mg/day. In the 1-Hz group, average age was 45.4 ± 9.7 years; average education 10.1 ± 5.2 years; disease course 8.4 ± 2.3 years (median 6.8 years); and drug dose (chlorpromazine equivalent) 268.2 ± 24.4 mg/day. There was no significant difference in the general demographic data and drug treatment dose between the three groups.

TMS

Three groups of patients received rTMS on the basis of original drug therapy. The TMS instrument was MagPro R30 (Tonica Elektronik, Farum, Denmark) and the stimulator head was MCF-B65. Parameter settings, stimulation frequency 10 Hz, stimulation intensity 100% motor threshold. In the rTMS method, except for the stimulation frequencies of 5 Hz, 10 Hz, and 15 Hz, the duration, interval time, total stimulation time, stimulation site, and weekly frequency of the other three parameter groups are the same. The stimulation coil was butterfly shaped (MCF-B65), and during treatment, the center was placed in the brain area corresponding to the left dorsolateral prefrontal cortex (DLPFC) of the frontal lobe, which was tangential to the scalp. Each patient received 30 stimulus sequences, with 50 stimuli per sequence. The stimulation lasted for 5 seconds, with intervals of 10 seconds, and a total stimulation time of 20 minutes per session. The above three groups of patients received TMS treatment once a day, five times a week, for a total of 25 times. During the above treatment, the patient had to lie flat for comfort, and maintain relaxation and stillness.

Cognitive function test

Event-related potential P300 is used as an indicator to evaluate cognitive function. Two tests were conducted after admission and treatment. The stimulation method used was an auditory oddity experimental approach. The standard stimulus was 500 Hz, 80 dB pure tone, and the probability of occurrence was 0.8 (a total of 160 times). The deviation stimulus was 2000 Hz, 90 dB pure tone, with a probability of 0.2 occurrence (a total of 40 times). The total number of standard and bias stimuli in the study was 200. The test was conducted in a shielded room with weak lighting of 2 Lux indoors. During the test, it was recommended that the patient sat at the edge of the chair, relaxed, wore headphones, stayed awake, concentrated, and remembered the frequency of deviant stimuli. The event-related potential recorder and analyzer used was Runjie WJ-1 made by Wuhan Medical Equipment Company, ranked first in China. The electrodes were placed according to the international 10/20 system: The recording electrode in the frontal domain (FZ); reference electrodes in both ears; the center of the forehead (PFz) was grounded; and electrodes were placed on the upper and lower eyelids of the right eye for monitoring vertical eye movement. The filtering frequency band was 0.05-70 Hz, and the sampling frequency was 1000 Hz. The impedance between the electrode and the scalp was < 5 KΩ, with an analysis time of 600 milliseconds.

The above-mentioned rTMS testing and P300 monitoring were conducted in a soundproof shielded room. All patients underwent specialized training in electrophysiology during treatment. Prior to the tests: (1) A contingency plan was developed for inspection requirements and quality; (2) Two evaluators independently controlled the quality of the contingency plan; (3) The monitoring time was set between 08:30 and 11:30; (4) Before the formal examination, the patient underwent a 5-minute prediction and adaptation (not recorded), followed by formal monitoring and recording; (5) During treatment, the therapist conducted safety assessments on each patient; (6) The entire quality control process was recorded and monitored in real time by the researchers; and (7) Data were independently saved and verified by two evaluators, and finally sealed by two nurses.

Clinical evaluation

SANS was used to assess negative symptoms before and after treatment. SANS contains 24 entries and five subscales assessing flat emotion, poor thinking, lack of will, lack of interest, and obstacles in attention. It is divided into 6 classes with a total score of 120.

Statistical analysis

SPSS version 23.0 was used for statistical analysis of the results. Measurement data were presented as mean ± SD. Analysis of variance was used to compare differences between groups. The paired t test was used for within-group comparison. Multiple stepwise regression analysis was used for patients in the 10-Hz group. P < 0.05 was considered statistically significant.

RESULTS

Patient demographics are shown in Table 1. No significant difference was observed in the demographic data and drug treatment dose between the three groups. The changes in SANS score of the three groups of patients before and after rTMS treatment are shown in Table 2. No significant difference in SANS scores was observed among the three groups before and after rTMS rehabilitation. Post-treatment SANS score of the 10-Hz group was significantly lower than that before treatment (P < 0.05). However, no significant difference was observed before and after treatment in the 5-Hz and 15-Hz groups (P > 0.05). The changes in the amplitude and latency period of P300 of the three groups of patients before and after rTMS treatment are shown in Table 3. The amplitude of P300 after treatment was significantly increased in the 10-Hz group (P < 0.05), and no significant change was observed in the latency period of P300 of the 5-Hz and 15-Hz groups after treatment (P > 0.05). There was no significant difference in latency and amplitude between the two groups before and after treatment (P > 0.05).

Table 1 Patient demographics.

Group	5 Hz	10 Hz	15 Hz	χ2/F	P value
Gender (male/female)	21/21	21/21	21/21	2.351	0.382
Age (year)	45.2 ± 9.5	44.8 ± 7.9	45.4 ± 9.7	1.736	0.561
Education (year)	9.9 ± 4.7	9.6 ± 4.7	10.1 ± 5.2	0.827	0.837
Disease course (year)	7.2 ± 2.5	9.4 ± 2.2	8.4 ± 2.3	0.911	0.920
Drug dose (mg/day)	260.5 ± 24.3	270.5 ± 38.3	268.2 ± 29.4	2.410	0.991

Table 2 Scale for Assessment of Negative Symptoms score.

Group	n	SANS score
		Before treatment	After treatment
5 Hz	42	48.3 ± 15.9	47.2 ± 14.7
10 Hz	42	47.9 ± 16.1	40.0 ± 16.8a
15 Hz	42	50.1 ± 19.4	49.4 ± 18.9
F		0.014	1.614
P value		0.979	0.219

^aP < 0.05, compared with the same group before treatment, t = 6.075.

SANS: Scale for Assessment of Negative Symptoms.

Table 3 Changes in P300 of the three groups of patients before and after repetitive transcranial magnetic stimulation.

Groups	n	Latency period (millisecond)		Amplitude (μV)
		Before treatment	After treatment	Before treatment	After treatment
5 Hz	42	334.4 ± 60.1	337.1 ± 66.1	5.3 ± 2.1	5.7 ± 2.5
10 Hz	42	337.9 ± 59.9	331.5 ± 69.2	5.0 ± 2.1	7.9 ± 3.1a
15 Hz	42	324.9 ± 62.0	321.4 ± 63.1	5.8 ± 2.7	5.9 ± 2.3

^aP < 0.05, compared with the same group before treatment, t = 5.451.

Regression analysis of factors affecting rehabilitation

Regression analysis of factors affecting rehabilitation in the 10-Hz group was conducted (Table 4). Treatment effects for the rehabilitation of negative symptoms (SANS scale before treatment - SANS scale after treatment) was used as the dependent variable and demographic data (gender, age, duration of education) were the independent variables. The patient’s age and disease course were considered in the final equation, while sex, duration of education, and drug dose were excluded. Older age of patients was associated with longer course of chronic schizophrenia, and lesser improvement in negative symptoms after rTMS.

Table 4 Regression analysis of factors affecting rehabilitation in patients in the 10 Hz group.

Dependent variable	Unstandardized		Typical coefficient	t	P value	R	R2	ΔR2	SEE
	B	SE
Constant	3.301	0.358		7.801	0.001	0.309	0.102	0.089	2.794
Age	0.179	0.035	0.166	4.955	0.000	-	-	-	-
Disease course	0.111	0.024	0.123	4.018	0.013	-	-	-	-

SE: Standard error; SEE: Standard estimation error.

DISCUSSION

Schizophrenia is a serious and common mental illness, ranking fourth among other similar diseases in terms of social burden. Many studies have been conducted on the etiology, pathogenesis, diagnosis and treatment of schizophrenia. However, patients with chronic schizophrenia often still have obvious negative symptoms and cognitive impairment, and their recovery is not ideal[1]. The present study compared the roles of three different frequencies of rTMS in the rehabilitation of negative symptoms and event-related potential P300 in chronic schizophrenia. A frequency of 10 Hz significantly improved negative symptoms and the amplitude of event-related potential P300. Research has found that patient improvement depends on age and disease duration, and patients with longer disease duration are less likely to show improvement in negative symptoms.

Antipsychotic drugs remain the main treatment for schizophrenia. The effect of classic antipsychotic drugs on positive symptoms in patients with schizophrenia has been confirmed through several clinical trials. However, the response to negative symptoms is still poor and is associated with many adverse reactions. In recent years, second-generation atypical antipsychotic drugs have been widely used; however, their impact on negative symptoms is still discouraging[6]. So far, no medication or adjuvant therapy has been proven to maintain improvement in negative symptoms. A meta-analysis of second-generation antipsychotic drugs showed that compared to first-generation drugs, the effect of second-generation drugs on negative symptoms was similar, but not superior[7]. It has been reported that rTMS has significant therapeutic effects on negative symptoms in schizophrenia patients[8]. rTMS can affect local cortical function, including functionally related distal regions, and achieve regional reconstruction of cortical function. Continuous biological effects can be achieved for a period of time until the stimulus stops. Based on its positive effects, rTMS is a good tool for studying the functional reconstruction of neural networks and can be used to improve the treatment of negative symptoms in schizophrenia[9]. The present study is not the first to report on the impact of rTMS on negative symptoms of schizophrenia. A previous study evaluated the impact of rTMS on symptoms in patients with acute schizophrenia.

Gan et al[10] and Schneider et al[11] found that 10-Hz rTMS improved refractory negative symptoms in the left DLPFC after 4 weeks. Meta-analysis supports that 10-Hz stimulation can improve negative symptoms[12]. Sun[13] reviewed 27 double-blind randomized controlled trials at home and abroad and found that 19 studies (with a sample size of 310) confirmed that rTMS improved negative symptoms in patients with schizophrenia. The stimulation site was mostly the DLPFC, using parameters 3: 20 Hz, 80%-110% motor threshold, and a new TMS treatment mode. A consensus on rTMS has been established in China[14], and based on the above experience, rTMS frequencies of 5, 10, and 15 Hz can be selected for use in patients with chronic schizophrenia. Our results showed that 10-Hz significantly improved negative symptoms in patients with chronic schizophrenia, although frequencies of 5 and 15 Hz did not show significant effects. The results indicate that, despite the use high-frequency rTMS, the recovery of negative symptoms in patients with chronic schizophrenia is also related to the stimulation frequency of rTMS, with a stimulation frequency of 10 Hz appearing to be more effective at improving negative symptoms. Stepwise regression analysis found that age and disease duration affected the improvement of negative symptoms in the 10-Hz group. Patients with older age and longer disease duration had a lesser response to rTMS.

We showed that SANS score was significantly lower after treatment at 10 Hz compared to before treatment. There was no significant difference in SANS scores in the 5-Hz and 15-Hz groups before and after treatment. Another evaluation tool was P300, which is a neurophysiological examination method that can objectively reflect the function of the central nervous system. It has high sensitivity and specificity, and can dynamically reflect the information processing process of neural circuits. The latent period reflects the psychological process of target selection in patients, and the wave amplitude shows the mobilization level of effective resources in brain information processing[15]. We used the improved auditory P300 as an indicator of electrophysiological changes before and after treatment. Since Polich and Herbst[16] reported a decrease in P300 in patients with schizophrenia, many studies have reported a decrease in P300 amplitude and an extension of latency[15-17]. Recently, it has been reported that rTMS in the DLPFC can improve the amplitude of P300[15], which is similar to our findings. There was a change in amplitude of P300 at after 10-Hz treatment but not after 5 and 15 Hz. However, the specific mechanism of P300 amplitude improvement is still unclear, so further research is needed to confirm the effect of rTMS treatment on amplitude changes.

At present, the mechanism of occurrence and development of negative symptoms of schizophrenia is not fully understood. Previous researchers believed that it was related to dysfunction of the dopamine and glutamate systems in the subendothelial layer of the brain[18]. In recent years, some researchers have found that the serotonin system is closely related to the occurrence and development of negative symptoms in schizophrenia[19]. Initially, rTMS was mainly used to study severe depression. With the development of medical technology and the application of functional magnetic resonance imaging, it was found that insufficient left DLPFC activity was associated with psychomotor deficits and developmental delays.

After applying 10-Hz rTMS to the left DLPFC, combined with functional magnetic resonance imaging, Hasan et al[20] found that patients had an increase in the volume of the left hippocampus, parahippocampal area, and pre-wedge area, which was significantly correlated with the improvement of negative symptoms. They speculated that rTMS of the left DLPFC induced changes in the plasticity of the corresponding brain regions, which may be a clinical response (effective or ineffective) pathway. In future, treatment should be given to schizophrenia patients who can be induced by rTMS to change the plasticity of the corresponding brain regions. There are also studies suggesting that low activity in the DLPFC is associated with the development of negative symptoms in schizophrenia. High frequency rTMS improves negative symptoms by increasing the excitability of the prefrontal cortex, leading to local neuronal differentiation[21]. Functional imaging studies have also found that schizophrenia patients with negative symptoms have low dopamine function in areas such as the DLPFC, limbic system, and nucleus accumbens[22]. High frequency rTMS stimulates the prefrontal cortex striatum pathway, promoting the release of dopamine in the ventral striatum, inducing and enhancing reward effects, thereby improving negative symptoms[23].

The present study had some limitations. Firstly, we demonstrated the impact of three different frequencies of rTMS on negative symptoms in patients with chronic schizophrenia, with 10 Hz showing effectiveness. However, there was no comparison with other stimulus frequencies. In theory, there are other more effective stimulation frequencies. Secondly, during the preliminary stage of this study, most patients with chronic schizophrenia refused to undergo evaluation using paper, pen or computer; therefore P300 was selected as an indicator of cognitive function. Thirdly, our results indicate that after rTMS rehabilitation, the amplitude of P300 improved. However, there was a lack of evidence regarding the patient’s cognitive performance.

CONCLUSION

Our results indicate that, within a certain range, rTMS with high stimulation intensity (100% motor threshold), high frequency (10 Hz), and appropriate stimulation dose (> 1500 pulses/day) is a suitable treatment for chronic adult schizophrenia, and can significantly improve negative symptoms within 5 weeks. This treatment option deserves further research. However, improving negative symptoms with stimulation levels of 5 and 15 Hz may take longer. Based on the encouraging effect of 10-Hz rTMS on negative symptoms and cognitive function in patients with chronic schizophrenia, we will strengthen follow-up and further explore the mechanism of action of rTMS to validate the findings of this study.