Efficacy of Repetitive Transcranial Magnetic Stimulation Over the Supplementary Motor Area on Motor Function in Parkinson’s Disease

Abstract

Objective

The objective of this study was to assess the effect of repetitive transcranial magnetic stimulation on the supplementary motor area in motor function in Parkinson’s disease patients.

Method

Databases searched included five databases from October 7, 2022, to January 4, 2023. The Cochrane Bias Risk Assessment Tool was used for quality assessment. Standardized mean differences were calculated using a random-effects model. Outcome measure is the motor function examination of the motor part of Unified Parkinson’s Disease Rating Scale.

Results

Seven studies totaling 374 patients were included. Meta-analysis showed that stimulation of supplementary motor area significantly improved motor function in Parkinson’s disease patients compared with sham stimulation (standardized mean differences = −1.24; 95% CI, −2.24 to −0.24; P = 0.02; I² = 93%). Stimulation of the same target (supplementary motor area) subgroup analysis showed that high-frequency repetitive transcranial magnetic stimulation is more effective than low-frequency repetitive transcranial magnetic stimulation in improving motor function in Parkinson’s disease (standardized mean differences = −1.39; 95% CI, −2.21 to −0.57; P = 0.04; I² = 77.2%).

Conclusions

Overall, repetitive transcranial magnetic stimulation over supplementary motor area had a statistically significant improvement in motor function in Parkinson’s disease patients, and high-frequency repetitive transcranial magnetic stimulation is statistically significantly more effective than low-frequency repetitive transcranial magnetic stimulation.

What Is Known

• Repetitive transcranial magnetic stimulation (rTMS) can improve the function of patients with Parkinson’s disease (PD). However, the therapeutic effect of rTMS on patients with PD remains controversial.

What Is New

• rTMS stimulation of supplementary motor area can statistically significantly improve the motor function of PD patients.

Parkinson’s disease (PD) is a prevalent and progressive neurodegenerative disorder that significantly impacts the lives of affected individuals. It primarily disrupts dopaminergic neurotransmission, leading to both motor and nonmotor signs that greatly affect daily functioning.^1,2 According to a 2016 epidemiological survey, the disease affects approximately 1–2 out of every 1000 individuals at any given time. The prevalence of PD rises with age, with around 1% of individuals over the age of 60 being affected, peaking around the age of 80.^3,4 Motor dysfunction is a prominent feature of PD and includes signs such as bradykinesia, rigidity, resting tremor, and postural instability.⁵

PD management involves various therapeutic approaches, including drug therapy and surgical interventions.⁶ Drug therapy, such as the use of levodopa, is a common treatment option. However, levodopa may come with side effects like nausea, delusions, somnolence, dystonia, among others.¹ Surgical interventions, particularly DBS, are often considered for the middle to late stages patients with PD.⁷ However, only a small percentage (approximately 4.5%) meet criteria and DBS may worsen PD symptoms and signs.^8,9 Repetitive transcranial magnetic stimulation (rTMS) has emerged as a nondrug treatment option for PD. It has demonstrated efficacy in improving both motor and nonmotor signs, as well as enhancing the overall quality of life for patients.¹⁰ rTMS involves the use of magnetic stimulation to induce changes in cortical excitability and has gained recognition as a promising therapeutic approach for PD.¹¹

rTMS is a type of indirect and noninvasive brain stimulation technique. High-frequency rTMS (HF-rTMS) and low-frequency rTMS (LF-rTMS) induce synaptic potential long-term enhancement and inhibition respectively and potentially promote plasticity.^12,13 The motor cortex (M1) is an effective target spot of transcranial magnetic stimulation in the treatment of PD. The supplementary motor area (SMA) is located in front of M1 and has a similar function.^14,15 Studies have shown that the hypomotor function of PD is associated with dysfunction in the SMA.^16,17 Using positron emission tomography, it has been found that SMA activation is impaired when PD patients perform internally generated motor tasks.¹⁶ Compared with M1, SMA is a more suitable and effective stimulus target spot for rTMS in PD.¹⁸ rTMS can induce motor cortex plasticity to improve the signs of PD.¹⁹ rTMS is a potential treatment intervention for PD and can be used in any stage of PD.

A growing body of research investigating the effectiveness of rTMS for PD treatment has had mixed results, with some treatments working and others not. Hamanda et al. and Mi et al. demonstrated that HF-rTMS targeting the SMA can improve the motor function of PD. Shirota et al. suggested that LF-rTMS can improve bradykinesia in PD^15,20 but Syin et al. showed that the effect of rTMS in PD is poor.²¹ Therefore, it is important to integrate data related to rTMS therapy in PD to estimate the effect of rTMS over SMA more accurately in PD. The aim of this meta-analysis was to systematically assess the efficacy of transcranial magnetic stimulation-assisted motor zones compared with sham controls for PD dysfunction in randomized clinical trials (RCTs).

METHODS

Study Design and Registration

Our meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (See Supplementary Checklist, http://links.lww.com/PHM/C503), which provide a standardized framework for conducting and reporting systematic reviews and meta-analyses.²² These guidelines ensure transparency, accuracy, and completeness in the reporting of our study. In addition, our study has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42022377048.

Search Strategy

In our meta-analysis, we conducted a comprehensive search for relevant articles from multiple databases, including PubMed, Cochrane, Embase, Wanfang Database, and China National Knowledge Infrastructure (CNKI). The search was initiated on 29 November 2022. A combination of the following terms are included: Parkinson disease and repetitive transcranial magnetic stimulation or rTMS or repetitive TMS and supplementary motor area or SMA.

Inclusion Criteria and Exclusion Criteria for Study Selection

During the screening process, articles were assessed based on the predefined inclusion and exclusion criteria. The screening began by evaluating the titles and abstracts of the identified articles. To be included in the meta-analysis, studies needed to meet the following criteria: (1) Population: The participants in the study should be diagnosed with PD. (2) Interventions: The intervention method should involve rTMS specifically targeting the SMA. (3) Comparators: The control group should receive either routine treatment or a placebo. (4) Outcome Measures: Outcome indicators related to motor function, such as the Unified Parkinson Disease Rating Scale or Timed Up and Go test. (5) Study Design: The study should be a parallel or crossover RCT and use sham control groups or conditions. Studies were excluded if they met any of the following criteria: (1) Nonrandomized controlled trials. (2) Unable to extract data. The screening process was carried out by two researchers who each assessed the same articles based on the criteria mentioned above. Then the researchers compared their findings. In cases where there was a discrepancy or disagreement, the opinion of a third investigator was sought.

Data Extraction

During the data extraction phase, two independent researchers, who were unaware of each other’s assessments, performed the data extraction and evaluation. The extracted data included the following information: year of publication, and the names of the authors. Research types: The type of research conducted (e.g., randomized controlled trial, crossover study). rTMS intervention: Details of the rTMS intervention, including the frequency, duration of stimulation and duration of the study. Treatment parts: The specific brain region or area targeted for the rTMS intervention. Quantity control method: The method used to control the intensity or dosage of the rTMS treatment. Intervention and control groups: Information about the groups receiving the rTMS intervention and the control group, including number of patients in the intervention and control groups, duration of illness, duration of study. Exercise outcomes assessment: Assessment measures or scales used to evaluate the outcomes related to motor function.

For the meta-analysis, the mean and standard deviation (SD) of the primary clinical outcomes were used as effect size measures. If the mean and SD were directly reported in the published tables of the studies, they were extracted from there. However, if the data were not provided directly, the corresponding author of the study would be contacted to obtain the necessary information. In cases where there were any discrepancies or differences in data extraction or evaluation, they would be resolved through discussion and consultation with a third researcher.

Data Synthesis and Statistical Analysis

The total duration of treatment in the articles we included ranged from 3 days to 20 wks. Because of the wide variation in study length and the largest sample size for the 4-wk treatment period, effect size in this meta-analysis was calculated using the SMD of the clinical scale scores after the 4-wk treatment period. The 95% CI was assessed using the Z test. To assess the heterogeneity between the included studies, the Cochran Q statistic and I² test were employed. We set I²>50% as heterogeneity and I²>70% as high heterogeneity. Subgroup analysis was conducted based on the preassigned comparison of rTMS frequency, specifically LF-rTMS (≤1 Hz) and HF-rTMS (≥5 Hz). This analysis aimed to explore potential differences in treatment effects between the two frequency ranges. A random-effects model was chosen for the meta-analysis. Sensitivity analysis was used to examine the robustness of the results obtained. If significant heterogeneity was observed among the groups, sensitivity analyses were conducted using a dropout-by-dropout method or subgroup analyses were conducted to explore potential sources of heterogeneity and to examine the impact of specific study characteristics on the results. The data

RESULTS

Search Results

The initial search of all databases yielded a total of 66 studies. However, it was found that several studies were replicated across different databases. Subsequently, the titles and abstracts of the remaining studies were screened to assess their relevance to the research question. Based on the screening of titles and abstracts, 20 articles were selected for a full-text reading. After a thorough evaluation of these articles, 13 studies were excluded as they did not meet the predefined inclusion criteria. Ultimately, a total of seven studies were considered eligible and were included in the meta-analysis. The screening process, including the selection of studies, is visually presented in Figure 1, providing a clear overview of the screening and selection process.

FIGURE 1.

Preferred Reporting Items for Systematic Reviews and Meta-analyses flow chart of study selection.

Study Characteristics

Table 1 and Table 2 provide a summary of the seven eligible studies included in the meta-analysis, comprising a total of 374 patients. In all these studies, the intervention targeted the SMA. The primary outcome measure assessed in all studies was the Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) score, which evaluates motor function.^{2,5,15,20,23–25} Regarding the rTMS frequency of the intervention, five studies (280 patients) utilized HF-rTMS at ≥5 Hz,^{5,15,20,23,24} while two studies (92 patients) employed LF-rTMS at 1 Hz.^2,25 Therefore, subgroup analyses were conducted to compare the effects of HF-rTMS and LF-rTMS on the outcomes.

TABLE 1.

The characteristic of the included studies

Study	Study Type	Patients (M/F)	Age (M ± SD)	Duration of Illness (Year)	Disease Type	Outcome Measure	Duration of the Study
Mi 2019	RCT	E1: 9/11 C1: 5/5	E1: 62.65 ± 10.56 C1: 65.60 ± 8.68	E1: 9.15 ± 5.82 C1: 7.40 ± 4.83	PD	UPDRS-III	6 wks
Lai 2020	RCT	E1: 12/8 C1: 14/6	E1: 69.55 ± 1.64 C1: 71.20 ± 1.67	E1: 4.23 ± 0.61 C1: 5.50 ± 1.28	PD	UPDRS-III	4 wks
Shirota 2013	RCT	E1: 14/22 E2: 12/22 C1: 19/17	E1: 68.8 ± 7.6 C1: 67.9 ± 8.4 E2: 65.7 ± 8.5	E1: 8.5 ± 7.3 C1: 7.8 ± 6.6 E2: 7.6 ± 4.4	PD	UPDRS-III	20 wks
Ji 2020	RCT	E1: 14/8 C1: 14/6	E1: 61.7 ± 1.57 C1: 60.2 ± 1.97	E1: 4.3 ± 0.52 C1: 5.3 ± 0.83	PD	UPDRS-III	2 wks
Hamada 2008	RCT	E1: 55 C1: 43	E1: 65.3 ± 8.9 C1: 67.4 ± 8.5	E1: 8.1 ± 4.2 C1: 7.8 ± 6.7	PD	UPDRS-III	12 wks
Yokoe 2018	RCT	E1: 7/12 C1: 7/12	E1: 69.1 ± 8.4 C1: 69.1 ± 8.4	E1: 9.5 ± 3.2 C1: 9.5 ± 3.2	PD	UPDRS-III	3 d
Lench 2021	RCT	E1: 7/5 C1: 7/1	E1: 66.6 ± 7.5 C1: 64.5 ± 8.9	E1: 8.7 ± 7.12 C1: 8.0 ± 5.63	PD	UPDRS-III	10 d

C1, control group; E1, experimental group 1; E2, experimental group 2; F, female; M, male.

TABLE 2.

Main parameters of rTMS

Study	Parameters
	Frequency	Stimulation Location	Intensity	No. Pulses a Day	Duration of Stimulation
Mi 2019	E1:(10 Hz) rTMS C1: sham	SMA	90%RTM	1000 pulses	20 mins a day, 5 d a week for 2 wks.
Lai 2020	E1:(10 Hz) rTMS C1: sham	SMA	80%RTM	1200 pulses	1 time a day, 5 d a week for 4 wks.
Shirota 2013	E1:(1 Hz) rTMS E2:(10 Hz) rTMS C1: sham	SMA	110%RTM	1000 pulses	E1: 17 mins a time, 8 times a week for 8 wks. E2: 20 mins a time, 8 times a week for 8 wks. C1: 20 mins a time, 8 times a week for 8 wks.
Ji 2020	E1:(50 Hz repeated every 200 ms (5 Hz) rTMS (CTBS) C1: sham	SMA	80%RTM	1800 pulses	40S a session, 3 sessions a day, continue 14 d.
Hamada 2008	E1:(5 Hz) rTMS C1: sham	SMA	110%RTM	1000 pulses	20 mins a time, once a week for the first 8 wks.
Yokoe 2018	E1: 10(Hz) rTMS C1: sham	SMA	100%RTM	1000 pulses	10 mins a time, continue 3 d.
Lench 2021	E1: 1(Hz) rTMS C1: sham	SMA	110%RTM	1200 pulses	20 mins a time for 10 d.

C1, control group; E1, experimental group 1; E2, experimental group 2.

Quality Assessment

The evaluation criteria of the Cochrane Bias Risk Assessment Tool were divided into seven items. Low bias, uncertain risk of bias, and high bias were used to judge and classify study quality and to assess whether studies were randomized, blinded, data complete, and biased. Two reviewers assessed risk of bias in these studies using the Cochrane Collaborative Guidelines, as shown in Figures 2A and B.

FIGURE 2.

A, Risk of bias graph. B, risk of bias summary.

Effect of rTMS on Motor Function

The overall effect size of rTMS on UPDRS-III score was found to be an improvement compared with sham stimulation (SMD = −1.24; 95% CI, −2.24 to −0.24) (Fig. 3). This result indicates active rTMS intervention can improve motor function in PD patients compared with sham stimulation (Z = 2.43; P = 0.02). There was significant heterogeneity between the included studies (I² = 93%; P < 0.0001). Main characteristics research is described in Table 1 and Table 2. Sensitivity analyses showed that there was no significant change (I² = 93%).

FIGURE 3.

Effect of rTMS on motor signs.

Subgroup Analysis

In our subgroup analysis comparing HF-rTMS and LF-rTMS, the results showed that HF-rTMS had a statistically significant improvement effect on UPDRS-III scores in patients with PD compared with LF-rTMS (SMD = −1.39; 95% CI, −2.21 to −0.57; P = 0.04; I² = 77.2%) (Fig. 4).

FIGURE 4.

Effect of HF-rTMS and LF-rTMS on motor signs.

DISCUSSION

Based on the findings of this meta-analysis, random effects from 7 RCTs showed a significantly higher effect size for active rTMS than sham rTMS in reducing motor dysfunction in patients with PD patients, and HF-rTMS has a significantly more effective than LF-rTMS.

rTMS on PD Motor Function

It is evident that the effects of rTMS on motor function were more pronounced and significant when the stimulation targeted the SMA region, as compared with sham stimulation. This highlights the potential of targeting the SMA with rTMS to yield stronger therapeutic effects in patients with PD. Studies have indicated that the hypomotor function observed in PD can be attributed to impaired activity in the SMA.¹⁶ In the basal ganglia loop, the absence of nigral dopaminergic neurons projecting to the striatum leads to diminished delivery through the substantia nigra pars reticulata/internal globus pallidus-thalamus ventrolateral nucleus to SMA, resulting in dyskinesia in PD patients.^26–28 Ji et al. applied continuous theta burst stimulation to stimulate the SMA of PD patients, and imagological examination shows that the volume of globus pallidus increased and motor function improvement.⁵ This may be achieved by regulating the SMA-pallidum pathway motor nerve loop. Functional magnetic resonance imaging studies have shown that PD patients with freezing of gait exhibit a relative reduction in blood oxygenation-level dependent response in the SMA.^23,29 The effective therapeutic mechanism of rTMS targeting the SMA may involve activating the SMA and improving its blood circulation.^23,29 In conclusion, rTMS has the potential to improve motor function in patients with PD by promoting SMA activation, enhancing SMA blood circulation, improving connectivity in the sensorimotor cortex, and addressing motor circuit dysfunction.

The seven studies included in this meta-analysis exhibited considerable heterogeneity in their investigation of rTMS on the result of movement signs. We performed sensitivity analyses and applied a one-by-one culling approach to explore sources of heterogeneity but did not find a reason for the high heterogeneity. Therefore, subgroup analyses were performed to further explore sources of high heterogeneity. However, this does not reduce heterogeneity. High heterogeneity in outcomes is possibly due to the impact of baseline, preintervention, and intervention end times. The subgroup analysis revealed a significant improvement in movement in PD with HF-rTMS compared with LF-rTMS. Four studies^5,15,23,24 reported improvement in PD dyskinesia with HF-rTMS, while two studies^20,25 showed improvement with LF-rTMS. Interestingly, one study²⁰ found no improvement in PD dyskinesia with HF-rTMS. We speculate that these results may be related to the degree of brain activation or interregional connectivity during stimulation. It has been shown that SMA activity is impaired in patients with PD.²⁷ The level of brain activation is known to be influenced by the frequency of rTMS stimulation. LF-rTMS (<1 Hz) reduces excitability in the motor cortex, while HF-rTMS (>5 Hz) increases cortical excitability.¹² HF-rTMS promotes underactivated neurons in the SMA, resulting in modulation of dysfunction in these neurons and/or the motor nerve circuitry of the SMA-pallidal pathway.^15,23,29 Our study shows that HF-rTMS is more effective in improving motor signs in PD patients.

In our meta-analysis, several limitations should be considered. First, there was a high heterogeneity among the included studies, which may affect the interpretation of the results. Despite we performed sensitivity analyses and applied a one-by-one culling approach to explore sources of heterogeneity, we did not find a reason for the high heterogeneity. Second, only two LF-rTMS studies were included in the subgroup analysis, it did not produce firm and robust results, but they could provide a reference. A larger sample size is required to validate this result. Third, various uncontrollable variables, such as patient characteristics and disease-related factors, could have influenced the results. Lastly, some studies predominantly focused on PD patients with gait freezing, which could introduce bias.

In future studies, there is a need to identify clinically important differences for the outcome measures researchers are using in this promising rTMS research. In addition, it is recommended to address these limitations by conducting larger and more rigorous trials, considering individualized targets based on freezing of gait subtypes, and exploring stimulation of other brain regions, such as the prefrontal cortex or cingulate gyrus, for the treatment of nonmotor signs in PD.

CONCLUSIONS

After rTMS over the SMA in PD, there was a statistically significant improvement in motor function. HF-rTMS statistically significantly improves motor signs in patients with PD compared with LF-rTMS.