Meta-analysis of the therapeutic effect and safety of repetitive transcranial magnetic stimulation combined with pramipexole in Parkinson’s disease

Abstract

Background:

The motor and non-motor symptoms of PD severely impair the quality of life of PD patients. rTMS improves neuroplasticity by modulating cortical striatal pathways and provides a new strategy for non-pharmacological interventions, but its synergistic effect and optimal combination with pharmacological therapies have not been clarified. Meta-analysis was used to assess the clinical efficacy and safety of rTMS combined with pramipexole in the treatment of PD.

Methods:

A comprehensive search was conducted in the CNKI, VIP, Wanfang, CBM, PubMed, Web of Science, and Cochrane Library databases for clinical randomized controlled trials (RCTs) on the combined use of rTMS and pramipexole for the treatment of PD. The literature was in Chinese and English. Researchers used the Cochrane risk of bias assessment tool to determine the quality of the included literature, as well as the GRADE to assess the quality of the data. The primary outcome measure was the UPDRS, and the secondary outcome measures were: HAMD, FAQ, STEF, BBS, MAS, MMSE, MoCA, PDSS, PDQ-39, NMSQuest, SCOPA-AUT, Adverse Event Rate. The analysis of autonomic nervous system function used a random effects model, while the rest used a fixed-effects model. Furthermore, we performed trial sequential analysis. Due to the small sample size, sensitivity analysis was performed by excluding individual RCTs 2 by 1.

Results:

Twelve studies, all RCTs, ultimately included 995 patients. Meta-analysis results showed: rTMS combined with pramipexole had a higher overall effective rate in treating PD patients than the control group, and significantly reduced the UPDRS total score (OR = 4.58, 95% CI: 2.91–7.19, P < .0001). Based on our validation through trial sequential analysis, this result is decisive and robust. rTMS with pramipexole treatment showed overall improvement in PD (OR = 4.58, 95% CI: 2.91–7.19, P < .0001), improvement in cognitive functioning (MD = 2.23, 95% CI: 1.91–2.54, P < .0001), improvement in depression level (MD = −2.22, 95% CI: −2.71 to −1.72, P < .0001), improvement in social functioning (MD = −2.64, 95% CI: −3.09 to −2.19, P < .00001), improvement in non-motor symptoms (MD = −1.29, 95% CI: −1.97 to −0.60, P = .0002), gait improvement (MD = 6.34, 95% CI: 2.66–10.02, P < .00001; MD = 4.59, 95% CI: 2.37–6.80, P < .0001; MD = –0.14, 95% CI: –0.19 to −0.09, P < .00001) and other significant efficacy. Safety analysis showed that the rTMS combined with pramipexole group had a lower incidence of adverse effects during treatment (OR = 0.77, 95% CI: 0.40–1.46, P = .42). The GRADE assessment showed two outcomes as moderate-quality evidence, 6 as low-quality evidence, and 3 as very-low-quality evidence. In terms of heterogeneity analyses, the heterogeneity of the analyses was relatively low, except for significant heterogeneity in autonomic function and sleep quality. Also, funnel plot analyses were performed without significant publication bias.

Conclusion:

rTMS combined with pramipexole treatment can significantly control the symptoms of PD, accelerate the healing of the disease, better than the single pramipexole treatment of the clinical effect, and the safety of the use of the drug is higher.

1. Introduction

Parkinson’s disease (PD), a neurodegenerative disease that is more common in the middle aged and elderly population, is mainly due to the degeneration and death of nigrostriatal dopaminergic neurons.^[1] Currently, PD affects more than 10 million people worldwide, and the main early symptoms are movement disorders, mental disorders, limb tremor, and slowness of movement,^[2] which have a greater impact on the quality of life of patients, who require long-term or even lifelong treatment, which can impose a heavy financial burden on the family.^[3] The pathogenesis of PD is intricate and involves a variety of biological processes, including oxidative stress, excitotoxicity, mitochondrial dysfunction and apoptosis.^[4] At this stage, the exact pathogenesis of the disease has not yet been summarized by clinical workers.

Treatment for PD includes both pharmacological and non-pharmacological treatments. At present, the clinical treatment of PD is mostly based on drugs, such as pramipexole as a non-ergot DA receptor agonist, which can relieve the symptoms of PD by specifically binding to the DA D2 receptor, inducing DA secretion, and supplementing the nigrostriatal DA of the brain. However, patients generally need to take long-term medication, and single-use drug therapy is likely to reduce the sensitivity of patients to drugs, which leads to a reduction in the overall efficacy.^[5] Repetitive transcranial magnetic stimulation (rTMS), one of the non-pharmacological treatments for PD, delivers repetitive magnetic pulses to specific brain areas over a short period of time via a stimulation coil placed on the scalp. rTMS improves motor and non-motor symptoms in patients with PD by altering the excitability of the cerebral cortex and promoting neuroplasticity as a means of improving motor and non-motor symptoms in patients with PD, which is a highly effective and cost-effective and safe treatment.^[6] Pramipexole directly supplements DA, primarily improving motor symptoms, but its effects on non-motor symptoms such as depression and cognitive impairment are limited. In contrast, rTMS modulates neural networks, primarily improving non-motor symptoms while also synergistically improving motor symptoms. The 2 approaches have complementary mechanisms in treating symptoms in PD patients. Preliminary clinical study results indicate that combination therapy has a significantly higher efficacy rate than monotherapy and offers a certain degree of safety assurance. These findings partially validate the rationality of combination use and provide a basis for further exploration of combination therapy.^[5,7–17] However, there is currently limited summarization and compilation of research findings on the efficacy and safety of rTMS combined with pramipexole for PD, and treatment outcomes remain controversial.

Based on this, this study used meta-analysis to systematically evaluate the therapeutic effect and safety issues of rTMS combined with pramipexole in PD and to provide an evidence-based basis for the application of this method in clinical therapeutic practice.

2. Materials and methods

2.1. Protocol and registration

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

The protocol of this meta-analysis was registered on the PROSPERO in April 2025 (registration number: CRD420251035967).

2.2. Literature search

The literature on the use of rTMS combined with pramipexole in the treatment of PD was comprehensively searched by 2 researchers in China Knowledge, Wipro, Wanfang, China Biomedical Literature Database, PubMed, Web of Science, and Cochrane Library databases, and the search strategy is shown in Table 1 (using PubMed and as an example), and the time was taken from the respective databases construction to November 2024, and the search was conducted by a combination of subject terms and free terms. English search terms include “Parkinsonian Disorders, Therapeutics, Transcranial Magnetic Stimulation, Pramipexole.”

Table 1.

Search strategies for PubMed databases.

PubMed data retrieval strategies	Search results
#1 TS = ((((((((((((((Parkinsonian Disorders[MeSH Terms]) OR (Parkinsonism[Title/Abstract])) OR (Parkinsonian Syndrome[Title/Abstract])) OR (Parkinsonian Diseases[Title/Abstract])) OR (Parkinsonian Syndromes[Title/Abstract])) OR (Autosomal Dominant Juvenile Parkinson Disease[Title/Abstract])) OR (Juvenile Parkinsonism, Autosomal Dominant[Title/Abstract])) OR (Parkinsonism, Experimental[Title/Abstract])) OR (Experimental Parkinsonism[Title/Abstract])) OR (Experimental Parkinsonism, MPTP-Induced[Title/Abstract])) OR (Parkinson Disease, Experimental[Title/Abstract])) OR (Parkinsonism, Juvenile[Title/Abstract])) OR (Autosomal Recessive Juvenile Parkinson Disease[Title/Abstract])) OR (Chromosome 6-Linked Autosomal Recessive Parkinsonism[Title/Abstract])) OR (Juvenile Parkinson Disease, Autosomal Recessive[Title/Abstract]) #2 TS = (((((Therapeutics[MeSH Terms]) OR (Therapeutic[Title/Abstract])) OR (Therapy[Title/Abstract])) OR (Therapies[Title/Abstract])) OR (Treatment[Title/Abstract])) OR (Treatments[Title/Abstract]) #3 TS = ((((((((Transcranial Magnetic Stimulation[MeSH Terms]) OR (Magnetic Stimulations, Transcranial[Title/Abstract])) OR (Magnetic Stimulation, Transcranial[Title/Abstract])) OR (Stimulations, Transcranial Magnetic[Title/Abstract])) OR (Stimulation, Transcranial Magnetic[Title/Abstract])) OR (Transcranial Magnetic Stimulations[Title/Abstract])) OR (Transcranial Magnetic Stimulation, Paired Pulse[Title/Abstract])) OR (Transcranial Magnetic Stimulation, Repetitive[Title/Abstract])) OR (Transcranial Magnetic Stimulation, Single Pulse[Title/Abstract]) #4 TS = ((((((((((((((((Pramipexole[MeSH Terms]) OR (Pramipexol[Title/Abstract])) OR (2-Amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole[Title/Abstract])) OR (4,5,6,7-Tetrahydro-N6-propyl-2,6-benzothiazole-diamine[Title/Abstract])) OR (Pramipexol Dihydrochloride, (S)-isomer[Title/Abstract])) OR (Pramipexol, (+-)-isomer[Title/Abstract])) OR (Pramipexol Dihydrobromide, (+-)-isomer[Title/Abstract])) OR (Mirapex[Title/Abstract])) OR (Sifrol[Title/Abstract])) OR (6,7-Tetrahydro-N6-propyl-2,6-benzothiazolediamine dihydrochloride monohydrate[Title/Abstract])) OR (2-Amino-6-propylaminotetrahydrobenzothiazole[Title/Abstract])) OR (2 Amino 6 propylaminotetrahydrobenzothiazole[Title/Abstract])) OR (Pramipexole Dihydrochloride[Title/Abstract])) OR (Pramipexole Hydrochloride Monohydrate[Title/Abstract])) OR (SND-919[Title/Abstract])) OR (SND 919[Title/Abstract])) OR (Pramipexole Dihydrochloride Anhydrous[Title/Abstract])	1,13,990
#5 #1 AND #2 AND #3 AND #4	796

2.3. Literature inclusion and exclusion criteria

Experimental design: A clinical RCT to investigate the therapeutic efficacy and safety of rTMS combined with pramipexole in PD.

Study Subject: PD patient.

Interventions: The test group was treated with rTMS combined with pramipexole, and the control group was treated with pramipexole.

Main outcome indicators: PD composite rating scale (UPDRS).

Secondary outcome indicators: Hamilton depression scale (HAMD), social functioning scale (FAQ), upper extremity functioning score (STEF), lower extremity balance functioning scale (BBS), modified assessment of muscle tone scale (MAS), modified measured scale of mental status for cognitive functioning (MMSE), montreal cognitive assessment scale (MoCA), PD sleep scale (PDSS), Parkinson’s disease quality of life questionnaire (PDQ-39), non-motor symptoms screening questionnaire (NMSQuest), PD autonomic dysfunction scale (SCOPA-AUT), and safety (Adverse Event Rate).

Exclusion criteria: Reviews, case reports, conference abstracts, animal experiments, letters; the same data were used as in the included studies; incomplete raw data or inability to extract ending indicators; non-RCT; and The full text of the literature is not available.

2.4. Quality assessment of data extraction and inclusion in the study

Literature titles and abstracts were read individually by 2 researchers (Jinyu Geng and Xiawei Ren) to exclude irrelevant literature based on the above inclusion and exclusion criteria. After further reading of the full text, the literature was again screened and finalized for inclusion and the information was extracted. Disagreements, if any, are resolved through discussion or consultation with third parties.

After the literature screening entry, the data were extracted and cross-checked, including: general information: first author, date and country of publication; intervention and control group details (sample size, dose administered, length of intervention); outcome indicator.

The 12 RCTs were independently assessed for risk of bias by 2 researchers using the Cochrane Risk of Bias Assessment Tool and for quality of data using the GRADE Quality of Data Assessment Tool and were cross-checked.

2.5. Statistical analysis

RevMan 5.4 (Cochrane) and Stata 14 (StataCorp) software were used for statistical analysis. Tests for heterogeneity between included studies can be analyzed quantitatively using statistics. If I² ≤ 50%, it indicates that there is no statistical heterogeneity between the results of each study, then fixed effects model was used for meta-analysis, on the contrary, it indicates that there is statistical heterogeneity between the results of each study, and further analysis of the source of heterogeneity is needed to exclude the influence of obvious heterogeneity and use random effects model to analyze the results of each study, and to analyze the results of each study. The random effects model was used for meta-analysis after excluding the influence of significant heterogeneity.

3. Results

3.1. Literature search results and identification of basic information for inclusion in the literature

The initial search yielded 1173 relevant papers; 756 papers remained after removing duplicates; 756 papers remained after reading the titles and abstracts; the full texts were read and evaluated, and 12 papers remained after a layer-by-layer screening^[5,7–17] were finally included in the analysis. A flowchart of the literature screening process is shown in Guidelines Flow Diagram. The 12 included studies were RCTs with 995 patients, of which 498 were treated with rTMS in combination with pramipexole and 497 were treated with pramipexole. Basic information about the included studies is shown in Table 2.

Table 2.

Basic information on included studies.

Inclusion of literature (first author, date of publication)	Explore type	Nations	Sample size		Age (experimental/control group)	Gender (male/female)	Intervention		Interventions duration	Outcome measurement
			Experimental group	Control group			Experimental group	Control group
Qiao, 2020	RCT	China	36	36	66.27 ± 8.47/65.85 ± 7.82	33/39	Low frequency rTMS combined with pramipexole therapy	Pramipexole treatment	12 wk	*,†
Song et al, 2019	RCT	China	28	28	64.05 ± 8.29/62.37 ± 7.42	39/17	rTMS combined with pramipexole therapy	Pramipexole treatment	4 wk	*,∥,¶,††,‡‡
Dai et al, 2021	RCT	China	40	40	60.78 ± 7.02/61.10 ± 6.44	39/41	High frequency rTMS combined with pramipexole therapy	Pramipexole treatment	4 wk	†,∥
Shi et al, 2024	RCT	China	51	51	71.21 ± 4.57/70.16 ± 4.38	51/51	rTMS combined with pramipexole therapy	Pramipexole treatment	8 wk	*,†,∥,††,§§,∥,∥,¶¶
Zhu et al, 2018	RCT	China	57	57	62.37 ± 5.18/63.20 ± 5.34	73/41	High frequency rTMS combined with pramipexole therapy	Pramipexole treatment	6 wk	*,‡,§
Li et al, 2022	RCT	China	30	30	62.36 + 9.26/60.87 + 8.93	36/24	rTMS combined with pramipexole therapy	Pramipexole treatment	12 wk	*,§§,§,∥,∥,¶¶
Wang, 2019	RCT	China	37	37	65.08 ± 8.81/64.81 ± 9.13	42/32	High frequency rTMS combined with pramipexole therapy	Pramipexole treatment	8 wk	*,§
Qin et al, 2024	RCT	China	46	46	63.9 ± 7.2/64.5 ± 6.7	65/27	rTMS combined with pramipexole therapy	Pramipexole treatment	12 wk	∥,#,*,*
Qin, 2023	RCT	China	48	48	73.56 ± 4.54/73.09 ± 4.02	52/44	rTMS combined with pramipexole therapy	Pramipexole treatment	8 wk	*,†
Shao et al, 2021	RCT	China	47	47	67.03 ± 8.16/66.87 ± 7.94	57/37	Low frequency rTMS combined with pramipexole therapy	Pramipexole treatment	24 wk	‡,∥
Guo, 2021	RCT	China	33	32	62.02 ± 6.79/60.71 ± 7.38	47/18	Low frequency rTMS combined with pramipexole therapy	Pramipexole treatment	4 wk	*,¶,*,*
Ma, 2023	RCT	China	45	45	65.14 ± 4.51/64.62 ± 4.15	47/43	Low frequency rTMS combined with pramipexole therapy	Pramipexole treatment	3 wk	*,†,¶,#,‡‡,¶¶

^*PD comprehensive rating scale (UPDRS).

^†Adverse reaction rate.

^‡Montreal cognitive assessment scale (MoCA).

^§Measured mental state exercise (MMSE).

^∥Hamilton depression scale (HAMD).

^¶PD autonomic dysfunction scale (SCOPA-AUT).

^#PD sleep scale (PDSS).

^**Parkinson’s disease quality of life questionnaire (PDQ)-39.

^††Social functioning scale (FAQ).

^‡‡Non-motor symptom screening questionnaire (NMSQuest).

^§§Upper extremity functioning score (STEF).

^∥∥lower extremity balance functioning scale (BBS).

^¶¶Modified assessment of muscle tone scale (MAS).

RCT = randomized controlled trial, rTMS = repetitive transcranial magnetic stimulation.

3.2. Quality assessment of the included literature

All of the 12 included papers referred to “randomized” or “randomized controlled trials,” all of which were randomized controlled trials (RCTs), and 8 of which referred to specific randomization methods such as random number tables or computer-generated random numbers^{[7,9,10,12,13,15–17]}; no selective reporting or incomplete data existed in any of the included literature, none mentioned other sources of bias, and all were at low risk. Therefore, the overall quality of literature included in the study was high. The specific distribution of risk of bias and results of the included literature are shown in Figures 1 and 2, respectively. Specific quality of data assessments are shown in Figure 3. The level of evidence was evaluated for each outcome included in the meta-analysis. The results showed that the 2 outcomes, clinical efficacy and depression level, were of moderate-quality evidence. Six outcomes – adverse reaction rate, cognitive function, social function, upper limb function, balance function of the lower limbs, and muscle tone – were of low-quality evidence. There is very-low-quality evidence for autonomic function, sleep quality, and quality of life.

Figure 1.

Distribution of risk of bias in the included literature.

Figure 2.

Risk of bias results for the included literature.

Figure 3.

Assessment of the quality of data for inclusion in the literature. CI = confidence interval,MD = Mean Differenc, OR = odds ratio, rTMS = repetitive transcranial magnetic stimulation.

3.3. Meta-analysis results

3.3.1. Clinical efficacy

A total of nine studies were included,^{[5,8,9,12–17]} including 729 patients, and the heterogeneity test showed, P = .99, I² = 0%, suggesting that the heterogeneity among the studies was small, and therefore, it was calculated by using a fixed-effects model. The analysis showed better overall clinical efficacy in the experimental group compared to the control group (OR = 4.58, 95% CI: 2.91–7.19, P < .0001), see Figure 4

Figure 4.

Comparison of the overall clinical efficacy of rTMS combined with pramipexole treatment group and the pramipexole treatment group. CI = confidence interval, rTMS = repetitive transcranial magnetic stimulation.

3.3.2. Adverse reaction rate

A total of 5 studies were included,^{[5,8,10,13,16]} including 440 patients, and the heterogeneity test showed, P = .26, I² = 24%, suggesting that the heterogeneity among the studies was small, and therefore, it was calculated by using a fixed-effects model. The results of the analysis showed a lower rate of adverse effects in the experimental group compared to the control group and a good clinical safety profile (OR = 0.77, 95% CI: 0.40–1.46, P = .42), see Figure 5

Figure 5.

Comparison of overall adverse effects in rTMS combined with pramipexole treatment group versus the pramipexole treatment group. CI = confidence interval, rTMS = repetitive transcranial magnetic stimulation.

3.3.3. Cognitive function

A total of 4 studies were included,^[9,11,14,15] including 342 patients, and the heterogeneity test showed, P = .26, I² = 25%, suggesting that the heterogeneity between studies was small, so it was calculated by using a fixed-effects model. The results of the analysis showed better cognitive functioning of the patients in the experimental group compared to the control group (Mean Difference = 2.23, 95% CI: 1.91–2.54, P < .0001).

3.3.4. Depression level

A total of 5 studies^{[5,7,10,11,17]} including 424 patients were included, and the heterogeneity test showed, P = .47, I² = 0%, suggesting that the heterogeneity among the studies was small, and therefore, it was calculated by using a fixed-effects model. The analysis showed that patients in the experimental group were less depressed compared to the control group (Mean Difference = −2.22, 95% CI: −2.71 to −1.72, P < .0001)

3.3.5. Autonomic function

A total of 3 studies^[8,12,17] including 211 patients were included. The heterogeneity test showed, P = .03, I² = 73%, suggesting that there was a large heterogeneity among studies. After excluding the literature of Guo F,^[12] I² = 0%, suggesting that the heterogeneity might be originated from this literature. It was calculated by using a random effects model. The results of the analysis showed better autonomic function in the experimental group of patients compared to the control group (Mean Difference = −1.54, 95% CI: −2.13 to −0.95, P < .0001)

3.3.6. Sleep quality

A total of 2 studies were included,^[7,8] including 182 patients, and the heterogeneity test showed, P = .07, I² = 70%, suggesting a large heterogeneity among the studies (Mean Difference = 1.45, 95% CI: 0.64–2.25, P = .0004).

3.3.7. Quality of life

A total of 2 studies were included,^[7,12] including 157 patients, and the test of heterogeneity showed, P = .59, I² = 0%, suggesting that the heterogeneity between studies was small, so it was calculated by using a fixed-effects model. The analysis showed better quality of life of patients in the experimental group compared to the control group (Mean Difference = −5.85, 95 % CI: −8.08 to −3.63, P < .00001).

3.3.8. Social function

A total of 2 studies were included,^[5,17] including 158 patients, and the test of heterogeneity showed, P = .45, I² = 0%, suggesting that the heterogeneity between studies was small, so it was calculated by using a fixed-effects model. The analysis showed better social functioning of the patients in the experimental group as compared to the control group (Mean Difference = −2.64, 95% CI: −3.09 to −2.19, P < .00001)

3.3.9. Non-motor symptoms

A total of 2 studies were included,^[8,17] including 146 patients, and the test of heterogeneity showed, P = .61, I² = 0%, suggesting that the heterogeneity between studies was small, and therefore, it was calculated by using a fixed-effects model. The results of the analysis showed that patients in the experimental group had milder non-motor symptoms compared to the control group (Mean Difference = −1.29, 95% CI: −1.97 to −0.60, P = .0002).

3.3.10. Gait indicators

A total of 3 studies were included,^[5,8,9] including 252 patients, comparing the scores of upper limb function in each experiment, and the test of heterogeneity showed, P = .80, I² = 0%, suggesting that the heterogeneity between studies was small, so it was calculated by using a fixed-effects model. Analysis of the results showed better upper limb function in the experimental group of patients compared to the control group (Mean Difference = 6.34, 95% CI: 2.66–10.02, P < .00001).

Comparing the scores of lower limb balance function in each experiment, the test of heterogeneity showed, P = .70, I² = 0%, suggesting that the heterogeneity between studies was small, so it was calculated by using the fixed effect model. The results of the analysis showed better lower limb balance function in the experimental group of patients compared to the control group (Mean Difference = 4.59, 95% CI: 2.37–6.80, P < .0001).

Comparing the scores of muscle tone in each experiment, the test of heterogeneity showed, P = .52, I² = 0%, suggesting that the heterogeneity between the studies was small, so it was calculated by using a fixed-effects model. Comparing the scores of muscle tone in each experiment, the test of heterogeneity showed, P = .52, I² = 0%, suggesting that the heterogeneity between the studies was small, so it was calculated by using a fixed-effects model (Mean Difference = −0.14, 95% CI: −0.19 to −0.09, P < .00001), see Table 3

Table 3.

Secondary outcome indicators.

Endpoint		Included studies	Heterogeneity test		Effect model	Meta-analysis results
			I2-value	P-value		Mean difference (95% CI)	P-value
Cognitive function		4[9,11,14,15]	25	.26	Fixed	2.23 (1.91–2.54)	<.0001
Depression level		5[5,7,10,11,17]	0	.47	Fixed	−2.22 (−2.71 to −1.72)	<.0001
Autonomic function		3[8,12,17]	73	.03	Random	−1.54 (−2.13 to −0.95)	<.0001
Sleep quality		2[7,8]	70	.07	Fixed	1.45 (0.64–2.25)	.0004
Quality of life		2[7,12]	0	.59	Fixed	−5.85 (−8.08 to −3.63)	<.00001
Social function		2[5,17]	0	.45	Fixed	−2.64 (−3.09 to −2.19)	<.00001
Non-motor symptoms		2[8,17]	0	.61	Fixed	−1.29 (−1.97 to −0.60)	.0002
Gait indicators	Upper limb function	2[5,9]	0	.80	Fixed	6.34 (2.66 to 10.02)	<.00001
	Balance function of the lower limbs	2[5,9]	0	.70	Fxed	4.59 (2.37 to 6.80)	<.0001
	Muscle tone	3[5,8,9]	0	.52	Fixed	−0.14 (−0.19 to −0.09)	<.00001

CI = confidence interval.

3.4. Sensitivity analysis

Although the included studies were of high quality, the sample size was small, and therefore sensitivity analyses were performed by excluding individual RCTs one by one. The results showed that none of the combined results changed significantly after the exclusion of the individual studies, thus demonstrating good stability of the results.

3.5. Publication bias

In this study, a funnel plot analysis was performed on RCTs of the change relative to baseline in the total effective rate of treatment of PD in the 2 groups of patients, and the results suggested that the scatter points of the funnel plots of the included studies were basically symmetrically distributed, suggesting that there was no significant publication bias, see Figure 6.

Figure 6.

Funnel plot of treatment efficacy rates for the 2 groups of patients.

3.6. Trial sequential analysis (TSA)

TSA 0.9.5.10 Beta software (Copenhagen Trial Unit, Copenhagen, Denmark) was used for trial sequential analysis, with clinical comprehensive efficacy as the index, limiting the probability of type I error to α = 0.05, the information axis is the cumulative sample size of the included studies, and the statistical efficacy was set at 0.8, while the desired information value (required information size, RIS) is the sample size required for this meta-analysis. The TSA results showed that the Z curve crossed both the traditional boundary value and the TSA boundaries, suggesting that the benefit of clinical integrated efficacy of rTMS combined with pramipexole for PD is superior to that of the control group has a definite and conclusive effect, and that the relevant study can be terminated in time to save social resources, see Figure 7.

Figure 7.

Trial sequential analysis for the clinical efficacy of rTMS combined with pramipexole in the treatment of PD. RIS = required information size, rTMS = repetitive transcranial magnetic stimulation.

4. Discussion

PD is a common neurodegenerative disorder that affects nearly 10 million people worldwide and imposes a considerable medical burden on society and families.^[18] However, due to the complexity of its pathomechanisms, the current treatment of PD mostly uses a single drug therapy to alleviate patients’ symptoms, which is prone to cause tolerance to the drugs, which decreases their efficacy, and the long-term use of these drugs may lead to complications, such as levodopa-induced dyskinesia, which reduces the quality of life of PD patients.^[19] Therefore, there is an urgent need for new therapeutic strategies in clinical practice to improve the clinical therapeutic effects of PD patients by actively adopting combination therapy on the basis of drug therapy.^[17] rTMS can improve neurotransmission and promote synaptic plasticity of neurons in specific regions of the brain by modulating their neural excitability, a mechanism that can improve patients’ cognition, such as attention, memory, and executive function.^[1] Thus, rTMS is a promising noninvasive brain stimulation technique that is well tolerated, painless, has minimal side effects, and has a very positive impact on PD,^[20] and has shown significant efficacy in improving motor and cognitive rehabilitation and depression in PD.^[21] Pramipexole is a novel non-ergot alkaloid DA receptor agonist that selectively activates DA D2 and D3 receptors and can provide high bioavailability and long-lasting effects.^[22] On the one hand, the drug can bind to highly selective D2 receptors, inhibit the induction of DA cells by matrix metalloproteinases, and can improve DA function by activating striatal DA receptors; on the other hand, it can selectively bind to D3 receptors and reduce the degree of depression, anxiety, and other adverse emotions in patients.^[23] And pramipexole has a long half-life, which can persistently act on DA receptors, avoiding damage to DA and nigrostriatal nerve cells, which is conducive to the relief of the disease.^[24] Combining rTMS with pramipexole to exert its synergistic effect can effectively improve clinical efficacy and clinical symptoms of patients.

This meta-analysis focuses on the less previously studied combination of rTMS with medication for PD, and examines whether rTMS combined with pramipexole therapy is more advantageous than pramipexole therapy alone for PD. In terms of safety, the incidence of adverse reactions in the rTMS combined with pramipexole treatment group was lower than that in the pramipexole group alone, suggesting that the combined rTMS group was safer than the single-use pramipexole treatment group. Seppänen et al^[25] showed that pramipexole treatment of PD did not increase the relative risk of any adverse events, serious adverse events, or adverse events leading to discontinuation of the medication compared with placebo. In addition, Fernandes et al^[26] have shown that rTMS is a noninvasive brain stimulation technique, which acts on the cerebral cortex through pulsed magnetic fields, and does not involve surgery or systemic medication, thus providing a high degree of safety. Chronic neuroinflammation is an important causative factor of cognitive dysfunction in PD, and Ye ^[27] showed that pramipexole can alleviate oxidative stress and significantly reduce the body’s inflammatory response. Wang et al^[28] showed that rTMS of the supplementary motor area or dorsolateral prefrontal cortex promotes striatal and prefrontal DA release, both of which improve cognitive deficits in PD patients. Ostadhadi^[29] and others have shown that pramipexole has a high affinity for DA D3 receptors, which are mainly distributed in the limbic system and are involved in emotion regulation and reward pathways, and that activation enhances DA transmission and improves depression-related symptoms. Xiong et al^[30] showed that rTMS acts on the left dorsolateral prefrontal cortex through high frequency stimulation, activates the cortico-striatal-nigrostriatal loop, and indirectly promotes the activity of nigrostriatal DA neurons, which compensates for the DA deficit in patients with PD and thus improves the depressive symptoms. Pu et al^[31] showed that pramipexole can increase the excitability of DA receptors, impede impaired neurological function, and promote the recovery of motor function; at the same time, rTMS is also able to significantly improve the motor symptoms of patients with PD, and the restoration of motor function makes it easier for patients to participate in daily activities, and enhances self-care ability and social participation.

In conclusion, rTMS combined with pramipexole treatment has significant efficacy in terms of overall improvement of PD, improvement of cognitive function, improvement of depression level, improvement of social function, improvement of non-motor symptoms, and improvement of gait.

4.1. Limitations of this study

The sample sizes of the included studies were small and some were short-term follow-ups with a lack of long-term data and volatility. Some of the literature included in the study was of poor quality and did not specify allocation concealment and blinding implementation. Large differences in study design (e.g., different parameters of rTMS) may introduce some bias into the study. There was significant heterogeneity among some of the included studies, with the source of heterogeneity being mainly the small sample size, which may have had some impact on the accuracy of the results.

4.2. Future research directions

Multicenter, double-blind RCTs with larger samples and long-term follow-up are needed as a way to optimize stimulation parameters, personalize treatment strategies for patients, and further confirm the efficacy and safety of rTMS combined with pramipexole. More multicenter collaborations are expected in the future to deepen and validate the feasibility of the findings.

5. Conclusion

Existing research data show that rTMS combined with pramipexole treatment can significantly control the symptoms of PD, accelerate the healing of the disease, can reduce the chances of adverse reactions in patients with PD, better than the clinical effect of single pramipexole treatment, and the safety of the drug is higher.

Author contributions

Conceptualization: Jinyu Geng, Xiaobei Wang.

Data curation: Jinyu Geng.

Formal analysis: Jinyu Geng, Xiawei Ren.

Investigation: Jinyu Geng.

Methodology: Jinyu Geng.

Project administration: Jinyu Geng, Xiaobei Wang.

Software: Jinyu Geng.

Supervision: Xiaobei Wang.

Validation: Xiawei Ren.

Visualization: Xiawei Ren.

Writing—original draft: Jinyu Geng, Xiaobei Wang.

Writing—review & editing: Jinyu Geng, Xiaobei Wang, Xiawei Ren.