Effects of repetitive transcranial magnetic stimulation combined with functional electrical stimulation on hand function of stroke: A randomized controlled trial

Abstract

BACKGROUND:

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has been widely used for hand function recovery in patients with subacute and chronic stroke.

OBJECTIVE:

To observe the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) combined with functional electrical stimulation (FES) on hand function recovery during convalescence of stroke.

METHODS:

Patients were divided into3 groups of 20 patients in each. All patients received routine training. rTMS group was treated with low-frequency repetitive transcranial magnetic stimulation (rTMS). FES group received functional electrical stimulation (FES) therapy. Observation group was treated with low-frequency rTMS and FES. The changes of TMS-MEP in the 3 groups were observed at the time of enrollment and after 2 courses of treatment, respectively, and the total active activity of fingers (TAM) and Fugl-Meyer assessment (FMA) rating scale were evaluated in wrist and hand parts.

RESULTS:

The amplitude of TMS-MEP was significantly higher than that of FES group. FMA score and TAM score in the observation group were significantly better than that of rTMS group and FES group.

CONCLUSION:

Low-frequency rTMS combined with FES treatment can effectively improve the range of motion of fingers, and significantly improve the grasp, pinching and other functions of hands.

Keywords

Low-frequency repetitive transcranial magnetic stimulation functional electrical stimulation stroke hand function

1 Introduction

Stroke, also called cerebrovascular accident (CVA), is a common disease that endangers human health, and its disability rate is still high (Feigin et al., 2015). According to the investigation of the World Health Organization, more than half of stroke patients suffer from hand dysfunction (Dobkin, 2005), which seriously affects the patients’ daily life. Studies have confirmed that the best time window for hand function recovery is around 12 weeks after stroke, and targeted recovery treatment in the window period is particularly important to promote the recovery of patients’ hand function (Kwakkel et al., 2003).

In recent years, some domestic scholars have proposed the “central-peripheral-central” closed-loop recovery intervention model, whose concept breaks the scope of hand function recovery only belongs to occupational therapy, integrates various latest recovery treatment means, and puts forward a comprehensive treatment mode combining central intervention and peripheral intervention (Jia, 2016). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has been widely used for hand function recovery in patients with subacute and chronic stroke (Lefaucheur et al., 2020). The theoretical basis of rTMS is derived from the competitive inhibition theory of both cerebral hemispheres. Stroke will cause structural and functional changes in the cortical network of both hemispheres, and both cortices may show imbalanced activity, thus inducing the dysfunction of the affected hand (Khedr et al., 2009). Low-frequency rTMS can inhibit the excitability of the motor cortex of the healthy hemisphere and correspondingly improve the excitability of the affected hemisphere, which can be translated into increasing the amplitude of the motor evoked potential (MEP) of the affected side, and finally show the recovery of the motor function of the hand on the affected side. (Lüdemann-Podubecká et al. 2014; Nowak et al. 2009; Tosun et al., 2017). Functional electrical stimulation (FES) is a common treatment for stroke recovery, which can improve or correct organ or limb function by stimulating the site of loss of function with low-frequency pulsed electric current (Eraifej et al., 2017). The principle of FES is to make use of the electroexcitability of nerve cells. Low-frequency current acts on nerve cell membranes and can generate action potentials on neurons. As the action potential generated by electrical stimulation is the same as that generated by natural physiological state, FES can artificially control the external current stimulation to generate a nerve impulse similar to the action potential caused by natural stimulation, and generate corresponding muscle contraction to achieve the effect of exercise (Eraifej et al., 2017). FES can not only enhance the information transmission of joints and muscles, provide better motion feedback and direct stimulation of motion points, promote the transformation of type II muscle fibers into type I, and significantly increase the anti-fatigue ability of peripheral muscle fibers. Its signals can be transmitted along the afferent nerve to the spinal cord and brain at the level above the spinal cord, promoting functional reconstruction established during the learning process (Straudi et al. 2020; Howlett et al., 2015). rTMS belongs to central intervention, which can enhance the neuroplasticity of the hand control area in the brain functional area and improve the efficiency of recovery therapy. FES is a peripheral intervention, which promotes nerve re-innervation through functional strengthening training and feedback center. They complement each other and can effectively promote functional recovery.

At present, even if guidelines recommend the combined use of different treatment methods in hand function recovery of stroke patients (Lefaucheur et al., 2020), few clinical studies have verified their efficacy. In this study, low-frequency rTMS and FES were combined to improve hand function in convalescent patients with stroke, proving its reliable efficacy.

2 Materials and methods

2.1 Patients

Patients included in this study met the diagnostic criteria specified in the “Main Points of Diagnosis of Various Cerebrovascular diseases in China 2019” formulated by the Chinese Society of Neurology, and be confirmed by head spiral CT or head magnetic resonance imaging (MRI) (Jinsheng et al., 2019). At the same time, the patients had unilateral disease, and all had varying degrees of hand dysfunction after clinical evaluation, and the onset time was more than 3 months. In addition, the enrolled patients were required to have no cognitive impairment or communication disorder, and the MINI-Mental State Examination (MMSE) was more than 17 points (Folstein et al., 1975). Patients diagnosed with progressive or secondary stroke or with a prior history of peripheral nerve injury or peripheral neuropathy in the affected upper extremity would be excluded from the study. Patient with a personal of family history of epilepsy, severe heart, lung, liver, kidney and other organ diseases, or with pacemakers, cochlear implants and other metal implants will not be included in this study.

2.2 Study design

A total of 60 stroke patients who met the above criteria and were admitted to our department from September 2019 to November 2020 were selected. After signing the informed consent form, all patients were divided into three groups: observation, rTMS group, and FES group according to the random number method, with 20 patients in each group. All patients received routine training. rTMS group was treated with low-frequency rTMS on the basis of routine training. The FES group received FES treatment with the cooperation of occupational therapists on the basis of routine training. The observation group was treated with low-frequency rTMS and FES on the basis of routine training. All patients in the 3 groups received 4 weeks of treatment.

2.3 Routine training

The routine hand function treatment program for stroke hemiplegic was adopted, including nerve promotion technology to reduce hand muscle tension, promote wrist extension and finger extension and grasp function, activities of daily living (ADL) ability training, necessary orthopedics application, etc. Each treatment sustained 60 minutes, once a day, 6 times a week.

2.4 rTMS therapy

Low-frequency rTMS (rTMS) was performed on the M1 region of the healthy hemisphere with a standard circular coil of 9 cm and a maximum intensity of 1.5T. The intensity was 110% of the motion threshold. The stimulation frequency was 1 Hz, and the total number of pulses per treatment was 1800 times of continuous stimulation, each treatment was 30 minutes, once a day, 6 times a week.

2.5 FES therapy

The comprehensive physical therapy apparatus (BLT-5000 SERIES) made in Britain was selected. Three pairs of electrodes (6.0 cm×5.5 cm) were placed on the motion points of extensor carpi radialis longus, extensor digitorum totalis and abductor polthumbis longus respectively, with the goal of corresponding movements. The motion point was the place where the maximum muscle contraction was induced by the same stimulation. The principle is to induce muscle contraction through programmed electrical stimulation, resulting in hand grasping, side pinching and wrist flexion and extension. According to the patient’s situation, appropriate stimulation intensity and stimulation parameters were selected: Bidirectional square wave, frequency adjustment range is 10–100 Hz, pulse width adjustment range is 10–100 ms, and on/off ratio adjustment range is 1:1–1:3. The adjustment range of wave rise and wave fall is 1–2s, the range of current intensity adjustment is 10–100 mA, and the current intensity is subject to the maximum patient can tolerate 20 min each time, once a day, 6 times a week.

2.6 Efficacy assessment and observation indicators

The following assessments were performed in the 3 groups at the time of enrollment and after 2 courses of treatment respectively, and were all completed by the same therapist in the assessment room without the knowledge of the grouping of patients. In addition, investigators documented any instances of epilepsy, dizziness, and pain during treatment. Adverse reactions such as nausea and fatigue should be recorded.

2.6.1 Transcranial magnetic stimulation-motor evoked potential (TMS-MEP)

Nanjing Magnetic stimulation instrument (Magneuro60) was used. The brain hemisphere of the affected side was used as the stimulation site, the center of the circular coil was placed in the Cz region, and the abductor pollicis muscle of the affected side was used as the target muscle to measure the motor evoked potentials (MEPs). The latency and amplitude of the test results were observed to assess cortical excitability of the affected side. To reduce error, each patient was tested at the same site and target muscle (Rossini et al., 2015).

2.6.2 Total activemotion (TAM) assessment

TAM was measured using the TAM systematic evaluation method recommended by the American Society of Hand Surgeons in 1975. The specific method is to measure the active flexion activity of the distal, proximal and metacarpophalangeal joints and the elongation during extension, and then calculate the TAM value. The formula is as follows: FMA = Active flexion motion of the distal, proximal and metacarpophalangeal joints (extension of active extension of distal, proximal and metacarpophalangeal joints). The normal value of TAM is 270°, and the evaluation results can be divided into four grades: The TAM value greater than 90% of the healthy side was considered as excellent, and 4 points were scored. TAM value greater than 75% of the healthy side was considered as good, and 3 points were recorded. When TAM value was more than 50% of the healthy side, it was considered acceptable and 2 points were recorded. When TAM value is less than 50% of the healthy side, it is considered as poor, and 1 point will be recorded.

2.6.3 Fugl-Meyer assessment (FMA) wrist and hand parts

The content includes the wrist and hand parts of Fugl-Meyer rating scale, including lateral wrist stability, finger joint flexion and extension, finger joint extension and finger pinch and grip strength. There are 12 items in total, and each item is divided into 0, 1 and 2 points according to the completion, and the total value is 24 points (Gladstone et al., 2002).

2.7 Sample size

The sample size was established by considering the Fugl-Meyer assessment (FMA) wrist and hand parts as a primary outcome and was based on the following assumptions: significance level (α) = 0.05,(2) type 2 error (β) = 0.2, and 80% test power. For sample calculation, G^*Power 3.1.9 was used based on an effect size of 0.8 (a large effect size according to Cohen). The calculated sample size was 19 patients per group. Considering a 5% dropout rate, a minimum total sample of 60 patients (20 per group) was required.

2.8 Statistical analysis

IBM SPSS v26.0 statistical software (IBM Corp., Armonk, NY, USA) was used for statistical analysis of the obtained data. Not all data fit the normal distribution, one-way analysis of variance was used when the measurement data met the normal distribution and homogeneity of variance, and Bonferroni test was used for pair comparison. When the measurement data were not normally distributed, Kruskal Wallis rank sum test was used, and Mann-Whitney U test was used for comparison between the two groups. The count data were tested by x² test. Statistical analysis was performed using a two-sided test. P < 0.05 indicated that the difference was statistically significant.

3 Results

3.1 General characteristics of patients

Sixty individuals, including those who were three months after stroke onset, were recruited in this study, and all patients completed the study. The study flowchart is shown in Fig. 1. The general clinical data of the enrolled patients, including gender, age, disease course and apoplexy type showed no statistically significant difference (P > 0.05), indicating comparability. The general and clinical characteristics are summarized in Table 1.

Table 1
General data of patients in 3 groups

Observation group rTMS group FES group p value

Age, year

Mean(SD) 52.5(8.0) 54.9(11.6) 57.9(10.5) 0.252

Course of disease, day

Mean(SD) 113.3(23.5) 109.7(13.4) 109.9(12.8) 0.765

Gender, n (%) 0.367

Male 16(80) 12(60) 13(65)

Female 4(20) 8(40) 7(35)

Type of stroke, n (%) 0.231

Cerebral infarction 16(80) 13(65) 12(60)

Cerebral hemorrhage 4(20) 7(35) 8(40)

	Observation group	rTMS group	FES group	p value
Age, year
Mean(SD)	52.5(8.0)	54.9(11.6)	57.9(10.5)	0.252
Course of disease, day
Mean(SD)	113.3(23.5)	109.7(13.4)	109.9(12.8)	0.765
Gender, n (%)	0.367
Male	16(80)	12(60)	13(65)
Female	4(20)	8(40)	7(35)
Type of stroke, n (%)				0.231
Cerebral infarction	16(80)	13(65)	12(60)
Cerebral hemorrhage	4(20)	7(35)	8(40)

rTMS: Repetitive transcranial magnetic stimulation; FES: Functional electrical stimulation.

Fig. 1

Flowchart of the study.

3.2 Comparison of TMS-MEP between 3 groups before and after treatment

There was no significant difference in TMS-MEP latency between 3 groups before and after treatment (P > 0.05). Before treatment, there was no significant difference in TMS-MEP amplitude among 3 groups (P > 0.05). After treatment, the amplitude of TMS-MEP in the observation group and the rTMS group was significantly greater than that before treatment, and the difference was statistically significant (P < 0.05).The amplitude of TMS-MEP in FES group was not significantly different from that before treatment (P > 0.05).Comparison between groups showed that the amplitude of TMS-MEP in the observation group was significantly higher than that in the FES group, with statistical significance (P < 0.05). The specific data are shown in Table 2.

Table 2
Comparison of TMS-MEP between 3 groups before and after treatment

Observation group (n = 20) rTMS group (n = 20) FES group (n = 20) p value

Before treatment After treatment Before treatment After treatment Before treatment After treatment

Incubation/latent period, ms 0.318

Mean(SD) 24.2(3.3) 24.6(2.4) 24.5(2.8) 25.1(2.2) 23.4(3.2) 25.3(2.2)

Amplitude, mV 0.000^*

Mean(SD) 0.5(0.1) 0.73(0.2) 0.4(0.1) 0.6(0.1) 0.5(0.1) 0.6(0.1)

	Observation group (n = 20)	rTMS group (n = 20)	FES group (n = 20)	p value
Incubation/latent period, ms							0.318
Mean(SD)	24.2(3.3)	24.6(2.4)	24.5(2.8)	25.1(2.2)	23.4(3.2)	25.3(2.2)
Amplitude, mV							0.000^*
Mean(SD)	0.5(0.1)	0.73(0.2)	0.4(0.1)	0.6(0.1)	0.5(0.1)	0.6(0.1)

Note: rTMS: Repetitive transcranial magnetic stimulation; FES: Functional electrical stimulation. TMS-ME: Transcranial magnetic stimulation-motor evoked potential; ^*P < 0.05.

3.3 Comparison of FMA score and TAM score between 3 groups before and after treatment

Before treatment, there was no significant difference in FMA score and TAM score among 3 groups (P > 0.05). After treatment, FMA score and TAM score in 3 groups were significantly improved compared with before treatment, the differences were statistically significant (P < 0.05). The FMA score and TAM score of the observation group were significantly better than those of the rTMS group and the FES group, with statistical significance (P < 0.05). See Table 3 for specific data.

Table 3
FMA score and TAM score were compared among 3 groups before and after treatment

Observation group (n = 20) rTMS group (n = 20) FES group (n = 20) p value

Before treatment After treatment Before treatment After treatment Before treatment After treatment

FMA score 0.000^*

Mean(SD) 9.9(3.8) 17.7(1.8) 10.1(3.1) 14.9(2.0) 10.1(3.2) 14.3(2.6)

TAM score 0.000^*

Mean(SD) 0.9(0.5) 2.2(0.8) 1.1(0.4) 1.6(0.8) 1.1(0.5) 1.5(0.8)

	Observation group (n = 20)	rTMS group (n = 20)	FES group (n = 20)	p value
FMA score							0.000^*
Mean(SD)	9.9(3.8)	17.7(1.8)	10.1(3.1)	14.9(2.0)	10.1(3.2)	14.3(2.6)
TAM score							0.000^*
Mean(SD)	0.9(0.5)	2.2(0.8)	1.1(0.4)	1.6(0.8)	1.1(0.5)	1.5(0.8)

Note: rTMS: Repetitive transcranial magnetic stimulation; FES: Functional electrical stimulation; TAM: Total activemotion assessment; FMA: Fugl-Meyer assessment;^*P < 0.05.

3.4 Adverse reactions

No epilepsy, dizziness, headache, nausea, fatigue and other adverse reactions occurred in the 3 groups during treatment.

4 Discussion

FMA was mainly for the evaluation of fine hand activities. As can be seen from the results, the FMA score of the observation group was significantly higher than that of the rTMS group and the FES group. However, during the FMA evaluation of patients, we noticed that the patients in the observation group had significantly improved hand joint flexion and hand grip strength compared with the other two groups, but the patients in the observation group had little difference in wrist joint stability and finger joint extension compared with the other two groups. TAM score was mainly based on active motion of patients’ hand joints. From the results, it is not difficult to see that the active joint activity of fingers in the observation group is significantly better than that in the other two groups. The above results may indicate that the combined use of rTMS and FES has certain advantages in improving patients’ hand muscle strength, but has little advantage in maintaining wrist joint stability, which needs to be confirmed by further studies.

TMS-MEP is a new technology used to monitor the integrity of descending motor conduction pathway. Its mechanism is that pulsed magnetic field generates induced current in cortical interneurons to excite cortical motor neurons, and then generates a series of excitatory postsynaptic potential (EPSP) (Rossini et al., 2015). Together, these impulses cause motor neurons to discharge. TMS-MEP amplitude reflects the excitability of cerebral cortex and pyramidal tract (Khedr et al., 2010). The amplitude of TMS-MEP in the observation group was significantly higher than that before treatment, and the amplitude of TMS-MEP in the observation group was significantly higher than that in the other two groups after treatment, suggesting that combined treatment can effectively improve cortical excitability of the affected cerebral hemisphere, change the interhemispheric inhibition state of stroke, and ultimately promote functional recovery.

This study is not without limitations. First, this study only included patients with hand dysfunction in the convalescent stage of stroke 3 months after onset, and did not observe the efficacy of patients in the subacute stage and early stages of recovery. Second, the sample size of this study was small, the study time was short, and the patients were not followed up in the long term. Third, due to the limitations of realistic conditions, functional magnetic resonance imaging (fMRI) was not used as an observation indicator to enhance persuativeness. At present, there are still few studies on the application of rTMS and other emerging recovery methods in the treatment of stroke hand function recovery in China, and the above deficiencies are expected to be further improved.

5 Conclusion

The results of this study show that, after 2 courses of treatment, TMS-MEP amplitude, and FMA score of patients in the observation group were significantly improved compared with those before treatment, and were better than those in the rTMS group and FES group, indicating that rTMS combined with FES treatment exerts a significant effect on improving the active hand activity of patients in the convalescence stage of stroke, and promoting the recovery of grasping and pinching functions. This is a significant advantage over rTMS alone or FES.

Conflict of interest

The author declare no conflict of interest.

Footnotes

Acknowledgments

The authors have no acknowledgments.

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