Low frequency repetitive transcranial magnetic stimulation improves motor dysfunction after cerebral infarction.

Low frequency (≤ 1 Hz) repetitive transcranial magnetic stimulation (rTMS) can affect the excitability of the cerebral cortex and synaptic plasticity. Although this is a common method for clinical treatment of cerebral infarction, whether it promotes the recovery of motor function remains controversial. Twenty patients with cerebral infarction combined with hemiparalysis were equally and randomly divided into a low frequency rTMS group and a control group. The patients in the low frequency rTMS group were given 1-Hz rTMS to the contralateral primary motor cortex with a stimulus intensity of 90% motor threshold, 30 minutes/day. The patients in the control group were given sham stimulation. After 14 days of treatment, clinical function scores (National Institute of Health Stroke Scale, Barthel Index, and Fugl-Meyer Assessment) improved significantly in the low frequency rTMS group, and the effects were better than that in the control group. We conclude that low frequency (1 Hz) rTMS for 14 days can help improve motor function after cerebral infarction.

RCT Entities:   Population Interventions Outcomes

Introduction

Cerebral infarction is a common and frequently occurring disease, with high mortality and disability rates. As a consequence, improving motor function in patients with cerebral infarction has become a focus in basic and clinical research. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive painless treatment that can affect the excitability of the cerebral cortex and effect changes in synaptic plasticity, which in turn enhance the recovery of neurological function (Hendricks et al., 2002; Rodger and Sherrard, 2016).

This study investigated the effect of 1-Hz low frequency rTMS on the recovery of motor function by analyzing neurological function scores in patients with subacute cerebral infarction.

Subjects and Methods

Subjects

Twenty patients with cerebral infarction combined with hemiparalysis were chosen from June 2012 to December 2012 in the Department of Rehabilitation Medicine, Xuanwu Hospital, Capital Medical University, China. Patients were collected in accordance with cerebral infarction standards. The 20 patients were randomly divided into a low frequency rTMS group (n = 10; 9 males; age: 64.8 ± 9.5 years) and a control group (n = 10; 8 males; age: 65.2 ± 9.7 years). All patients were right-handed. The study was approved by the Ethical Committee of Capital Medical University Xuanwu Hospital.

Inclusion criteria

Patients meeting all the following criteria were included in the study: (1) cerebral infarction of the internal carotid artery that was diagnosed based on clinical symptoms and signs, cranial computed tomography, or magnetic resonance imaging; (2) unilateral limb dysfunction resulting from unilateral cortical damage; (3) first-time stroke; (4) age range: 35–80 years; (5) signed informed consent before treatment by the patients and their families.

Exclusion criteria

Patients meeting any of the following criteria were excluded from the study: (1) use of cardiac pacemakers, implantable defibrillator, or other similar equipment; (2) presence of cerebral hemorrhage, subarachnoid hemorrhage, or transient ischemic attack; (3) worsening of the illness or emergence of new infarctions; (4) medical history of epilepsy; (5) failure of the heart, liver, lung, kidney, or other important organs; (6) severe cognitive or communicative barriers.

rTMS

rTMS was delivered with a Magstim Rapid stimulator (The Magstim Company, Ltd., Carmarthenshire, UK). The figure-8-shaped stimulating coil had a coil diameter of 70 mm. The site of stimulation, parameters, and motor threshold for the rTMS were set according to a previous study (Rossi et al., 2009). Stimulation frequency was 1 Hz and the intensity was 90% of motor threshold. The stimulation site was the contralateral primary motor cortex (M1) contralateral to the infarction. Continuous stimulation was delivered daily in one 30-minute session for 14 days. A total of 1,800 pulses were administered each day. In the control group, patients were given 30 minutes of sham stimulation once per day. Patients were able to hear magnetic stimulator, but did not receive any real magnetic stimulation. Rehabilitation training (exercise) was conducted twice a day for each group, with each session lasting 40 minutes. Therapeutic responses and adverse reactions were observed during all treatments.

Neurological assessment

Neurological function was scored in each group before the experiment and after 14 days of treatment. Functions were assessed using the National Institute of Health Stroke Scale (NIHSS; Vanacker et al., 2016). Additionally, the Barthel Index (BI) was utilized to assess daily living ability and the Fugl-Meyer Assessment (FMA) was employed to evaluate motor function of the limbs (Wei et al., 2011; Kaushal et al., 2014).

Statistical analysis

Data were analyzed using SPSS 17.0 software (SPSS, Chicago, IL, USA). Intergroup comparison was done by independent samples t test or paired t test. A mixed-effect model was used to analyze the influence of confounding factors. The dependent variables were NIHSS, BI, and FMA. The fixed effects were age, sex, course of disease, hypertension, diabetes, coronary heart disease, smoking, and drinking. Significance was set at P < 0.05.

Results

Baseline data

None of the patients had new clinical symptoms. Before the experiment, NIHSS, BI, and FMA scores did not differ significantly between the two groups (P > 0.05; and Tables , ).

Flow chart of the study.

Effect of low frequency rTMS on the recovery of motor function

Fourteen days after treatment, NIHSS scores significantly decreased, BI and FMA scores significantly increased in each group (P < 0.01). Further, NIHSS scores significantly decreased and BI and FM scores significanty increased in the low frequency rTMS group than in the control group (all P < 0.05; Tables , ).

Multivariate analysis results

The dependent variables were, NIHSS, BI, and FMA. The analysis showed that none of the factors (age, gender, duration, hypertension, diabetes, coronary heart disease, smoking, or drinking) significantly affected FMA, NIHSS and BI scores (P > 0.05).

Adverse reaction

None of the patients had any severe adverse reactions such as recurrent stroke or seizures. One individual in the low frequency rTMS group experienced dizziness, but the symptoms disappeared soon after treatment.

Discussion

The interhemispheric competition theory suggests that some motor function deficits in patients after stroke result from the loss of inhibition to the cortex contralateral to the injury (Hiscock et al., 2008). rTMS can help achieve regional cortical reorganization of function through the regulation of cortical excitability, which affects neural function (Reis et al., 2008; Liu and Liu, 2015; Hara et al., 2016). The effect of stimulation depends on the frequency and intensity of the stimulation. Generally, low rTMS (less than 1 Hz) can inhibit cortical excitability in the stimulated hemisphere (Murase et al., 2004), facilitate excitatory interhemispheric balance, increase contralateral hemisphere excitability, or reduce the excitability of the contralateral hemisphere to promote the recovery of motor function (Gao et al., 2010; Feng et al., 2016). The results indicated that they led to significantly improved motor function in patients (Ramakrishna and Kim, 2010) and indirectly supported the hemispheric competition theory.

Low frequency stimulation of the contralateral hemisphere not only can reduce the excitability of the contralateral cortex, but also can enhance the effect of functional exercise. Thus, all kinds of exercise training may improve motor function in patients with cerebral infarction. Kakuda et al. (2011) used low frequency rTMS (1 Hz) combined with occupational therapy in post stroke hemiplegic patients with spastic upper extremity, and found that the therapy promoted sports recovery and improved limb spasticity. In the current study, we combined low frequency (1 Hz) rTMS, delivered at 90% of motor threshold (1,800 pulses) to contralateral M1 with daily rehabilitation training. Our results showed that after 14 days of treatment, neurological function improved significantly in rTMS group than in the control group. However, Nichols-Larsen et al. (2005) reported that rTMS did not enhance the therapeutic effect of exercise therapy, possibly because of severe movement disorders in patients; in the short-term, the protocol was not enough to significantly improve motor function.

Lefaucheur (2006) believed that rTMS could promote the recovery of motor function in patients with cerebral infarction, but the duration of improvement was short and was only observed during stimulation or a few minutes afterward. A relationship between the duration and dose of stimulation and the therapeutic effect of rTMS could explain this result. However, many other studies have confirmed that rTMS also produces significant long-term effects (Fitzgerald et al., 2006; Chang et al., 2010). Khedr et al. (2010) studied the long-term effects of two different rTMS frequencies on motor stroke and found that rTMS stimulation significantly improved motor function.

Here, the long-term efficacy of rTMS has been confirmed. Because the brain is a functional network, the absence of motor function after cerebral infarction is not only associated with the local impairments that are directly related with the affected side or its related corticospinal tract, but it is also associated with corticospinal tract integrity and the whole brain. When local brain damage occurs, the network of non-damaged areas is activated, and compensation can gradually occur to alleviate the deficits. Different brain regions, such as dorsal premotor cortex, ventral premotor cortex, supplementary motor area, and top posterior cortex, contribute to the recovery of motor function. Moreover, rTMS promotes the functional reconstruction of the brain neural network, and plays a lasting regulatory role in modulating cortical excitability at the stimulation site and remote areas (Gilio et al., 2003; Quartarone et al., 2005).

In conclusion, low frequency rTMS is useful because it is painless, safe to use, convenient, and because it facilitates motor function recovery in patients with ischemic stroke.

Table 1

Changes in NIHSS, BI, and FMA scores for each group

Table 2

Multivariate analysis of factors that might influence post-treatment motor function (P value)