Repetitive transcranial magnetic stimulation for improving function after stroke

  • Review
  • Intervention

Authors


Abstract

Background

It had been assumed that suppressing the undamaged contralesional motor cortex by repetitive low-frequency transcranial magnetic stimulation (rTMS) or increasing the excitability of the damaged hemisphere cortex by high-frequency rTMS will promote function recovery after stroke.

Objectives

To assess the efficacy and safety of rTMS for improving function in people with stroke.

Search methods

We searched the Cochrane Stroke Group Trials Register (April 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), the Chinese Stroke Trials Register (April 2012), MEDLINE (1950 to May 2012), EMBASE (1980 to May 2012), Science Citation Index (1981 to April 2012), Conference Proceedings Citation Index-Science (1990 to April 2012), CINAHL (1982 to May 2012), AMED (1985 to May 2012), PEDro (April 2012), REHABDATA (April 2012) and CIRRIE Database of International Rehabilitation Research (April 2012). In addition, we searched five Chinese databases, ongoing trials registers and relevant reference lists.

Selection criteria

We included randomised controlled trials comparing rTMS therapy with sham therapy or no therapy. We excluded trials that reported only laboratory parameters.

Data collection and analysis

Two review authors independently selected trials, assessed trial quality and extracted the data. We resolved disagreements by discussion.

Main results

We included 19 trials involving a total of 588 participants in this review. Two heterogenous trials with a total of 183 participants showed that rTMS treatment was not associated with a significant increase in the Barthel Index score (mean difference (MD) 15.92, 95% CI -2.11 to 33.95). Four trials with a total of 73 participants were not found to have a statistically significant effect on motor function (standardised mean difference (SMD) 0.51, 95% CI -0.99 to 2.01). Subgroup analyses of different stimulation frequencies or duration of illness also showed no significant difference. Few mild adverse events were observed in the rTMS groups, with the most common events being transient or mild headaches (2.4%, 8/327) and local discomfort at the site of the stimulation.

Authors' conclusions

Current evidence does not support the routine use of rTMS for the treatment of stroke. Further trials with larger sample sizes are needed to determine a suitable rTMS protocol and the long-term functional outcome.

Résumé scientifique

Stimulation magnétique transcrânienne répétitive pour l'amélioration de la fonction après un AVC

Contexte

L'hypothèse a été faite que l'inhibition du cortex moteur contralésionnel non endommagé par une stimulation magnétique transcrânienne répétitive (SMTr) basse fréquence ou l'accroissement de l'excitabilité du cortex de l'hémisphère endommagé par une SMTr haute fréquence favorise la récupération fonctionnelle après un AVC.

Objectifs

Évaluer l'efficacité et l'innocuité de la SMTr dans l'amélioration de la fonction chez les personnes victimes d'un AVC.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre d'essais du groupe Cochrane sur les accidents vasculaires cérébraux (avril 2012), le registre Cochrane des essais contrôlés - Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, numéro 4), le registre des essais chinois sur les AVC (avril 2012), MEDLINE (de 1950 à mai 2012), EMBASE (de 1980 à mai 2012), Science Citation Index (de 1981 à avril 2012), Conference Proceedings Citation Index-Science (de 1990 à avril 2012), CINAHL (de 1982 à mai 2012), AMED (de 1985 à mai 2012), PEDro (avril 2012), REHABDATA (avril 2012) et CIRRIE Database of International Rehabilitation Research (avril 2012). Nous avons également effectué des recherches dans cinq bases de données chinoises, des registres d'essais en cours et des listes bibliographiques pertinentes.

Critères de sélection

Nous avons inclus des essais contrôlés randomisés comparant le traitement par SMTr à une thérapie fantôme ou à l'absence de traitement. Nous avons exclu les essais qui n'indiquaient que les paramètres de laboratoire.

Recueil et analyse des données

Deux auteurs de la revue ont sélectionné les essais, évalué leur qualité et extrait des données de manière indépendante. Nous avons résolu les désaccords par des discussions.

Résultats principaux

Nous avons inclus 19 essais, totalisant 588 patients, dans cette revue. Deux essais hétérogènes portant sur un total de 183 participants indiquaient que le traitement par SMTr n'était pas associé à une augmentation significative de l'indice de score de Barthel (différence moyenne (DM) 15,92, IC à 95 % -2,11 à 33,95). Quatre essais portant sur un total de 73 participants n'ont révélé aucun effet statistiquement significatif sur la fonction motrice (différence moyenne standardisée (DMS) 0,51, IC à 95 % -0,99 à 2,01). Les analyses en sous-groupes de différentes fréquences de stimulation ou durées de la maladie n'ont pas non plus révélé de différence significative. Quelques événements indésirables mineurs ont été observés dans les groupes affectés à la SMTr, les événements les plus fréquents étant les céphalées transitoires ou légères (2,4 %, 8/327) et une gêne locale au niveau du site de la stimulation.

Conclusions des auteurs

Les données actuelles n'étayent pas le recours systématique à la SMTr pour le traitement de l'AVC. Des essais supplémentaires avec de plus grands échantillons sont nécessaires pour déterminer un protocole de SMTr adéquat et le résultat fonctionnel à long terme.

Resumo

Estimulação magnética transcraniana repetitiva para melhora da função após acidente vascular cerebral

Introdução

Acredita-se que a estimulação magnética transcraniana repetitiva de baixa frequência (inglês: rTMS) possa ser útil na recuperação funcional cerebral após um acidente vascular cerebral (AVC). Essa intervenção atuaria suprimindo o córtex motor não danificado contrário à lesão ou aumentando a excitabilidade do córtex do hemisfério lesionado.

Objetivos

Avaliar a eficácia e a segurança da rTMS para melhorar a função cerebral de pessoas que tiveram um AVC.

Métodos de busca

As seguintes bases de dados eletrônicas foram pesquisadas: Cochrane Stroke Group Trials Register (abril de 2012), o Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), o Chinese Stroke Trials Register (abril de 2012), MEDLINE (1950 a maio de 2012), EMBASE (1980 até maio de 2012), Science Citation Index (1981 a abril de 2012), Conference Proceedings Citation Index-Science (1990 a abril de 2012), CINAHL (1982 a maio de 2012), AMED (1985 a maio de 2012), PEDro (abril de 2012), REHABDATA (abril de 2012) e CIRRIE Database of International Rehabilitation (abril de 2012). A estratégia foi complementada por busca em cinco bases de dados chinesas, em plataformas de registros de ensaios clínicos em andamento e nas listas de referências relevantes.

Critério de seleção

Foram incluídos ensaios clínicos randomizados comparando a terapia com rTMS versus placebo ou nenhuma terapia. Excluímos estudos que avaliaram apenas parâmetros laboratoriais como desfechos.

Coleta dos dados e análises

Dois revisores independentes selecionaram os estudos, avaliaram sua qualidade e extraíram os dados. As discordâncias foram resolvidas através de discussão.

Principais resultados

Incluímos 19 estudos envolvendo um total de 588 participantes. Segundo dois estudos heterogêneos que incluíram um total de 183 participantes, o tratamento com rTMS não foi associado com um aumento significativo na pontuação do índice de Barthel (diferença média (MD) 15,92, IC95% -2,11 a 33,95). Segundo quatro estudos envolvendo um total de 73 participantes, o tratamento com rTMS não produziu um efeito estatisticamente significativo na função motora (diferença média padronizada (SMD) 0,51, ICV -0,99 a 2,01). Foram feitas análises de subgrupos com diversas frequências de estimulação e com grupos com diferentes durações da doença. Essas análises de subgrupo também não encontraram nenhuma diferença significativa. Alguns eventos adversos leves foram observados nos grupos tratados com rTMS; os eventos mais comuns foram dores de cabeça leves ou transitórias (2,4%, 8/327) e desconforto local no local da estimulação.

Conclusão dos autores

As evidências atualmente existentes não apoiam o uso rotineiro de rTMS para o tratamento de pacientes com AVC. São necessários mais estudos com tamanhos amostrais maiores para se encontrar um protocolo adequado de rTMS e para avaliar o desfecho funcional a longo prazo dos pacientes tratados com essa intervenção.

Plain language summary

Magnetic brain stimulation for improving people’s functional ability after stroke

The human brain has two hemispheres. For people who have had a stroke, activity in the affected hemisphere is disrupted not only by the damage caused by the stroke itself, but also by the reaction of the unaffected hemisphere, which tries to limit the damage caused by the stroke. This limiting effect, while beneficial in the initial stage after stroke, may subsequently become detrimental as it interferes with the brain’s capacity to recover functional ability. Repetitive transcranial magnetic stimulation (rTMS) is a method of non-invasive brain stimulation that can help the affected hemisphere to repair the damage of the stroke, while decreasing the limiting effect on recovery caused by undamaged hemisphere. rTMS has been investigated in the treatment of many conditions, including depression, tinnitus and movement disorders. The aim of this review was to assess randomised controlled trials of rTMS on functional recovery in patients with stroke. We included 19 trials with a total of 588 patients in the review. We found that rTMS treatment was not associated with improved activities of daily living nor had a statistically significant effect on motor function. The current evidence is not yet sufficient to support the routine use of rTMS for the treatment of stroke.

Résumé simplifié

Stimulation magnétique crânienne pour l'amélioration de la capacité fonctionnelle des personnes victimes d'un AVC

Le cerveau humain comporte deux hémisphères. Chez les personnes ayant été victimes d'un AVC, l'activité dans l'hémisphère affecté est perturbée non seulement par les lésions dues à l'AVC proprement dit, mais également par la réaction de l'hémisphère non affecté, qui tente de limiter les dommages causés par l'AVC. Cet effet limitant, bien que bénéfique au stade initial après un AVC, peut ensuite s'avérer néfaste car il interfère avec la capacité du cerveau à récupérer sa capacité fonctionnelle. La stimulation magnétique transcrânienne répétitive (SMTr) est une méthode de stimulation non invasive du cerveau qui peut aider l'hémisphère affecté à réparer les dommages de l'AVC, tout en réduisant l'effet limitant sur la récupération causé par l'hémisphère non endommagé. La SMTr a été étudiée dans le traitement de nombreuses pathologies, notamment la dépression, les acouphènes et les troubles du mouvement. L'objectif de cette revue était d'évaluer les essais contrôlés randomisés de la SMTr sur la récupération fonctionnelle chez les patients ayant subi un AVC. Nous avons inclus 19 essais, totalisant 588 patients, dans cette revue. Nous avons constaté que le traitement par SMTr n'était pas associé à des activités améliorées de la vie quotidienne et n'avait pas un effet statistiquement significatif sur la fonction motrice. Les données actuelles ne sont pas encore suffisantes pour recommander le recours systématique à la SMTr dans le traitement de l'AVC.

Notes de traduction

Traduit par: French Cochrane Centre 3rd June, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Resumo para leigos

Estimulação magnética do cérebro para melhorar a capacidade funcional de pessoas que tiveram um derrame

O cérebro humano tem dois hemisférios. Nas pessoas que tiveram um derrame (AVC), a atividade do hemisfério lesado fica prejudicada não só pelos danos causados pelo próprio AVC, mas também pela reação do hemisfério não afetado, que tenta limitar o dano causado pelo derrame. Este efeito limitante, embora benéfico na fase inicial logo após o AVC, pode posteriormente tornar-se prejudicial porque ele interfere com a capacidade do cérebro de recuperar sua capacidade funcional. A estimulação magnética transcraniana repetitiva (rTMS) é um método de estimulação cerebral não-invasivo que pode ajudar o hemisfério afetado a reparar os danos causados pelo AVC e também controla o efeito limitante causado pelo hemisfério não lesado. A rTMS já foi estudada no tratamento de muitos problemas de saúde como a depressão, distúrbios do movimento e zumbido. O objetivo desta revisão foi avaliar estudos randomizados que testaram o rTMS na recuperação funcional de pacientes que tiveram um derrame. Esta revisão incluiu 19 estudos que envolveram um total de 588 pacientes. Chegamos à conclusão que o tratamento com rTMS não foi associado com melhora das atividades de vida diária nem modificou de forma estatisticamente significativa a função motora dos pacientes. A evidência atual ainda não é suficiente para apoiar o uso rotineiro do rTMS para o tratamento de pacientes que tiveram um derrame.

Notas de tradução

Traduzido por: Brazilian Cochrane Centre
Tradução patrocinada por: None

Background

Description of the condition

Stroke is the second most common cause of death and the leading cause of adult disability in the world. As a result of the ageing population, the burden of stroke will increase in the next 20 years (Donnan 2008). At present, there are limited effective interventions for patients with acute stroke (Langhorne 2009). Consequently, the management of most patients with stroke remains primarily focused on secondary prevention and rehabilitation (European Stroke Organisation 2009). Any intervention that enables patients to recover more rapidly or gain functional independence would have major benefits for patients and their families. In addition, brain recovery and rehabilitation will also be a prioritised field in future stroke research (Hachinski 2010).

Description of the intervention

Repetitive transcranial magnetic stimulation (rTMS) is a method of non-invasive brain stimulation that affects the cerebral cortex (Hummel 2006). Fast-oscillating magnetic fields, created by a strong electric current, penetrate human tissue painlessly and result in electrical currents in the brain that can modulate cortical excitability by decreasing or increasing it (depending on parameters of stimulation) (Fregni 2008; Rossini 2007) and potentially improve functional outcomes.

How the intervention might work

The idea of using rTMS to improve motor function in patients with stroke is based on interhemispheric inhibition, which means the contralesional hemisphere might inhibit surviving cortical motor systems by transcallosal inhibition (Murase 2004; Ward 2004). In people with stroke, activity in the affected hemisphere is disrupted not only by the damage caused by the stroke itself but also by inhibition from the unaffected hemisphere, which further reduces the excitability of the affected hemisphere. Consequently, it is assumed that a possible target for rTMS is the contralesional motor cortex or damaged hemisphere cortex, which means that suppressing the undamaged contralesional motor cortex by low-frequency rTMS or increasing the excitability of the damaged hemisphere cortex by high-frequency rTMS will promote motor recovery after stroke (Hummel 2006; Ward 2004). High-frequency rTMS refers to stimulus rates of more than 1 Hz, and low-frequency rTMS refers to stimulus rates of 1 Hz or less (Rossi 2009).

Why it is important to do this review

The use of this technique has been investigated in the treatment of many conditions, including depression (Rodriguez-Martin 2002), tinnitus (Meng 2009), movement disorders (Edwards 2008) and obsessive compulsive disorder (Rodriguez-Martin 2003). Although there are a few published studies of the clinical efficacy of rTMS on motor recovery in stroke patients (Ameli 2009; Khedr 2009; Kirton 2008; Mansur 2005; Takeuchi 2009; Yozbatiran 2009), the potential therapeutic effect of rTMS has been controversial. The aim of this review was to assess systematically all the randomised controlled trials of rTMS on functional recovery in patients with stroke to provide the best available evidence.

Objectives

To assess the efficacy and safety of rTMS for improving function after stroke.

Methods

Criteria for considering studies for this review

Types of studies

We include randomised controlled trials (RCTs) in which the authors compare rTMS therapy with sham therapy or no therapy. We excluded trials in which the authors report only laboratory parameters.

Types of participants

We include studies with participants of any age or sex after stroke, regardless of the duration of illness or severity of the initial impairment. The clinical definition of stroke was that of the World Health Organization criteria (Stroke 1989), excluding stroke mimics by computerised tomography (CT) or magnetic resonance imaging (MRI) scan.

Types of interventions

We include all trials that evaluated rTMS therapy in patients with stroke, regardless of ipsilateral or bilateral stimulation, frequency, age or duration of illness. The control interventions were sham treatment or other conventional treatment.

We investigated the following comparisons:

  1. rTMS only compared with sham treatment;

  2. rTMS add-on baseline treatment compared with sham treatment add-on baseline treatment;

  3. rTMS add-on baseline treatment compared with baseline treatment alone.

Types of outcome measures

We assessed outcomes at the end of treatment period and scheduled follow-up.

Primary outcomes

Activities of daily living, such as the Barthel index, the Functional Independence Measure, and the modified Rankin Scale.

Secondary outcomes
  1. Motor function: upper limb function (e.g. Motor Assessment Scale (MAS), Action Research Arm Test, Nine-Hole Peg Test, etc); lower limb function (e.g. changes in stride length (centimetres) or speed (time taken to walk a specific distance), Timed Up and Go Test, Rivermead Motor Assessment Scale, etc); Global motor function (e.g. MAS, Rivermead Motor Assessment Scale, etc).

  2. Death or disability.

  3. Any other impairment improvement (e.g. visual, perceptual, depression, cognition, etc).

  4. Adverse outcome (e.g. seizure, headache, dizziness, etc).

Search methods for identification of studies

See the 'Specialized register' section in the Cochrane Stroke Group module. We searched for trials in all languages and arranged translation of relevant reports published in languages other than English and Chinese.

Electronic searches

We searched the Cochrane Stroke Group Trials Register, which was last searched by the Managing Editor in April 2012 . In addition, and in collaboration with the Cochrane Stroke Group Trials Search Co-ordinator, we searched the following bibliographic databases:

  • the Chinese Stroke Trials Register (April 2012);

  • the Cochrane Central Register of ControlledTrials (CENTRAL) (The Cochrane Library 2012, Issue 4);

  • MEDLINE (1950 to May 2012) (Appendix 1);

  • EMBASE (1980 to May 2012) (Appendix 2);

  • ISI Science Citation Index (1981 to April 2012);

  • CINAHL (1982 to May 2012) (Appendix 3);

  • AMED (the Allied and Complementary Medicine Database (1985 to May 2012) (Appendix 4);

  • PEDro (Physiotherapy Evidence Database) (www.pedro.org.au/) (April 2012);

  • REHABDATA (www.naric.com/research/rehab/default.cfm) (April 2012);

  • CIRRIE Database of International Rehabilitation Research (http://cirrie.buffalo.edu/index.html) (April 2012);

  • The China Biological Medicine Database (CBM) (1978 to April 2012);

  • The Chinese National Knowledge Infrastructure (CNKI) (1979 to April 2012);

  • Chinese Science and Technique Journals Database (VIP) (1989 to April 2012);

  • Wanfang Data (www.wanfangdata.com/) (1984 to April 2012).

We also searched the following international trials registers in April 2012:

Searching other resources

In an effort to identify further published, unpublished and ongoing studies, we searched databases of conference abstracts: Conference Proceedings Citation Index Science (CPCI-S) and China Medical Academic Conferences (CMAC 1995 to present) in CMCC (Chinese Medical Current Contents) (April 2012), and all reference lists of retrieved articles.

Data collection and analysis

Selection of studies

Two review authors (ZH and DW) independently scanned the titles, abstracts and keywords of records identified from the electronic searches and excluded obviously irrelevant citations. We obtained the full text of the remaining studies and the same two authors selected studies for inclusion based on the criteria outlined previously. We resolved any disagreements through discussion with a third author (ML).

Data extraction and management

Two review authors (ZH and DW) independently extracted details of patient characteristics, methods, interventions and outcomes by using a data extraction form. We resolved disagreements through discussion with a third author (YZ). For dichotomous outcomes we extracted the number of participants experiencing the event and the total number of participants in each arm of the trial. For continuous outcomes we extracted the mean value and standard deviation for the changes in each arm of the trial along with the total number in each group.

Assessment of risk of bias in included studies

We assessed the methodological quality of selected studies as described in the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane Handbook). We created a 'Risk of bias' table and included a description and a judgement (low risk of bias, high risk of bias, or unclear risk of bias) for the following domains for each of the included studies:

  1. random sequence generation;

  2. allocation concealment;

  3. blinding of participants and personnel;

  4. blinding of outcome assessment;

  5. incomplete outcome data;

  6. selective reporting;

  7. other sources of bias.

Two review authors independently performed quality assessment; we resolved any disagreements between authors arising at any stage through discussion or with a third author.

Measures of treatment effect

We expressed results for dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI), and expressed results for continuous outcomes as mean difference (MD) if the same scale for each trial was available, or standardised mean difference (SMD) if different scales were used. For continuous outcomes, we intended to compare the change scores between groups after treatment and at the end of the follow-up period.

Unit of analysis issues

For studies with non-standard designs (e.g. cross-over trials, cluster-randomised trials), we planned to manage the data according to the Cochrane Handbook. For example, if we had found any cross-over trials, we would only have analysed the data from the first period.

Dealing with missing data

If data were missing, we contacted the investigators for additional information. If some data remained unavailable, we considered both best-case and worst-case scenarios.

Assessment of heterogeneity

We determined heterogeneity by using the I² statistic. We considered I² greater than 50% to be substantial heterogeneity (Higgins 2003).

Assessment of reporting biases

We used the funnel plot method (Egger 1997).

Data synthesis

We performed statistical analysis using RevMan 5.1 (RevMan 2013) and performed all analyses in accordance with the intention-to-treat method. We reported the results as RRs with 95% CIs for dichotomous data and as MDs or SMDs with 95% CIs for continuous data. We used a random-effects model to combine individual results. If there were no suitable studies, we planned to provide a narrative summary of the study results.

Subgroup analysis and investigation of heterogeneity

We planned a priori subgroup analyses based on:

  1. stroke type: ischaemic stroke versus intracranial haemorrhage;

  2. ipsilateral or bilateral stimulation;

  3. different frequency (low frequency or high frequency);

  4. duration of illness;

  5. severity of initial impairment;

  6. stimulus parameters.

Sensitivity analysis

We planned to perform sensitivity analyses by:

  1. excluding studies with inadequate concealment of allocation;

  2. excluding studies in which outcome evaluation was not blinded;

  3. excluding studies in which loss to follow-up was not reported or was greater than 10%;

  4. re-analysing the data by removing studies with nonstandard designs if we included these studies;

  5. re-analysing the data by removing studies with assumed values to replace missing data.

Results

Description of studies

Results of the search

After screening 2431 titles and abstracts, we retained 60 studies for further assessment. We included 19 trials involving a total of 588 participants in the review (Avenanti 2012; Barwood 2011a; Chen 2005; Du 2005; Fregni 2006; Jin 2002; Jorge 2004; Khedr 2005a; Khedr 2009a; Khedr 2010; Kirton 2007; Koch 2012; Liepert 2007; Malcolm 2006; Mansur 2005; Pomeroy 2006; Takeuchi 2008; Wang 2012; Weiduschat 2011) (see Characteristics of included studies). We excluded 34 studies (Ackerley 2010; Acket 2011; Barwood 2011; Boyd 2010; Chang 2010; Conforto 2010; Conforto 2011; Cotelli 2011; Davis 2007; Fridman 2002; Hirayama 2006; Joen 2008; Jorge 2008; Kakuda 2011; Kate 2010; Khedr 2005; Kim 2006; Kisten 2004; Lefaucheur 2004; Linsdell 2010; Meehan 2011; Nowak 2008; Nyffeler 2009; Ravindran 2003; Rektorova 2005; Routhier 2010; Sedlackova 2005; Talelli 2007a; Talelli 2007b; Tretriluxana 2009; Wang 2010; Weiduschat 2009; Yoo 2008; Yoon 2010) (see Characteristics of excluded studies). We identified and included six ongoing trials (Ackerley 2010a; ContraStim 2010; Humphreys 2010; Leker 2008; NINDS 2006; Stinear 2006) (see Characteristics of ongoing studies).

Two trials used a cross-over design with random allocation to the order of treatment sequences (Liepert 2007; Mansur 2005). However, we could not obtain outcome data from the first period of these studies, so the data for these trials could not be pooled together with the data from other studies.

One trial was awaiting classification because it was completed but no data were available.

Included studies

Characteristics of participants in included studies

The 19 included trials involved 588 participants (Avenanti 2012; Barwood 2011a; Chen 2005; Du 2005; Fregni 2006; Jin 2002; Jorge 2004; Khedr 2005a; Khedr 2009a; Khedr 2010; Kirton 2007; Koch 2012; Liepert 2007; Malcolm 2006; Mansur 2005; Pomeroy 2006; Takeuchi 2008; Wang 2012; Weiduschat 2011). One trial included paediatric stroke (10 participants), with a mean age of 13.25 years (Kirton 2007). The mean age of participants in the remaining 18 trials ranged from 53.3 to 74.8 years. The proportion of men was 30% to 80% among these trials. The time between stroke and recruitment varied from four hours to six years. Eight trials included participants with stroke within 30 days of symptom onset (Jin 2002; Khedr 2005a; Khedr 2009a; Khedr 2010; Koch 2012; Liepert 2007; Pomeroy 2006; Weiduschat 2011), and 10 trials included participants with stroke from more than one month to six years of symptom onset (Avenanti 2012; Barwood 2011a; Chen 2005; Fregni 2006; Jorge 2004; Kirton 2007; Malcolm 2006; Mansur 2005; Takeuchi 2008; Wang 2012). One trial did not report the duration of illness (Du 2005). All participants had a CT or MRI scan before treatment. People with severe medical comorbidity or at risk of epilepsy were excluded from each trial.

Interventions in included studies

See the Characteristics of included studies table for details of the interventions. Trials were categorised into comparisons of: (1) repetitive transcranial magnetic stimulation (rTMS) compared with sham treatment (Barwood 2011a; Fregni 2006; Jorge 2004; Khedr 2005a; Khedr 2009a; Khedr 2010; Kirton 2007; Koch 2012; Liepert 2007; Mansur 2005; Pomeroy 2006); (2) rTMS add-on baseline treatment compared with sham treatment add-on baseline treatment (Avenanti 2012; Malcolm 2006; Takeuchi 2008; Wang 2012; Weiduschat 2011); (3) rTMS add-on baseline treatment compared with baseline treatment alone (Chen 2005; Du 2005; Jin 2002). The frequency of rTMS ranged from 0.5 Hz to 50 Hz. The duration of treatment varied from 10 minutes to four weeks.

Outcome measures of included studies

The included trials used a large number of heterogeneous outcome measures. Five trials reported activities of daily living in survivors (Du 2005; Jin 2002; Khedr 2005a; Khedr 2009a; Khedr 2010). Eight trials reported motor function of affected extremities (Avenanti 2012; Fregni 2006; Khedr 2009a; Liepert 2007; Malcolm 2006; Mansur 2005; Pomeroy 2006; Takeuchi 2008). Other reported outcome measures included depression (Chen 2005; Du 2005; Jorge 2004), cognitive function (Fregni 2006), poststroke aphasia (Weiduschat 2011) and neglect (Koch 2012).The durations of follow-up were: three months in two trials (Avenanti 2012; Khedr 2009a), six months in one trial (Malcolm 2006) and one year in another trial (Khedr 2010). Most included trials evaluated the outcome at the end of treatment period or within one month.

Excluded studies

We excluded 34 of the 60 trials we identified (Ackerley 2010; Acket 2011; Barwood 2011; Boyd 2010; Chang 2010; Conforto 2010; Conforto 2011; Cotelli 2011; Davis 2007; Fridman 2002; Hirayama 2006; Joen 2008; Jorge 2008; Kakuda 2011; Kate 2010; Khedr 2005; Kim 2006; Kisten 2004; Lefaucheur 2004; Linsdell 2010; Meehan 2011; Nowak 2008; Nyffeler 2009; Ravindran 2003; Rektorova 2005; Routhier 2010; Sedlackova 2005; Talelli 2007a; Talelli 2007b; Tretriluxana 2009; Wang 2010; Weiduschat 2009; Yoo 2008; Yoon 2010). We excluded these trials for various reasons: non-RCT (Ackerley 2010; Hirayama 2006; Kakuda 2011; Nyffeler 2009; Talelli 2007a) or pseudo-RCT (Chang 2010; Khedr 2005; Kim 2006; Meehan 2011); the participants (Jorge 2008; Lefaucheur 2004; Rektorova 2005) or outcome measurements (Barwood 2011; Nowak 2008) or interventions (Ravindran 2003) did not meet the inclusion criteria, or the trials were confounded (Cotelli 2011). The remaining 18 excluded studies were only available as meeting abstracts that did not contain enough information to evaluate them. We therefore plan to re-evaluate them for the next version of this review (Acket 2011; Boyd 2010; Conforto 2010; Conforto 2011; Davis 2007; Fridman 2002; Joen 2008; Kate 2010; Kisten 2004; Linsdell 2010; Routhier 2010; Sedlackova 2005; Talelli 2007b; Tretriluxana 2009; Wang 2010; Weiduschat 2009; Yoo 2008; Yoon 2010).

Risk of bias in included studies

Allocation

Two trials allocated participants by using a computer random generator (Avenanti 2012; Pomeroy 2006), and two trials reported the drawing of lots to divide the treatment and control groups (Chen 2005; Du 2005). In one trial, the patient whose hospital identification number had the lowest final digit (or lowest penultimate digit, if the final digits of the two patients were the same) was assigned to rTMS treatment, the other to sham (Kirton 2007). The other included trials only reported 'randomly allocating' participants but the method of randomisation was not described (Barwood 2011a; Fregni 2006; Jin 2002; Jorge 2004; Khedr 2005a; Khedr 2009a; Khedr 2010; Koch 2012; Liepert 2007; Malcolm 2006; Mansur 2005; Takeuchi 2008; Wang 2012; Weiduschat 2011).

Five trials adequately concealed the randomisation sequence by using sealed envelopes (Khedr 2009a; Khedr 2010; Pomeroy 2006; Wang 2012; Weiduschat 2011).The concealment of the other trials was unclear.

Blinding

Sixteen trials used sham stimulation as the control group, but the success of blinding was not recorded. In these trials, three trials reported that participants, investigators and assessors were blinded (Fregni 2006; Koch 2012; Weiduschat 2011), 10 trials reported participants and assessors were blinded (Avenanti 2012; Jorge 2004; Khedr 2005a; Khedr 2009a; Khedr 2010; Kirton 2007; Liepert 2007; Malcolm 2006; Pomeroy 2006; Wang 2012), and three trials reported participants were blinded (Barwood 2011a; Mansur 2005; Takeuchi 2008). Three trials used regular treatments as the control group: of these, one trial reported assessors were blinded (Chen 2005) and two trials did not report the method of blinding (Du 2005; Jin 2002).

Incomplete outcome data

None of included trials stated that an intention-to-treat analysis had been performed. No exclusions after randomisation or losses to follow-up were reported in 13 trials (Avenanti 2012; Barwood 2011a; Chen 2005; Du 2005; Fregni 2006; Jin 2002; Jorge 2004; Khedr 2005a; Khedr 2009a; Kirton 2007; Liepert 2007; Malcolm 2006; Takeuchi 2008) for the overall outcome. In one trial, 10 of the 48 participants did not complete the follow-up. In another trial, three participants were lost to follow-up (Weiduschat 2011). Four trials reported that participants were excluded after randomisation (Koch 2012; Mansur 2005; Pomeroy 2006; Wang 2012) (see Characteristics of included studies).

Selective reporting

There was insufficient information for us to make a judgement on selective reporting.

Other potential sources of bias

The funnel plots with the greatest number of trials investigating improvement of motor function showed a slightly asymmetrical funnel distribution, which indicated that there was likely to have been some publication bias (Figure 1).

Figure 1.

Funnel plot of comparison: 1 rTMS compared with control, outcome: 1.2 Motor function.

Please see summary figures of risk of bias (Figure 2; Figure 3).

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Effects of interventions

rTMS versus control

1.1 Activities of daily living

Five trials (Du 2005; Jin 2002; Khedr 2005a; Khedr 2009a; Khedr 2010) with a total of 319 participants recorded activities of daily living but this was recorded at different time points. Data were available for 183 (57.4%, 183/319) participants (Du 2005; Jin 2002). Meta-analysis showed that rTMS treatment was not associated with a significant increase in the Barthel Index score (MD 15.92, 95% CI -2.11 to 33.95). However, there was statistically significant heterogeneity between the trials (I² = 97%) (Analysis 1.1).

1.2 Motor function

Eight trials with a total of 173 participants reported motor function of the affected extremities. However, data from four trials were available for 73 participants (42.2%, 73/173) (Fregni 2006; Khedr 2009a; Malcolm 2006; Pomeroy 2006). Meta-analysis showed that rTMS treatment was not associated with a significant improvement in motor function (SMD 0.51, 95% CI -0.99 to 2.01). However, there was statistically significant heterogeneity between trials (I² = 87.6%) (Analysis 1.2). In this analysis, we found that one study was visually totally heterogenous to the other studies (Khedr 2009a) and sensitivity analysis removing these data reduced I² to 0%, but there was also no significant effect on motor function (SMD -0.29, 95% CI -0.88 to 0.29).

1.3 Death or disability

No data on death or disability at the end of follow-up were available in any of the included trials.

1.4 Any other impairment improvement (e.g. visual, perceptual, depression, cognition, etc)

Two trials with a total of 92 participants reported depression (Chen 2005; Du 2005). Meta-analysis showed that rTMS treatment was not associated with a significant decrease in the Hamilton depression scale score (MD -0.12, 95% CI -13.84 to 13.59). However, there was statistically significant heterogeneity between the trials (I² = 96%) (Analysis 1.3).

Two trials with a total of 75 participants reported cognitive function (MMSE score) (Du 2005; Fregni 2006). Meta-analysis showed that there was no statistically significant difference between the groups (MD 1.87, 95% CI -5.93 to 9.68) (Analysis 1.4).

One trial with 20 participants reported that a two-week course of continuous theta-burst stimulation over the posterior parietal cortex of the left hemisphere may be an effective strategy in accelerating recovery from visuospatial neglect in subacute stroke patients (Koch 2012).

Another trial with 14 participants reported a clinically significant improvement in the rTMS group, with a mean of 19.8 points in the Aachen Aphasia Test total score, whereas the control group did not improve (Weiduschat 2011).

1.5 Adverse outcome

Eight trials (Du 2005; Jin 2002; Khedr 2009a; Khedr 2010; Koch 2012; Takeuchi 2008; Wang 2012; Weiduschat 2011) reported that there were no adverse effects. Six trials reported adverse outcomes: eight transient or mild headaches (2.4%, 8/327) were observed in the rTMS group (Chen 2005; Fregni 2006; Jorge 2004; Khedr 2005a); one participant reported an increase in anxiety (0.3%, 1/327) (Fregni 2006); two participants had single episodes of neurocardiogenic syncope (0.6%, 2/327) with their initial exposure to rTMS (Kirton 2007); an exacerbation of initial insomnia was observed in one participant (0.3%, 1/327) (Jorge 2004); and local discomfort at the site of the stimulation (Jorge 2004; Malcolm 2006). Five trials made no mention of adverse outcomes (Avenanti 2012; Barwood 2011a; Liepert 2007; Mansur 2005; Pomeroy 2006).

2. Subgroup analysis

2.1 Different frequency of stimulation

Subgroup analyses of different stimulation frequencies showed no significant difference between the low-frequency group and the high-frequency group in their effects on motor function (Analysis 2.1).

2.2 Different duration of illness

Subgroup analyses by duration of illness showed no significant difference between 'within 30 days of symptom onset' and 'more than one month' on motor function (Analysis 3.1).

From the available information, it was not possible to perform the originally planned sensitivity analyses because of insufficient numbers of trials.

Discussion

Summary of main results

We included 19 trials involving a total of 588 participants in this review. Two heterogenous trials (183 participants) assessing the effect of repetitive transcranial magnetic stimulation (rTMS) on activities of daily living showed that rTMS treatment was not associated with a significant increase in the Barthel Index score. Four trials assessing the effect of rTMS on motor function were not found to have a statistically significant effect on motor function. Limited data revealed rTMS may have effects on aphasia and neglect in patients with stroke. Few mild adverse events were observed in the rTMS group, with the most common events being transient or mild headaches and local discomfort at the site of the stimulation.

Overall completeness and applicability of evidence

The results of the review were limited by the following factors.

  1. The sample size was small, ranging from 10 to 123 participants, and the small number of participants in each trial may not have adequate power to detect a difference between the two groups. It is necessary to perform large-scale RCTs to verify the efficacy of the intervention. In addition, many of the trials had strict inclusion criteria, which limited the applicability.

  2. The stimulation parameters (frequency, intensity, pulses) also varied across studies. The most suitable rTMS protocol is still uncertain.

  3. Various motor function assessment measures were used as the primary outcome across the studies, but functional outcome was scarce.

  4. Most of the included trials evaluated the outcome at the end of the treatment period or within one month. Whether rTMS had long-term effects on functional recovery was not clear. The short-term follow-up could not detect the long-term effect of rTMS. In consideration of spontaneous recovery after stroke, long-term outcome measurement should be performed (three months or longer) after stroke.

  5. Although we included 19 trials in the review, we pooled the three types of controls to a single analysis instead of the three analyses planned in the Methods section, due to limited available data. For example, data from four trials were available for motor function. It was therefore not possible to assess whether there were significant differences in treatment effect in important subgroups such as low frequency compared with high frequency and acute stroke patients compared with chronic patients.

  6. There was huge heterogeneity between the studies pooled within the meta-analyses. The potential reasons for this heterogeneity were: (a) the time between stroke and recruitment varied from four hours to six years; (b) various rTMS protocols were used; and (c) different motor function assessments were used across the studies.

Quality of the evidence

The quality of reporting in general was poor. Most trials only reported 'randomly allocating' participants but the method of randomisation was not described. Only five trials adequately concealed the randomisation sequence. Although 16 trials used sham stimulation in the control group, the success of blinding was not recorded. None of included trials stated that an intention-to-treat analysis had been performed.

Potential biases in the review process

The funnel plots showed a slightly asymmetrical funnel distribution, which indicated likely publication bias. In addition, we cannot deny the possibility that there are additional trials that are unpublished or published in sources not covered by our search.

Agreements and disagreements with other studies or reviews

Recently, a systematic review indicated that rTMS had a positive effect on motor recovery in patients with stroke, and it also found low-frequency rTMS over the unaffected hemisphere may be more beneficial than high-frequency rTMS over the affected hemisphere (Hsu 2012). In contrast, we did not find rTMS to have a statistically significant effect on motor function. However, treatment with rTMS may have effects on aphasia and neglect in patients with stroke. These findings should be clarified in further studies.

Authors' conclusions

Implications for practice

Based on this review, the routine use of rTMS for patients with stroke is not recommended until its efficacy is verified in high-quality, large-scale RCTs.

Implications for research

Future studies with larger sample sizes are needed to validate this therapeutic approach. Particularly, the most suitable rTMS protocol should be investigated as a priority. In addition, functional outcome measured at long-term follow-up (at least three months or longer after stroke) should be used as the primary outcome.

Acknowledgements

We would like to thank Hazel Fraser (Managing Editor of Cochrane Stroke Group), Brenda Thomas (Trials Search Co-ordinator), attending staff of the West China Hospital, and editors of the Cochrane Stroke Group for their valuable advice on writing this review.

Data and analyses

Download statistical data

Comparison 1. rTMS compared with control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Activities of daily living2183Mean Difference (IV, Random, 95% CI)15.92 [-2.11, 33.95]
1.1 Barthel Index2183Mean Difference (IV, Random, 95% CI)15.92 [-2.11, 33.95]
2 Motor function473Std. Mean Difference (IV, Random, 95% CI)0.51 [-0.99, 2.01]
2.1 Jebsen-Taylor Hand Function Test115Std. Mean Difference (IV, Random, 95% CI)-0.16 [-1.24, 0.92]
2.2 Pegboard task124Std. Mean Difference (IV, Random, 95% CI)2.93 [1.72, 4.14]
2.3 Wolf Motor Function Test119Std. Mean Difference (IV, Random, 95% CI)-0.80 [-1.74, 0.15]
2.4 Action Research Arm Test115Std. Mean Difference (IV, Random, 95% CI)0.19 [-0.84, 1.23]
3 Depression (Hamilton Depression Scale score )292Mean Difference (IV, Random, 95% CI)-0.12 [-13.84, 13.59]
4 Cognitive function (MMSE)275Mean Difference (IV, Random, 95% CI)1.87 [-5.93, 9.68]
Analysis 1.1.

Comparison 1 rTMS compared with control, Outcome 1 Activities of daily living.

Analysis 1.2.

Comparison 1 rTMS compared with control, Outcome 2 Motor function.

Analysis 1.3.

Comparison 1 rTMS compared with control, Outcome 3 Depression (Hamilton Depression Scale score ).

Analysis 1.4.

Comparison 1 rTMS compared with control, Outcome 4 Cognitive function (MMSE).

Comparison 2. Different frequency of stimulation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Motor function473Std. Mean Difference (IV, Random, 95% CI)0.51 [-0.99, 2.01]
1.1 Low frequency354Std. Mean Difference (IV, Random, 95% CI)0.97 [-0.86, 2.79]
1.2 High frequency119Std. Mean Difference (IV, Random, 95% CI)-0.80 [-1.74, 0.15]
Analysis 2.1.

Comparison 2 Different frequency of stimulation, Outcome 1 Motor function.

Comparison 3. Different duration of illness
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Motor function473Std. Mean Difference (IV, Random, 95% CI)0.51 [-0.99, 2.01]
1.1 < 30 days of symptom onset239Std. Mean Difference (IV, Random, 95% CI)1.54 [-1.14, 4.23]
1.2 > 30 days of symptom onset234Std. Mean Difference (IV, Random, 95% CI)-0.52 [-1.23, 0.19]
Analysis 3.1.

Comparison 3 Different duration of illness, Outcome 1 Motor function.

Appendices

Appendix 1. MEDLINE (Ovid) search strategy

1. cerebrovascular disorders/ or exp basal ganglia cerebrovascular disease/ or exp brain ischemia/ or exp carotid artery diseases/ or exp intracranial arterial diseases/ or exp "intracranial embolism and thrombosis"/ or exp intracranial hemorrhages/ or stroke/ or exp brain infarction/ or vertebral artery dissection/
2. (stroke or poststroke or post-stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or apoplex$ or SAH).tw.
3. ((brain$ or cerebr$ or cerebell$ or intracran$ or intracerebral) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$)).tw.
4. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracranial or subarachnoid) adj5 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).tw.
5. hemiplegia/ or exp paresis/
6. (hemipleg$ or hemipar$ or paresis or paretic).tw.
7. exp Gait Disorders, Neurologic/
8. or/1-7
9. Transcranial Magnetic Stimulation/
10. Magnetic Field Therapy/
11. Magnetics/
12. Electromagnetic Fields/ or Electromagnetic Phenomena/
13. ((magnet$ or electromagnet$ or electro-magnet$) adj5 (stimulat$ or field$ or coil$)).tw.
14. (TMS or rTMS).tw.
15. or/9-14
16. Randomized Controlled Trials as Topic/
17. random allocation/
18. Controlled Clinical Trials as Topic/
19. control groups/
20. clinical trials as topic/ or clinical trials, phase i as topic/ or clinical trials, phase ii as topic/ or clinical trials, phase iii as topic/ or clinical trials, phase iv as topic/
21. double-blind method/
22. single-blind method/
23. Placebos/
24. placebo effect/
25. cross-over studies/
26. Therapies, Investigational/
27. Research Design/
28. evaluation studies as topic/
29. randomized controlled trial.pt.
30. controlled clinical trial.pt.
31. (clinical trial or clinical trial phase i or clinical trial phase ii or clinical trial phase iii or clinical trial phase iv).pt.
32. (evaluation studies or comparative study).pt.
33. random$.tw.
34. (controlled adj5 (trial$ or stud$)).tw.
35. (clinical$ adj5 trial$).tw.
36. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw.
37. (quasi-random$ or quasi random$ or pseudo-random$ or pseudo random$).tw.
38. (therapeutic) adj5 (trial$ or stud$)).tw.
39. ((control or experiment$ or conservative) adj5 (treatment or therapy or procedure or manage$)).tw.
40. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw.
41. (coin adj5 (flip or flipped or toss$)).tw.
42. versus.tw.
43. (cross-over or cross over or crossover).tw.
44. placebo$.tw.
45. sham.tw.
46. (assign$ or alternate or allocat$ or counterbalance$ or multiple baseline).tw.
47. controls.tw.
48. or/16-47
49. 8 and 15 and 48
50. limit 49 to humans

Appendix 2. EMBASE (Ovid) search strategy

1. cerebrovascular disease/ or basal ganglion hemorrhage/ or exp brain hematoma/ or exp brain hemorrhage/ or exp brain infarction/ or exp brain ischemia/ or exp carotid artery disease/ or cerebral artery disease/ or cerebrovascular accident/ or exp intracranial aneurysm/ or exp occlusive cerebrovascular disease/ or stroke/
2. stroke unit/ or stroke patient/
3. (stroke or poststroke or post-stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or apoplex$ or SAH).tw.
4. ((brain$ or cerebr$ or cerebell$ or intracran$ or intracerebral) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$)).tw.
5. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracranial or subarachnoid) adj5 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).tw.
6. hemiparesis/ or hemiplegia/ or paresis/
7. (hemipleg$ or hemipar$ or paresis or paretic).tw.
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. transcranial magnetic stimulation/
10. magnetic stimulation/ or magnetotherapy/ or magnetism/ or electromagnetic field/ or magnet/ or magnetic field/
11. "magnetic and electromagnetic equipment"/
12. ((magnet$ or electromagnet$ or electro-magnet$) adj5 (stimulat$ or field$ or coil$)).tw.
13. (TMS or rTMS).tw.
14. 9 or 10 or 11 or 12 or 13
15. Randomized Controlled Trial/
16. Randomization/
17. Controlled Study/
18. control group/
19. clinical trial/
20. Crossover Procedure/
21. Double Blind Procedure/
22. Single Blind Procedure/ or triple blind procedure/
23. Parallel Design/
24. placebo/
25. experimental design/ or experimental study/ or quasi experimental study/
26. experimental therapy/
27. research subject/
28. Comparative Study/
29. random$.tw.
30. (controlled adj5 (trial$ or stud$)).tw.
31. (clinical$ adj5 trial$).tw.
32. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw.
33. (quasi-random$ or quasi random$ or pseudo-random$ or pseudo random$).tw.
34. ((control or experiment$ or conservative) adj5 (treatment or therapy or procedure or manage$)).tw.
35. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw.
36. (coin adj5 (flip or flipped or toss$)).tw.
37. (cross-over or cross over or crossover).tw.
38. placebo$.tw.
39. sham.tw.
40. (assign$ or alternate or allocat$ or counterbalance$ or multiple baseline).tw.
41. controls.tw.
42. (treatment$ adj6 order).tw.
43. or/15-42
44. 8 and 14 and 43
45. limit 44 to human

Appendix 3. CINAHL search strategy

S19 .S11 and S18
S18 .S12 or S13 or S16 or S17
S17 .TI ( TMS or rTMS ) OR AB ( TMS or rTMS )
S16 .S14 and S15
S15 .TI ( stimulat* or field* or coil* ) OR AB ( stimulat* or field* or coil* )
S14 .TI ( magnet* or electromagnet* or electro-magnet* ) OR AB ( magnet* or electromagnet* or electro-magnet* )
S13 .(MH "Magnetics") OR (MH "Electromagnetics") OR (MH "Electromagnetic Fields")
S12 .(MH "Magnet Therapy")
S11 .S1 or S2 or S5 or S8 or S9 or S10
S10 .TI ( hemipleg* or hemipar* or paresis or paretic ) or AB ( hemipleg* or hemipar* or paresis or paretic )
S9 .(MH "Hemiplegia")
S8 .S6 and S7
S7 .TI ( haemorrhage* or hemorrhage* or haematoma* or hematoma* or bleed* ) or AB ( haemorrhage* or hemorrhage* or haematoma* or hematoma* or bleed* )
S6 .TI ( brain* or cerebr* or cerebell* or intracerebral or intracranial or subarachnoid ) or AB ( brain* or cerebr* or cerebell* or intracerebral or intracranial or subarachnoid )
S5 .S3 and S4
S4 .TI ( ischemi* or ischaemi* or infarct* or thrombo* or emboli* or occlus* ) or AB ( ischemi* or ischaemi* or infarct* or thrombo* or emboli* or occlus* )
S3 .TI ( brain* or cerebr* or cerebell* or intracran* or intracerebral ) or AB ( brain* or cerebr* or cerebell* or intracran* or intracerebral )
S2 .TI ( stroke or poststroke or post-stroke or cerebrovasc* or brain vasc* or cerebral vasc or cva or apoplex or SAH ) or AB ( stroke or poststroke or post-stroke or cerebrovasc* or brain vasc* or cerebral vasc or cva or apoplex or SAH )
S1 .(MH "Cerebrovascular Disorders+") or (MH "stroke patients") or (MH "stroke units")

Appendix 4. AMED (Ovid) search strategy

1. cerebrovascular disorders/ or cerebral hemorrhage/ or cerebral infarction/ or cerebral ischemia/ or cerebrovascular accident/ or stroke/
2. (stroke or poststroke or post-stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or apoplex$ or SAH).tw.
3. ((brain$ or cerebr$ or cerebell$ or intracran$ or intracerebral) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$)).tw.
4. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracranial or subarachnoid) adj5 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).tw.
5. (hemipleg$ or hemipar$ or paresis or paretic).tw.
6. hemiplegia/
7. 1 or 2 or 3 or 4 or 5 or 6
8. magnetics/ or electromagnetics/ or electromagnetic fields/
9. ((magnet$ or electromagnet$ or electro-magnet$) adj5 (stimulat$ or field$ or coil$)).tw.
10. (TMS or rTMS).tw.
11. 8 or 9 or 10
12. 7 and 11

History

Protocol first published: Issue 12, 2010
Review first published: Issue 5, 2013

DateEventDescription
1 February 2011AmendedCorrection to the 'Types of participants' section in the original protocol

Contributions of authors

Drafted the protocol: Zilong Hao, Deren Wang, Yan Zeng, Ming Liu.
Developed a search strategy: Zilong Hao, Deren Wang, Yan Zeng, Ming Liu.
Searched for trials: Zilong Hao, Deren Wang.
Obtained copies of relevant references: Zilong Hao, Deren Wang.
Selected trials for inclusion and appraised the quality of papers: Zilong Hao, Deren Wang, Ming Liu, Yan Zeng.
Extracted data from papers and data management: Zilong Hao, Deren Wang.
Wrote the review and interpreted the results: Zilong Hao, Deren Wang, Yan Zeng, Ming Liu.
The review will be updated by Zilong Hao and Deren Wang.

Declarations of interest

None known.

Sources of support

Internal sources

  • Chinese Cochrane Centre, Chinese Centre of Evidence-Based Medicine, West China Hospital, Sichuan University, China.

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Avenanti 2012

MethodsS: computer generated sequence 
C: unclear
B: participants and assessor blinded
Ex: none
Losses to FU: none
Participants

Country: Italy

30 participants
Age: unknown
Sex: unknown
Chronic stroke patients with mild motor disabilities (> 6 months after the first-ever stroke)

Interventions

Rx: participants received 10 daily sessions of 1 Hz rTMS over the intact motor cortex + before or after PT

Control: participants received sham rTMS + before or after PT

Duration: 10 days

Outcomes

Jebsen-Taylor Hand Function Test (JHFT), the Nine-Hole Peg Test (NHPT), and the Box and Block test (B&B) were used to assess hand dexterity

Maximal force of key grip and tip-pinch was evaluated by means of a pinch-meter

Outcomes were assessed for 3 months after the end of treatment
Adverse events: unclear

NotesEx: moderate to severe motor deficits, any other clinically significant medical comorbidity and epilepsy
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated sequence
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessors were blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Barwood 2011a

MethodsS: unclear 
C: unclear
B: participants blinded
Ex: none
Losses to FU: none
Participants

Australia

12 participants
Age: rTMS: mean 60.8 ± 5.98 years; control group: 67.0 ± 13.11 years
Sex: 75% male
Participants had suffered a left middle cerebral artery stroke between 2 and 6 years previously and had residual language impairments

Interventions

Rx: low frequency, 1 Hz rTMS was applied to participants for 20 minutes per day (1200 pulses)

Control: sham stimulation

Duration: 10 days

OutcomesBehavioural language outcome measures were taken at baseline and 2 months post-stimulation
Adverse events: unclear
NotesEx: epilepsy or seizures, metal anywhere in the head, cardiac pacemakers, implanted medication pumps, intracardiac lines, other serious medical conditions including serious heart disease, any medications which lower neural thresholds (tricyclic antidepressants, neuroleptic agents etc). Patients who had suffered multiple strokes were excluded due to increased risk of adverse reactions to stimulation.Those patients who had severe visual or hearing impairments were also excluded
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Chen 2005

Methods

S: drawing of lots

C: unclear
B: assessor blinded
Ex: none
Losses to FU: none

ParticipantsCountry: China
32 participants
Age: rTMS: mean 61.3 ± 4.9 years; control group: 61.2 ± 4.7 years
Sex: 59.4% male
Poststroke depression
Interventions

Rx: 0.5 Hz rTMS was given each side of the prefrontal lobe for 30 stimulations each day + regular treatment

Control: regular treatment

Duration: 7 days

OutcomesHamilton Depression Scale score at 1 week after completing the treatment phase days
Adverse events: 1 transient headache was observed in rTMS group
NotesEx: intracerebral haemorrhage; aphasic patients with severe language comprehension deficits; seizures; severe systemic disease
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskDrawing of lots
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
High riskUnblinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskThe study protocol was not available
Other biasUnclear riskNone known

Du 2005

Methods

S: drawing of lots

C: unclear
B: unblinded
Ex: none
Losses to FU: none

Participants

Country: China
60 participants
Age: mean 57.6 ± 10.8 years (range 56 to 83 years)
Sex: 56.7% male
Poststroke depression accompanied by cognitive impairment
Depression: Hamilton (24 items) ≥ 8; cognitive impairment: MMSE illiteracy ≤ 17, primary school ≤ 20, high school ≤ 24

100% CT or MRI before entry

InterventionsRx: low frequency rTMS (0.5Hz) stimulate bilateral frontal lobes with 60% of maximal stimulus intensity, 30 minutes for each side, 1 sequence every day for 5 days as a course
Control: baseline treatment alone (vasodilators, neuronutrition and fluoxetine 20mg/d for 8 weeks)
Duration: 4 weeks
OutcomesActivities of daily life: BI at 8 weeks
Hamilton Depression Scale and MMSE at 8 weeks
Adverse events: no adverse event was observed
NotesEx: coma, aphasia, history of depression or mental disorders, severe heart disease, pulmonary or renal or hepatic failure
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskDrawing of lots
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
High riskUnblinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Fregni 2006

Methods

S: unclear

C: unclear
B: participants, investigator and assessor blinded
Ex: none
Losses to FU: none

ParticipantsCountry: USA
15 participants
Age: mean 56 ± 11.5 years
Sex: 73.3% male
At least 1 year after stroke
Interventions

Rx: participants received 5 sessions of rTMS to the unaffected hemisphere over the primary motor cortex with the following parameters: intensity of 100% MT, frequency of 1 Hz, 1200 stimuli as a single, continuous train lasting 20 minutes

Control: a sham coil was placed at the same place and used the same stimulation parameters

Duration: 2 weeks

Outcomes

Jebsen-Taylor Hand Function Test (JTT), simple reaction time (sRT), choice reaction time (cRT), and Purdue Pegboard test (PTT)

Adverse events: in the active group, 1 participant reported a mild headache (contralateral to the side of TMS application) and 1 participant reported an increase in anxiety. In the sham rTMS group, 1 participant reported an increase in the tiredness and 1 participant reported a mild headache

NotesEx: any clinically significant or unstable medical disorder, a history of substance abuse, any neuropsychiatric comorbidity other than stroke, and contraindications to rTMS
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and investigator were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor was blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Jin 2002

Methods

S: unclear

C: unclear
B: unclear
Ex: none
Losses to FU: none

Participants

Country: China

123 participants
Age: rTMS: mean 64.0 ± 7.9 years; control group: 63.5 ± 7.9 years
Sex: 47.2% male
Acute ischaemic stroke (4 hours to 10 days)

Interventions

Rx: rTMS was given over the affected hemisphere once a day for 14 days + regular treatment

Control: regular treatment

Duration: 14 days

Outcomes

Fugl-Meyer score and BI were evaluated at the end of treatment

Adverse events: all the participants tolerated rTMS well without any adverse effects

NotesEx: epilepsy, brain trauma, severe heart diseases, GCS < 8 and contraindications to rTMS
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Jorge 2004

Methods

S: unclear

C: unclear
B: participants and assessor blinded
Ex: none
Losses to FU: none

ParticipantsCountry: USA
20 participants
Age: rTMS:mean 63.1 ± 8.1 years; sham rTMS: 66.5 ± 12.2 years
Sex: 55% male
Poststroke depression who do not respond to antidepressants
Interventions

Rx: receive 10 sessions of active (10 Hz, 110% of the motor threshold, 20 trains of 5 seconds duration) left prefrontal rTMS

Control: sham rTMS with the same parameters was applied with the coil angled away from the head to reproduce the noise of the stimulation as well as some local sensation.
Duration: 14 days

OutcomesHamilton Depression Scale score at 1 week after completing the treatment phase days
Neuropsychological variables at week 4
Adverse events: transient headaches; local discomfort at the site of the stimulation; an exacerbation of initial insomnia observed in 1 participant
NotesEx: severe systemic disease or an ongoing neoplasia, neurodegenerative disorders, patients with clinical evidence of dementia or aphasic patients with severe language comprehension deficits, alcohol or drug abuse during the past 12 months, seizures, major head trauma
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Khedr 2005a

Methods

S:unclear

C: unclear
Participant and assessor blinded
Ex: none
Losses to FU: none

Participants

Country: Egypt
52 participants
Age: rTMS:mean 53.5 ± 9.5 years; sham rTMS: 52.2 ± 8.2 years
Sex: 69.2% male
Acute ischaemic stroke (middle cerebral artery)

100% CT before entry

InterventionsRx: rTMS consisted of 10 x 10-second trains of 3 Hz stimulation with 50 seconds between each train
Control: sham rTMS with the same parameters was applied with the coil angled away from the head to reproduce the noise of the stimulation as well as some local sensation
Duration: 10 days
OutcomesActivities of daily life: BI at 10 days
Scandinavian Stroke Scale at 10 days
Adverse events: occasional headache
NotesEx: unstable cardiac dysrhythmia, and previous administration of tranquilliser, severe aphasia, anosognosia, or cognitive deficit
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Khedr 2009a

Methods

S: unclear

C: closed envelope
B: participants and assessor blinded
Ex: none
Losses to FU: none

Participants

Country: Egypt

36 participants
Age: mean 57.9 ± 11.0 years
Sex: 52.8% male
Acute ischaemic stroke of middle cerebral artery territory (7 to 20 days)

Interventions

Rx: Group 1: participants received real rTMS with 1 Hz continuous, for 15 minutes at 100% of RMT over the unaffected hemisphere with total 900 pulses

Group 2: participants received real rTMS with 3 Hz, 10 seconds, 30 trains, inter-train interval 2 seconds with total 900 pulses at 130% of RMT over the affected hemisphere

Control: sham rTMS with the same parameters as Group 2 but rTMS was applied with the coil angled away from the head to reproduce the noise of the stimulation as well as some local sensation

Duration: 5 days

Outcomes

Hand grip
NIHSS
BI

Pegboard Tasks Score

Keyboard Tapping Score

All outcomes were evaluated at the end of treatment and 3 months
Adverse events: All the participants tolerated rTMS well without any adverse effects.

NotesEx: extensive infarction, severe flaccid hemiplegia, unstable cardiac dysrhythmia, epilepsy, previous administration of tranquilliser, severe aphasia, ansognosia or cognitive deficit and contraindications to rTMS
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Low riskClosed envelope
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Khedr 2010

Methods

S: unclear

C: closed envelope
B: participants and assessor blinded
Ex: none
Losses to FU: 10 participants out of the 48 participants did not complete the follow-up at the end of the year

Participants

Country: Egypt

48 participants
Age: mean 57.9 ± 11.0 years
Sex: 50% male
Acute ischaemic stroke of middle cerebral artery territory (5 to 15 days)

Interventions

Rx: Group 1: participants received real rTMS with 3 Hz, 5 seconds, 50 trains, with total 750 pulses at 130% of RMT (of the unaffected hemisphere)

Group 2: participants received real rTMS with 10 Hz, 2 seconds, 37 trains, with total 750 pulses at 100% of RMT (of the unaffected hemisphere)

Control: participants received sham rTMS with the same parameters of Group 1 but the sessions were applied with the coil angled away from the head to reproduce the noise of the stimulation as well as some local sensation

Duration: 5 days

Outcomes

NIHSS

mRS

All outcomes were evaluated at the end of treatment and 12 months
Adverse events: all the participants tolerated rTMS well without any adverse effects

NotesEx: extensive infarction, severe flaccid hemiplegia, unstable cardiac dysrhythmia, epilepsy, previous administration of tranquilliser, severe aphasia, ansognosia or cognitive deficit and contraindications to rTMS
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Low riskClosed envelope
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded
Incomplete outcome data (attrition bias)
All outcomes
High risk20.8% participants did not complete the follow-up at the end of the year
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Kirton 2007

Methods

S: hospital identification number

C: unclear
B: participants and assessor blinded
Ex: none
Losses to FU: none

Participants

Country: Canada

10 participants
Age: 13.25 years (7-21 years)
Sex: 60% male
Chronic hemiparesis in subcortical paediatric stroke (mean time post stroke 6.33 ± 3.56 years)

Interventions

Rx: low frequency rTMS over contralesional motor cortex once per day for 8 days. The TMS coil was held in standard position, parallel to the motor cortex with the handle of the coil pointed backwards at 45° relative to midline

Parameters: intensity that was 100% of the rest motor threshold on the non-lesioned side; frequency of 1 Hz; and duration of 20 minutes (1200 stimuli)

Control: same as treatment group, but the coil was placed perpendicular to the skull

Duration: 8 days

Outcomes

Melbourne Assessment of Upper Extremity Function

Grip strength

Purdue Peg Board Test

Halstead-Reitan finger tapping

Adverse events: no serious adverse events were reported. 2 participants had single episodes of neurocardiogenic syncope with their initial exposure to TMS

NotesEx: neonatal; seizures for more than 1 month post stroke; a movement disorder; current use of drugs that potentially alter cortical excitability; or a disease state with ongoing risk of recurrent stroke (e.g. moyamoya or sickle cell disease)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe participant whose hospital identification number had the lowest final digit (or lowest penultimate digit, if the final digits of the two participants were the same) was assigned to rTMS treatment, the other to sham
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Koch 2012

Methods

S: unclear

C: unclear
B: participants, investigator and assessor blinded
Ex: 1 in Rx and 1 in control
Losses to FU: none

Participants

Italy

20 participants
Age: rTMS: mean 61.4 years; control group: 71.9 years
Sex: 55.6% male
Subacute ischaemic stroke patients (24 - 102 days after the first-ever stroke)

Interventions

Rx: in every session, 3-pulse bursts at 50 Hz repeated every 200 msec for 40 seconds were delivered at 80% of the active motor threshold over the left posterior parietal cortex (PPC) (600 pulses). Every day 2 sessions of left PPC continuous theta-burst stimulation (cTBS) were applied with an interval of 15 minutes

Control: sham stimulation was delivered with the coil angled at 90°, with only the edge of the coil resting on the scalp. Stimulus intensity, expressed as a percentage of the maximum stimulator output, was set at 80% active motor threshold for the first dorsal interosseous, inducing the same acoustic sensation as for real TBS

Duration: 10 days

Outcomes

Behavioral Inattention Test Scores

Outcomes were assessed at the end of treatment and at 1 month follow-up
Adverse events: no significant adverse effect was reported

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and investigators blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk2 participants did not complete the intervention (1 in the control group and 1 in the experimental group)
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Liepert 2007

Methods

S: unclear

C: unclear
B: participants and assessor blinded
Ex: none
Losses to FU: none

Participants

Germany

12 participants
Age: mean 63 ± 11 years
Sex: 66.7% male
Acute subcortical stroke (less than 14 days after the stroke)

Interventions

Rx: inhibitory 1 Hz rTMS over the contralesional M1. Stimulus intensity was subthreshold (90% of motor threshold at rest)

Control: sham stimulation.

Duration: 20 minutes

OutcomesGrip strength and Nine-Hole-Peg Test
Adverse events: unclear
NotesEx: dementia, aphasia and all other neurological diseases apart from the stroke, the intake of drugs known to interfere with brain excitability, pregnancy, heart pacemakers and metallic objects in the brain.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Malcolm 2006

Methods

S: unclear

C: unclear
B: participants and assessor blinded
Ex: none
Losses to FU: none

Participants

Country: USA

19 participants
Age: rTMS: mean 68.4 ± 8.4 years; control group: 65.7 ± 5.1 years
Sex: 57.9% male
Chronic hemiparesis in subcortical stroke (mean time post stroke 3.8 ± 3.3 years)

Interventions

Rx: participants received 2000 stimulations daily for 10 consecutive weekdays. Each daily treatment of 2000 stimuli was administered as 50 trains of 40 stimuli, stimulus rate of 20 Hz, stimulus train duration of 2 seconds, with an intertrain interval of 28 seconds. Stimulus intensity was 90% of motor threshold + constraint-induced therapy

Control: sham rTMS + constraint-induced therapy

Duration: 14 days

Outcomes

The primary outcome measures: the Wolf Motor Function Test (WMFT) and the Motor Activity Log (MAL)–Amount of Use

Secondary outcome measures including the Box and Block Test (BBT) and the MAL-How Well

Adverse events: no discernible adverse effects of rTMS beyond scalp discomfort

NotesEx: use of medications that may lower seizure threshold, history of epilepsy, brain tumour, drug or alcohol abuse, dementia, major head trauma or major psychiatric illness, arteriovenous malformation, intracortical haemorrhage, subarachnoid haemorrhage, pregnancy and contraindications to rTMS
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Mansur 2005

Methods

S: unclear

C: unclear
B: participants blinded
Ex: 2 participants were excluded
Losses to FU: none

Participants

Brazil

10 participants
Age: mean 53.3 years
Sex: 30% male
People within 12 months of a stroke

Interventions

Participants received 3 sessions of rTMS (1 Hz, 100% of motor threshold, 600 pulses) to the unaffected hemisphere over the primary motor (real or sham rTMS) and over the premotor cortex (real rTMS)

The order of these different rTMS sessions was randomised and counterbalanced across participants

Duration: 10 minutes

Outcomes

Simple reaction time (sRT)

Four-choice reaction time (cRT)

Purdue Pegboard Test

Finger tapping.
Adverse events: unclear

NotesEx: unclear
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
High risk2 participants were excluded after randomisation
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Pomeroy 2006

Methods

S: computer generated

C: sequentially-numbered opaque envelopes

B: participants and assessor blinded
Ex: During the treatment stage, 2 participants transferred to another hospital, and 1 withdrew as rTMS produced headache
Losses to FU: none

Participants

Country: UK

27 participants
Age: mean 74.8 years
Sex: 33.3 % male
Middle cerebral artery infarct (mean time after stroke was 26.6 days (range 7-85))

Interventions

Rx:  real rTMS consisted of 200 1 Hz stimuli at 120% motor threshold in 5 blocks of 40 separated by 3 minutes delivered to the lesioned hemisphere

Control: placebo rTMS used a dummy coil

Duration: 8 days

OutcomesAction Research Arm Test (ARAT)
Adverse events: not reported
NotesEx: contraindications to rTMS
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated
Allocation concealment (selection bias)Low riskSequentially-numbered opaque envelopes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk11% participants did not complete the study
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Takeuchi 2008

Methods

S: unclear

C: unclear
B: participants blinded
Ex: none
Losses to FU: none

Participants

Country: Japan

20 participants
Age: mean 62.3 ± 8.4 years
Sex: 80% male
Chronic subcortical stroke (more than 6 months duration)

Interventions

Rx: rTMS was applied over the motor cortex of the unaffected hemisphere at a frequency of 1 Hz and a stimulus intensity of 90% rMT measured with Magstim Rapid for 25 minutes (1500 pulses) + motor training

Control: sham stimulation was applied over the unaffected hemisphere by positioning the coil perpendicular to the scalp and at the same frequency and intensity used for real rTMS+ motor training

Duration: 25 minutes

Outcomes

Pinch force and acceleration

Adverse events: no adverse effects were reported

NotesEx: severe internal carotid artery stenosis, seizure, and an intracranial metallic implant
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions after randomisation or losses to follow-up were reported
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Wang 2012

Methods

S: unclear

C: sealed envelopes
B: participants and assessor blinded
Ex: 2 in Rx and 2 in control
Losses to FU: none

Participants

Taiwan

28 participants
Age: rTMS: mean 64.90 ± 12.37 years; control group: 62.98 ± 10.88 years
Sex: 62.5% male
Chronic stroke patients (> 6 months after the first-ever stroke)

Interventions

Rx: rTMS was applied at a 1 Hz frequency over the leg area of the motor cortex of the unaffected hemisphere for 10 minutes + task-oriented training

Control: participants received sham rTMS + task-oriented training

Duration: 10 days

Outcomes

Lower-extremity Fugl-Meyer score and gait performance

Outcomes were assessed at the end of treatment
Adverse events: none of the participants reported any adverse events

NotesEx: moderate to severe motor deficits, any other clinically significant medical comorbidity and epilepsy
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Low riskSealed envelopes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk4 participants did not complete the intervention (2 in the control group and 2 in the experimental group)
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Weiduschat 2011

  1. a

    B: blinding method
    BI: Barthel Index
    C: concealment of allocation
    CT: computerised tomography
    Ex: exclusion
    FU: follow-up
    GCS: Glasgow Coma Scale
    MMSE: Mini-Mental Status Examination
    MRI: magnetic resonance imaging
    mRS: modified Rankin Scale
    NIHSS: National Institutes of Health Stroke Scale
    PT: physical treatment
    RMT: resting motor threshold
    rTMS: repetitive transcranial magnetic stimulation
    Rx: treatment
    S: sequence generation

Methods

S: unclear

C: sealed envelopes
B: participants, investigators and assessor blinded
Ex: a participant with amnesic aphasia was also excluded
Losses to FU: 3 were lost to follow-up

Participants

Germany

14 participants
Age: rTMS: mean 66.6 years; control group: 63.75 years
Sex: 50% male
Poststroke aphasia in the subacute stage

Interventions

Rx: inhibitory 1 Hz rTMS over the right triangular part of the inferior frontal gyrus + conventional speech and language therapy

Control: inhibitory 1 Hz rTMS the vertex + conventional speech and language therapy

Duration: 2 weeks

OutcomesAachen Aphasia Test
Adverse events: no serious adverse effect was reported
NotesEx: symptomatic prior cerebrovascular accidents, neurodegenerative or psychiatric disease, epilepsy or electroencephalography-documented epileptic discharges, insulin-dependent diabetes mellitus, renal or liver failure, metal parts in the body, life-threatening diseases, and auditory or visual deficits that might impair testing
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Low riskSealed envelopes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and investigators blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAssessor blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk3 were lost to follow-up
Selective reporting (reporting bias)Unclear riskNone known
Other biasUnclear riskNone known

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    RCT: randomised controlled trial
    rTMS: repetitive transcranial magnetic stimulation

Ackerley 2010Non-RCT
Acket 2011Meeting abstract
Barwood 2011Outcome is outside the scope of the review
Boyd 2010Meeting abstract
Chang 2010Pseudo-randomised cross-over trial
Conforto 2010Meeting abstract
Conforto 2011Meeting abstract
Cotelli 2011Confounded (real rTMS for 4 weeks versus placebo rTMS for 2 weeks + real rTMS for 2 weeks)
Davis 2007Meeting abstract
Fridman 2002Meeting abstract
Hirayama 2006Non-RCT
Joen 2008Meeting abstract
Jorge 2008Participants without stroke were included in this study
Kakuda 2011Non-RCT
Kate 2010Meeting abstract
Khedr 2005Quasi-RCT
Kim 2006Pseudo-randomised cross-over trial
Kisten 2004Meeting abstract
Lefaucheur 2004Participants without stroke were included in this study
Linsdell 2010Meeting abstract
Meehan 2011Pseudo-randomised controlled trial
Nowak 2008Outcome is outside the scope of the review
Nyffeler 2009Non-RCT
Ravindran 2003Intervention is outside the scope of the review
Rektorova 2005Participants are outside the scope of the review
Routhier 2010Meeting abstract
Sedlackova 2005Meeting abstract
Talelli 2007aNon-RCT
Talelli 2007bMeeting abstract
Tretriluxana 2009Meeting abstract
Wang 2010Meeting abstract
Weiduschat 2009Meeting abstract
Yoo 2008Meeting abstract
Yoon 2010Meeting abstract

Characteristics of studies awaiting assessment [ordered by study ID]

NCT00044798

  1. a

    RCT: randomised controlled trial
    rTMS: repetitive transcranial magnetic stimulation

MethodsRCT
Participants

Patients with depression associated with small vascular lesions in the brain (vascular depression)

Estimated enrolment: 132

Interventions

Experimental: participants will receive treatment with rTMS and citalopram

Active comparator: participants will receive treatment with sham repetitive transcranial magnetic stimulation and citalopram

OutcomesPrimary outcome measures: response rates to treatment; relapse rates; the size, number, and location of the vascular lesions; and the amount of regional brain atrophy (time frame: measured at Week 12)
NotesClinicalTrials.gov identifier: NCT00044798

Characteristics of ongoing studies [ordered by study ID]

Ackerley 2010a

Trial name or titleSensorimotor integration after theta burst stimulation primed upper-limb training in subcortical stroke patients
MethodsCross-over RCT
Participants

First-ever subcortical stroke and upper-limb impairment (age > 18 years)

Target sample size: 18

InterventionsTheta burst stimulation (TBS) was given intermittently (iTBS) or continuously (cTBS) over the primary motor cortex. ITBS (600 stimuli) is applied for 2 seconds on and 8 seconds off, for a total of 192 seconds. CTBS (600 stimuli) is applied continuously for 40 seconds. Either iTBS, cTBS or sham TBS will be delivered in a randomised order over 3 experimental sessions held at least 1 week apart (wash-out period)
OutcomesEffect on grip function and arm function
Starting date1 May 2010
Contact informationSuzanne Ackerley, Department of Sport and Exercise Science, Private Bag 92010, Auckland 1142, New Zealand
Tel: +64 9 373 7599 ext 84897; email: s.ackerley@auckland.ac.nz
Notes

http://www.anzctr.org.au/. 2010

ACTR Number: ACTRN12610000314022

ContraStim 2010

Trial name or titleRepetitive transcranial magnetic stimulation (rTMS) to contralesional hemisphere in patients with stroke for upper limb recovery (ContraStim)
MethodsRCT
Participants

Chronic stroke patients (suffered 3 - 9 months prior to the study) with arm and hand dysfunction (age: 18 - 90 years)

Estimated enrolment: 36

Interventions

Experimental: contralesional rTMS with arm rehabilitation. Experimental participants will receive subthreshold or suprathreshold rTMS to contralesional hemisphere for up to 20 minutes at 1 Hz followed by task-oriented arm and hand therapy to affected limb

Placebo comparator: sham contralesional rTMS plus arm rehabilitation. Participants will receive sham rTMS to contralesional hemisphere for up to 20 minutes followed by task-oriented arm and hand rehabilitation to affected limb

OutcomesPrimary outcome measures: Action Research Arm Test (time frame: baseline, post-treatment, 1 month, 6 months)
Starting dateJanuary 2010
Contact information

Contact: Michael O Schmitt, email: mschmitt@ric.org
Contact: Lynn Rogers, email: lynnrogers2008@u.northwestern.edu

The Rehabilitation Institute of Chicago, Chicago, Illinois, United States
Principal investigator: Richard L Harvey

NotesClinicalTrials.gov Identifier: NCT01049802

Humphreys 2010

Trial name or titleTest of transcranial magnetic stimulation (TMS) intervention on unilateral neglect
MethodsRCT
Participants

Presence of left unilateral neglect after right hemisphere stroke (age: 30 - 90 years)

Estimated enrolment: 100

Interventions

Experimental: TMS intervention transcranial magnetic stimulation will be applied at a 1 Hz rate for 20 minutes over the ipsilesional posterior parietal cortex of patients showing left neglect after a right hemisphere stroke

Placebo comparator: placebo TMS 1 Hz transcranial magnetic stimulation will be applied over the vertex

OutcomesPrimary outcome measures: standardised measure of visual neglect (time frame: 9 months)
Starting dateOctober 2010
Contact informationUnited Kingdom
Contact: Glyn Humphreys, email:g.w.humphreys@bham.ac.uk
Contact: Adrian Williams, email: adrian.williams@uhb.nhs.uk
NotesClinicalTrials.gov Identifier: NCT01174641

Leker 2008

Trial name or titleUse of deep transcranial magnetic stimulation after stroke (tmstroke)
MethodsRCT
Participants

Acute ischaemic stroke (age:18 - 85 years)

Estimated enrolment: 40

InterventionsDeep TMS every alternate day for 14 days (7 treatments) versus sham TMS in acute stroke patients 3 - 5 days from onset
OutcomesPrimary outcome measures: proportion of participants achieving excellent functional outcome as determined by a mRS < 2 and BI > 95 obtained at 3 months after stroke onset (time frame: 2 years)
Starting dateMarch 2009
Contact informationContact: Ronen R Leker, email: leker@hadassah.org.il
NotesClinicalTrials.gov Identifier: NCT00697645

NINDS 2006

Trial name or titleInfluence of Theta Burst Stimulation and carbidopa-levodopa on motor performance in stroke patients
MethodsExperimental, controlled trial
Participants

Ischaemic cerebral infarction more than 6 months prior to testing not involving cortical motor areas (age: 18 - 90 years)

Estimated enrolment: 58

InterventionsTranscranial magnetic stimulation (TMS) + carbidopa-levodopa versus TMS + placebo versus sham TMS + carbidopa-levodopa vs sham TMS + placebo
OutcomesThe primary outcome measure will be reaction times (time frame: 8 days)
Starting date2006
Contact informationShashi Ravindran, Human Cortical Physiology and Neurorehabilitation Section, NINDS Building 10, Room 5S-208, 10 Center Drive, MSC 1428, Bethesda, MD, USA, email: ravindrs@ninds.nih.gov
NotesISRCTN# NCT00366184

Stinear 2006

  1. a

    BI: Barthel Index
    mRS: modified Rankin Scale
    RCT: randomised controlled trial
    rTMS: repetitive Transcranial magnetic stimulation

Trial name or titleTheta Burst Stimulation to promote balanced brain activity following stroke
MethodsRCT
Participants

First-ever monohemispheric subcortical stroke at least 3 months prior to enrolment, upper limb weakness

Target sample size: 20

Interventions

Magnetic brain stimulation applied for up to 2 minutes, once a week, for up to 5 weeks

Placebo

OutcomesMotor cortex excitability, arm and hand function
Starting date8 September 2006
Contact informationWinston Byblow, Human Motor Control Laboratory Department of Sport and Exercise Science University of Auckland Privage Bag 92019 Auckland, New Zealand, email: w.byblow@auckland.ac.nz
NotesACTR Number: ACTRN12605000740695

Ancillary