Repetitive Transcranial Magnetic Stimulation (rTMS)

Evidence Reviewed as of before: 01-04-2012
Author(s): Adam Kagan, B.Sc.; Sarah Bouchard-Cyr; Mylène Boudreau; Amélie Brais; Valérie Hotte; Jo-Annie Paré; Anne-Marie Préville; Mylène Proulx
Patient/Family Information Table of contents

Introduction

Transcranial magnetic stimulation is a pain-free, non-invasive technique used to stimulate the central nervous system. The electric currents necessary to stimulate the brain are produced by rapidly changing magnetic fields that are initiated by a brief high-intensity electric current that passes through a wire coil held over the scalp. The subsequent magnetic field is projected perpendicular to the electric current and is able to passes through the layers of human tissue (skin, bone, cortex) with very little impedence. TMS can be delivered via single-pulse, double-pulse, paired-pulse and repetitive pulse (rTMS). rTMS is the method currently under investigation for use as a treatment for stroke mainly due to its ability to modulate excitability in the cerebral cortex over longer time periods (compared to other types of TMS). It can also enhance some cognitive processes, regulate activity in specific brain regions and provide causal information about the roles of different cortical regions in behavioural performance. The use of rTMS can also enhance neuroplasticity during motor training. Theta burst stimulation is a type of rTMS that has been found to effectively induce synaptic long-term potentiation and depression and is also currently under investigation for use as a treatment therapy for stroke. According to some experimental studies, a stroke would cause a relative hyperactivity of the unaffected hemisphere due to the release from reciprocal inhibition by the opposite hemisphere which would explain some of the dysfunctions observed in this population (Brighina et al, 2003). This phenomenon is called “interhemispheric inhibitory interactions”. Thus inhibitory stimulation (low frequency rTMS) to the unaffected hemisphere could work to curb this problem. In addition, other researchers like Talelli et al. (2007) suggest that excitation of the affected hemisphere (with high frequency rTMS) enhances corticospinal output and leads to promising therapeutic results. Nevertheless, there is still a clear lack of knowledge on the exact mechanisms of TMS.

Note: Only the studies that looked at rTMS as a rehabilitation intervention were considered in this module.

Patient/Family Information

Author: Shreya Prasanna, PhD student

What is Repetitive Transcranial Magnetic Stimulation?

After a stroke, changes in the electrical activity of the cells within your brain take place. These changes may explain why you are experiencing functional problems after the stroke (e.g. difficulty moving your arm or leg). Repetitive Transcranial Magnetic Stimulation (rTMS) is a pain-free, non-invasive technique used to stimulate the cells in your brain. This stimulation alters the electrical activity of cells in targeted areas of the brain. Specifically, pulsed magnetic fields are generated by passing current pulses through a conducting coil. The coil is held close to your scalp so that the pulsed magnetic field passes through the skull and stimulates your brain cells. When this stimulation is delivered at regular intervals, it is termed as rTMS. This therapy has been studied by high quality research studies and has been found beneficial for arm function in patients.

Are there different kinds of rTMS?

rTMS can be applied at low, medium and high frequencies depending on which side of your brain is being treated. A low frequency rTMS is often used to stimulate the part of the brain on the same side as your weaker arm/leg. A medium or high frequency rTMS is used to stimulate the part of the brain on the opposite side of your weaker arm/leg.

Does it work for stroke?

Although the exact mechanisms of rTMS are still being studied, there is evidence that the use of rTMS as an adjunct can help improve hand function for some people after stroke, especially those who already have some use of their hand and arm. For example, research studies have reported that patients who receive rTMS have better control of their affected hand and have better ability to try and manipulate fine objects.

What can I expect?

Typically a session of rTMS is non-invasive and painless. A small, plastic-covered coil is placed against your head to deliver the rTMS. The rTMS is provided for several minutes. You will be required to wear earplugs during this session. It is often followed by a session of physical and/or occupational therapy, which involves exercises to promote the use of your weaker arm and hand.

Side effects/risks?

Common side-effects after a session of rTMS can include a minor headache which often resolves after a few hours or with a dose of acetaminophen (i.e. Tylenol®). A very rare side-effect is the risk of seizures. However, your doctor will examine you thoroughly before beginning this treatment in order to examine the possibility for this risk. Some people should not be treated with rTMS. These include people with: a history of seizures, cardiac pacemakers, and metal implants anywhere in the head or mouth.

Who provides the treatment?

A trained medical technician provides the rTMS. The exercise session following that is provided by a physical or occupational therapist. You can speak to your therapist or physician about whether you are a suitable candidate for rTMS and where you can obtain this treatment.

How many treatments?

The exact number of treatment sessions can vary based on your goals, your needs and your tolerance to the intervention. While there is some variability in regards to the frequency/duration of rTMS treatments as reported in research studies, rTMS is often provided for approximately 5-10 sessions, with each session lasting from 10-25 mins. As such, the frequency/duration of your rTMS treatment sessions will be suggested by your therapist or physician.

Is rTMS for me?

rTMS can be beneficial to those individuals who have difficulty in their arm and hand function after stroke. Studies have shown that rTMS may be useful for individuals who have had a stroke very recently, over the past couple of months and those who have experienced a stroke six or more months ago.

Clinician Information

Note: When reviewing the findings, it is important to note that they are always made according to randomized clinical trial (RCT) criteria – specifically as compared to a control group. To clarify, if a treatment is “effective” it implies that it is more effective than the control treatment to which it was compared. Non-randomized studies are no longer included when there is sufficient research to indicate strong evidence (level 1a) for an outcome.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method of stimulating the central nervous system and is currently being considered as a possible treatment for stroke. rTMS is usually delivered via an electronic device that is placed over the scalp and transmits rapidly changing magnetic fields down through a specific section of the brain. While the exact mechanisms of how rTMS works are still under investigation, it is believed that the changing magnetic fields act to modulate the cortical excitability. Low frequency rTMS appears to lower cortical excitability and is thus usually delivered to the unaffected hemisphere (which can become over active post stroke), while high frequency rTMS raises cortical excitability and is often delivered to the affected hemisphere.

To date, 26 studies are included and reviewed in this module. More specifically: 13 high quality RCTs, 2 fair quality crossover studies, 2 quasi-experimental studies, 2 repeated measures studies, 1 randomly controlled feasibility study, 6 pre-post studies.

Note: Low-frequency rTMS implies 1-4Hz, high-frequency rTMS implies 5-10Hz. As well, the term ‘affected’ refers to the brain hemisphere affected by stroke (for example ‘affected motor cortex’ refers to the motor cortex on the affected side of the brain).

Note: Please see the Authors results table and publication abstracts for further details of rTMS (e.g. intensity, motor threshold, location).

Results Table

View results table

Outcomes

Acute phase: Low-frequency rTMS over the affected motor cortex vs. control conditions

Activities of daily living
Effective
1b

One high quality RCTs (Khedr et al., 2005) studied the effect of rTMS on activities of daily living (ADLs) in patients with acute stroke. This high quality RCT found a significant difference on the Barthel Index immediately post-intervention and at a 10-day follow up, following 10 sessions of low-frequency rTMS over the motor cortex of the affected hemisphere compared to sham rTMS. Both groups also received usual care. As well, a significantly higher percentage of patients who received low-frequency rTMS compared to sham rTMS scored in the ‘independent’ range (Barthel Index greater or equal to 75) at the 10-day follow-up only.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that low-frequency rTMS over the motor cortex of the affected hemisphere is more effective than sham rTMS in improving activities of daily living in patients with acute stroke.

Elbow torque
Insufficient evidence
5

One randomized controlled feasibility study (Pomeroy et al., 2007) investigated the effect of rTMS combined with muscle contraction on elbow torque as measured by an isokinetic dynamometer. No significant effect was found for low-frequency rTMS over the motor cortex of the affected hemisphere, combined with either real or placebo muscle contraction when compared to sham rTMS combined with either real or placebo muscle contraction exercises. However, because it was a feasibility study, it was not powered to find significant differences between groups – nor was it a hypothesis testing study.
Note: This study involved some patients with subacute stroke, however the average time after stroke was 27 days, and the majority of patients were in the acute stage.

Conclusion: There is insufficient scientific evidence (level 5) describing the effect of low-frequency rTMS over the motor cortex of the affected hemisphere on elbow torque of the paretic arm in patients with acute stroke, however it should be noted that one randomized controlled feasibility study found no effect.

Purposeful movement
Insufficient evidence
5

One randomized controlled feasibility study (Pomeroy et al., 2007) investigated the effect of rTMS combined with muscle contraction on purposeful movement measured by the Action Research Arm Test. No significant effect was found for a single session of low-frequency rTMS over the motor cortex of the affected hemisphere, combined with either real or placebo muscle contraction, when compared to sham rTMS combined with either real or placebo muscle contraction exercises. However, because it was a feasibility study, it was not powered to find significant differences between groups – nor was it a hypothesis testing study.
Note: This study involved some patients with subacute stroke, however the average time after stroke was 27 days, and the majority of patients were in the acute stage.

Conclusion: There is insufficient scientific evidence (level 5) describing the effect of low-frequency rTMS over the motor cortex of the affected hemisphere on purposeful movement of the paretic arm in patients with acute stroke, however it should be noted that 1 randomized controlled feasibility study found no effect.

Acute phase: Low-frequency rTMS over the oesophageal motor cortex of both hemispheres simultaneously vs. control conditions

Activities of daily living
Effective
1b

The high quality RCT (Khedr et al., 2010) involved patients with lateral medullary infarction (LMI) or other brainstem infarctions. At post-treatment and at 2-month follow-up the study found a significant difference in ADLs (measured by the Barthel Index) for the LMI patients only, in favour of low-frequency rTMS over the oesophageal motor cortex of both hemispheres, compared to sham rTMS.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that low-frequency rTMS over the oesophageal motor cortex of both hemispheres is more effective than sham rTMS in improving activities of daily living in patients with acute stroke resulting from lateral medullary infarction.

Dysphagia
Effective
1b

One high quality RCT (Khedr et al., 2010) studied the effect of rTMS on dysphagia in patients with acute stroke. This high quality RCT found a significant difference in dysphagia (measured by a standardized swallowing questionnaire) in favour of a group of patients who received 5 sessions of low-frequency rTMS over the oesophageal motor cortex of both hemispheres (simultaneously), compared to a group who received sham rTMS.

Conclusion: There is moderate (level 1b) evidence from 1 high quality RCT that low-frequency rTMS over the oesophageal motor cortex of both hemispheres is more effective than sham rTMS for improving dysphagia in patients with acute stroke.

Grip strength
Not effective
1b

One high quality RCT (Khedr et al., 2010) studied the effect of rTMS on grip strength in patients with acute stroke. This high quality RCT found no significant difference in grip strength at post-treatment between a group of patients who received 5 sessions of low-frequency rTMS over the oesophageal motor cortex of both hemispheres (simultaneously), and a group who received sham rTMS.

Conclusion: There is moderate evidence (level 1b) from one high quality RCT that low- frequency rTMS over the motor cortex of both hemispheres is not more effective than sham rTMS in improving grip strength in patients with acute stroke.

Neurological outcomes and recovery
Not effective
1b

One high quality RCTs (Khedr et al., 2010) studied the effect of rTMS on neurological outcomes and recovery in patients with acute stroke. This high quality RCT found no significant difference in neurological outcomes and recovery (measured by the National Institute of Health Stroke Scale) between a group of patients who received 5 sessions of low-frequency rTMS over the oesophageal motor cortex of both hemispheres, compared to a group who received sham rTMS.

Conclusion: There is moderate (level 1b) evidence from 1 high quality RCT that low-frequency rTMS over the oesophageal motor cortex of both hemispheres is not more effective than sham rTMS in improving neurological outcomes and recovery in patients with acute stroke.

Acute phase: Low-frequency rTMS over the unaffected motor cortex vs. control conditions

Grip strength
Not effective
1b

One high quality crossover RCT (Lieperta et al., 2007) studied the effect of rTMS on grip strength in patients with acute stroke. This high quality crossover RCT reported no significant change in grip strength following a single session of low-frequency rTMS over the motor cortex of the unaffected hemisphere compared to sham rTMS.

Conclusion : There is moderate evidence (level 1b) from one high quality crossover RCT that low- frequency rTMS over the motor cortex of the unaffected hemisphere is not more effective than sham rTMS in improving grip strength in patients with acute stroke.

Manual dexterity
Effective
1b

One high quality crossover study (Lieperta et al., 2007) studied the effect of rTMS on manual dexterity in patients with acute stroke. The study reported a significant improvement in the Nine Holes Peg Test (NHPT) following a single session of low-frequency rTMS over the motor cortex of the unaffected hemisphere compared to sham rTMS (control).

Conclusion: There is moderate evidence (level 1b) from one high quality crossover RCT that low-frequency rTMS over the motor cortex of the unaffected hemisphere is more effective than sham rTMS for improving manual dexterity in patients with acute stroke.

Subacute phase: Low-frequency rTMS over the unaffected motor cortex vs. control conditions

Activities of daily living
Effective
1b

One high quality RCT (Emara et al., 2010) investigated the effect of rTMS on activities of daily living in patients with subacute stroke. This high quality RCT randomized patients into 3 groups: 1) low-frequency rTMS over the motor cortex of the unaffected hemisphere (low-rTMS), 2) high-frequency rTMS over the motor cortex of the affected hemisphere (high-rTMS), or 3) sham rTMS. All 3 groups also received standard rehabilitation. At 10 days, the study found a significant between-group difference in activities of daily living (measured by the Activity Index) in favour of both low-rTMS and high-rTMS compared to sham rTMS. These differences were maintained over 12 weeks of follow-up.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that low-frequency rTMS over the motor cortex of the unaffected hemisphere is more effective than sham rTMS for improving activities of daily living in patients with subacute stroke.

Cognitive impairment
Not effective
1b

One high quality RCT (Emara et al., 2010) investigated the effect of rTMS on cognitive impairment in patients with subacute stroke. This high quality RCT randomized patients into 3 groups: 1) low-frequency rTMS over the unaffected hemisphere (low-rTMS), 2) high-frequency rTMS over the affected hemisphere (high-rTMS), or 3) sham rTMS. In addition, all 3 groups received standard rehabilitation. At 10 days, the study found no significant between-group difference in cognitive impairment (measured by the Mini-Mental State Examination).

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that low-frequency rTMS over the motor cortex of the unaffected hemisphere is not more effective than sham rTMS for improving cognitive impairment in patients with subacute stroke.

Grip strength
Effective
2b

One repeated measures study (Dafotakis et al., 2008) examined the effect of rTMS on grip strength in patients with subacute stroke. This repeated measures study found that low-frequency rTMS over the  primary motor cortex of the unaffected hemisphere improved the efficiency of grip force scaling and spatio-temporal scaling coupling between grip and lift forces significantly more than sham rTMS (control).

Conclusion: There is limited evidence (level 2b) from 1 repeated measures study that low-frequency rTMS over the motor cortex of the unaffected hemisphere is more effective in improving some aspects of grip strength related to object lifting.

Manual dexterity
Effective
1b

One high quality crossover study (Mansur et al., 2005) investigated the effects of rTMS on manual dexterity in patients with subacute stroke. This high quality crossover study  randomised patients to receive the following 3 treatments scenarios in random order: (1) low-frequency rTMS over the primary motor cortex of the unaffected hemisphere (2) low-frequency rTMS over the premotor cortex of the unaffected hemisphere, or (3) sham rTMS (control). The study found a significant improvement in the Purdue Pegboard test following ‘scenario 1’ compared to the sham condition, whereas the improvement was not significant for ‘scenario 2’ compared to the sham condition.

Conclusion1: There is moderate evidence (level 1b) from 1 high quality crossover study that low-frequency rTMS over the primary motor cortex of the unaffected hemisphere is more effective than sham rTMS for improving manual dexterity in patients with subacute stroke.

Quality of life
Effective
1b

One high quality RCT (Emara et al., 2010) investigated the effect of rTMS on quality of life in patients with subacute stroke. This high quality RCT randomized patients to 3 groups: 1) low-frequency rTMS over the unaffected hemisphere (low-rTMS), 2) high-frequency rTMS over the affected hemisphere (high-rTMS), or 3) sham rTMS. All 3 groups also received standard rehabilitation. At 10 days, the study found a significant between-group difference in quality of life (measured by the Modified Rankin Scale) in favour of both low-rTMS and high-rTMS compared to sham rTMS. These differences were maintained over 12 weeks of follow-up.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that low-frequency rTMS over the motor cortex of the unaffected hemisphere is more effective than sham rTMS in improving quality of life in patients with subacute stroke.

Reaction time of the hand
Effective
1b

One high quality crossover study (Mansur et al., 2005) investigated the effects of rTMS on reaction time of the hand in patients with subacute stroke. In the study, patients received the following 3 treatments scenarios in random order: (1) low-frequency rTMS over the primary motor cortex of the unaffected hemisphere (2) low-frequency rTMS over the premotor cortex of the unaffected hemisphere, or (3) sham rTMS (control). A significant improvement in simple reaction time, and 4-choice reaction time was found following ‘scenario 1’ compared to the sham condition, however there was no significant improvement reported for the finger tapping test. None of these three tests showed any improvement following ‘scenario 2’ compared to the sham condition.

Conclusion: There is moderate evidence (level 1b) from 1 high quality crossover study that low-frequency rTMS to the primary motor cortex of the unaffected hemisphere is more effective than sham rTMS for improving some aspects of reaction time of the hand in patients with subacute stroke.

Subacute phase: Low-frequency rTMS over the right inferior frontal gyrus vs. control conditions

Aphasia
Effective
1b

One high quality RCT (Weiduschat et al., 2010) investigated the effect of rTMS on aphasia in patients with subacute stroke. This high quality RCT randomized patients with subacute stroke to receive low-frequency rTMS over the right triangular part of the inferior frontal gyrus or sham rTMS. At 2 weeks (following 10 sessions) a significant between-group difference in aphasia (measured by the Aachen Aphasia Test) was found in favour of rTMS compared to sham rTMS. It should be noted that both groups also received speech and language therapy.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that low-frequency rTMS over the right triangular part of the inferior frontal gyrus is more effective than sham rTMS for improving aphasia in patients with subacute stroke.

Subacute Phase: Low-frequency rTMS over the parietal lobe of the unaffected hemisphere vs. control conditions

Unilateral spatial neglect
Effective
2b

One quasi-experimental study (Lim et al. 2010) and 1 pre-post study (Brighina et al, 2003) investigated the effect of rTMS on unilateral spatial neglect in patients with subacute stroke.

The quasi-experimental study (Lim et al. 2010) found a significant between-group difference at 2 weeks (immediately post-treatment) in contra-lesional neglect, measured by the Line bisection test (p=.053), with less neglect found for a group that received low-frequency rTMS group over the parietal area of the unaffected hemisphere combined with behavioural therapy, compared to a group that received behavioural therapy alone.

The pre-post study (Brighina et al, 2003) found a significant improvement in the Length judgment of prebisected lines, the Line bisection task and the Clock drawing task following 2 weeks of low-frequency rTMS over the parietal cortex of the unaffected hemisphere in 3 patients with contralateral visuospatial neglect and right brain ischemic stroke.

Conclusion: There is limited evidence (level 2b) from 1 quasi-experimental study that low-frequency rTMS over the parietal lobe of the unaffected hemisphere + behavioral therapy is more effective than behavioural therapy alone for improving certain aspects of unilateral spatial neglect in patients with subacute stroke. In addition 1 pre-post study found improvements in unilateral spatial neglect in patients with subacute stroke following low-frequency rTMS over the parietal cortex of the unaffected hemisphere.

Subacute phase: High-frequency rTMS over the affected motor cortex vs. control conditions

Activities of daily living
Conflicting
4

Two high quality RCTs (Chang et al., 2010, Emara et al., 2010) investigated the effect of rTMS on activities of daily living in patients with subacute stroke.

The first high quality RCT (Chang et al., 2010) found no significant difference at 2 weeks (post-treatment) or at 3 months (follow-up) in activities of daily living (measured by the Barthel Index) between high-frequency rTMS over the motor cortex of the affected hemisphere combined with motor training, compared to sham rTMS combined with motor training.

The second high quality RCT (Emara et al., 2010) randomized patients into 3 groups: 1) low-frequency rTMS over the motor cortex of the unaffected hemisphere (low-rTMS), 2) high-frequency rTMS over the motor cortex of the affected hemisphere (high-rTMS), or 3) sham rTMS. All 3 groups also received standard rehabilitation. At 10 days, the study found a significant between-group difference in activities of daily living (measured by the Activity Index) in favour of both low-rTMS and high-rTMS compared to sham rTMS. These differences were maintained over 12 weeks of follow-up.

Conclusion: There is conflicting evidence (level 4) between 2 high quality RCTs regarding the effect of high-frequency rTMS over the motor cortex of the affected hemisphere on activities of daily living in patients with subacute stroke.

Cognitive impairment
Not effective
1b

One high quality RCT (Emara et al., 2010) investigated the effect of rTMS on cognitive impairment in patients with subacute stroke. This high quality RCT randomized patients into 3 groups: 1) low-frequency rTMS over the unaffected hemisphere (low-rTMS), 2) high-frequency rTMS over the affected hemisphere (high-rTMS), or 3) sham rTMS. In addition, all 3 groups received standard rehabilitation. At 10 days, the study found no significant between-group difference in cognitive impairment (measured by the Mini-Mental State Examination).

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that high-frequency rTMS over the motor cortex of the affected hemisphere is not more effective than sham rTMS in improving cognitive impairment in patients with subacute stroke.

Grip strength
Not effective
1b

One high quality RCT (Chang et al., 2010) examined the effect of rTMS on grip strength in patients with subacute stroke. This high quality RCT found no significant difference at 2 weeks (immediately post-treatment) or at 3 months post-stroke in grip strength between a group of patients who received high-frequency rTMS over the motor cortex of the affected hemisphere combined with motor training, compared to sham rTMS combined with motor training. However it should be noted that this study may not have been adequately powered (n=28) and that a within-group pre-post improvement in grip strength was found for the real rTMS group, but not the sham rTMS group at 3 months post-stroke.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that high-frequency rTMS over the motor cortex of the affected hemisphere is not more effective than sham rTMS for improving grip strength in patients with subacute stroke. However it should be noted that this study may not have been adequately powered (n=28) and that a within-group pre-post improvement in grip strength was found for real rTMS group, but not sham rTMS group at 3 months post-stroke.

Manual dexterity
Not effective
1b

One high quality RCT (Chang et al., 2010) investigated the effects of rTMS on manual dexterity in patients with subacute stroke. This high quality RCT found no significant difference at 2 weeks (post-treatment) or at 3 months post-stroke in manual dexterity, as measured by the Box and Block Test, between high-frequency rTMS over the motor cortex of the affected hemisphere combined with motor training, compared to sham rTMS combined with motor training.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that high-frequency rTMS over the motor cortex of the affected hemisphere is not more effective than sham rTMS for improving manual dexterity in patients with subacute stroke.

Mobility
Not effective
1b

One high quality RCT (Chang et al., 2010) investigated the effect of rTMS on lower extremity motor function in patients with subacute stroke. There were no significant differences found at either post-treatment (2 weeks), or at follow-up (3 months post stroke) on the Functional Ambulation Category between a group of patients who received high-frequency rTMS over the motor cortex of the affected hemisphere combined with motor training, compared to sham rTMS combined with motor training.

Conclusion: There is moderate evidence (level 1b) from one high quality RCT, that high-frequency rTMS over the motor cortex of the affected hemisphere is not more effective than sham rTMS for improving mobility in patients with subacute stroke.

Motor function (lower extremity)
Not effective
1b

One high quality RCT (Chang et al., 2010) investigated the effect of rTMS on lower extremity motor function in patients with subacute stroke. There were no significant differences found at either post-treatment (2 weeks), or at follow-up (3 months post stroke) on the leg score of the Motricity Index (MI-A) or the Fugl-Meyer Assessment –lower limb score between a group of patients who received high-frequency rTMS over the primary motor cortex of the affected hemisphere combined with motor training, compared to sham rTMS combined with motor training.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT, that high-frequency rTMS over the motor cortex of the affected hemisphere is not more effective than sham rTMS for improving lower extremity motor function in patients with subacute stroke.

Motor function (upper extremity)
Effective
1b

One high quality RCT (Chang et al., 2010) investigated the effects of rTMS on upper extremity motor function in patients with subacute stroke. This high quality RCT found a significant difference at 2 weeks (post-treatment) in motor function (measured by the arm section of the Motricity Index) in favour of high-frequency rTMS over the motor cortex of the affected hemisphere combined with motor training (hi-rTMS), compared to sham rTMS combined with motor training. Additionally a significant group X time interaction was found at 3-months post-stroke suggesting that hi-rTMS may have resulted in additional improvements that lasted at 3 months after onset of stroke.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT, that high-frequency rTMS over the motor cortex of the affected hemisphere is more effective than sham rTMS for improving upper extremity motor function in the short-term in patients with subacute stroke. While a significant group by time interaction indicated that real rTMS may have resulted in additional improvements that lasted 3 months after onset of stroke, the between-group difference at 3 months was not significant.

Quality of life
Effective
1b

One high quality RCT (Emara et al., 2010) investigated the effect of rTMS on quality of life in patients with subacute stroke. This high quality RCT randomized patients to 3 groups: 1) low-frequency rTMS over the unaffected hemisphere (low-rTMS), 2) high-frequency rTMS over the affected hemisphere (high-rTMS), or 3) sham rTMS. All 3 groups also received standard rehabilitation. At 10 days, the study found a significant between-group difference in quality of life (measured by the Modified Rankin Scale) in favour of both low-rTMS and high-rTMS compared to sham rTMS. These differences were maintained over 12 weeks of follow-up.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that high-frequency rTMS over the motor cortex of the affected hemisphere is more effective than sham rTMS in improving quality of life in patients with subacute stroke.

Chronic phase: Bilateral rTMS (Low-frequency rTMS over the unaffected motor cortex combined with high frequency rTMS over the affected motor cortex) vs. control conditions

Pinch acceleration
Effective
1b

One high quality RCT (Takeuchi et al., 2009) investigated the effect of rTMS on pinch acceleration in patients with chronic stroke. This high quality RCT randomized patients into 3 groups: 1) low-frequency rTMS over the motor cortex of the unaffected hemisphere (low-rTMS) 2) high-frequency rTMS over the motor cortex of the affected hemisphere (high-rTMS), or 3) bilateral rTMS (bi-rTMS), which consisted of low-rTMS combined with hi-rTMS. All 3 groups also received motor training. At post-treatment (1 session) a significant between-group difference in pinch acceleration (measured by a monoaxial accelerometer) was found in favour of both bi-rTMS and low-rTMS compared to high-rTMS and these differences were maintained at 7-day follow-up.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that bilateral rTMS, involving low-frequency rTMS over the unaffected motor cortex (low-rTMS) combined with high-frequency rTMS over the affected motor cortex (high-rTMS) is more effective than high-rTMS alone for improving pinch acceleration in patients with chronic stroke.

Pinch force
Effective
1b

One high quality RCT (Takeuchi et al., 2009) investigated the effect of rTMS on pinch force in patients with chronic stroke. This high quality RCT randomized patients into 3 groups: 1) low-frequency rTMS over the motor cortex of the unaffected hemisphere (low-rTMS) 2) high-frequency rTMS over the motor cortex (high-rTMS) of the affected hemisphere, or 3) bilateral rTMS (bi-rTMS), which consisted of low-rTMS combined with hi-rTMS. All 3 groups also received motor training. At post-treatment (1 session) and 7-day follow-up, a significant between-group difference was found in pinch force (measured by a pinch gauge), in favour of bi-rTMS compared to both high- and low-rTMS.

Conclusion: There is moderate evidence (level 1b) from one high quality RCT that bilateral rTMS, involving low-frequency rTMS over the motor cortex of the unaffected hemisphere (low-rTMS) combined with high-frequency rTMS over the motor cortex of the affected hemisphere (high-rTMS) is more effective for improving pinch force compared to either low-rTMS or high-rTMS alone, in patients with chronic stroke.

Chronic phase: Excitatory theta burst stimulation over the motor cortex of the affected hemisphere and Inhibitory theta burst stimulation over the motor cortex of the unaffected hemisphere vs. control conditions

Grip strength
Not effective
2a

One fair quality cross-over study (Talelli et al., 2007) investigated the impact of rTMS on grip strength in patients with chronic stroke. The study reported no significant effects on grip strength following either excitatory theta burst stimulation (iTBS) over the motor cortex of the affected hemisphere, inhibitory theta burst stimulation (cTBS) over the motor cortex of the unaffected hemisphere or sham stimulation.
Note:  iTBS involved 20 trains of 10 theta bursts with 8-sec intervals (600 bursts) whereas cTBS involved 100 continuous trains of theta burst stimulation.
Note: This study involved only 6 patients and thus may not have been adequately powered to provide significant results.

Conclusion: There is limited evidence (level 2a) from 1 fair quality crossover study that excitatory theta burst stimulation over the motor cortex of the affected hemisphere or inhibitory theta burst stimulation over the motor cortex of the affected hemisphere is not more effective than sham rTMS for improving grip strength in patients with chronic stroke.

Reaction time of the hand
Effective
2a

One fair quality crossover study (Talelli et al., 2007) investigated the impact of rTMS on reaction time and speed of the paretic hand of 6 patients with chronic stroke. This fair quality cross-over study found significant improvement in simple reaction time with the application of excitatory stimulation (iTBS) over the affected cortex compared to inhibitory stimulation (cTBS) over the unaffected hemisphere immediately after stimulation, and compared to sham stimulation up to 30 minutes after stimulation. No significant improvement was found for choice reaction time for any of the 3 conditions.
Note: iTBS involved 20 trains of 10 the same theta bursts with 8-sec intervals (600 bursts) whereas cTBS involved 100 continuous trains of theta burst stimulation.

Conclusion: There is limited evidence (level 2a) from one fair quality crossover study, that excitatory theta burst stimulation over the motor cortex affected hemisphere is more effective than inhibitory theta burst stimulation over the primary cortex of the unaffected hemisphere (immediately after stimulation only)  or sham rTMS (up to 30 minutes after stimulation) for improving simple reaction time in patients with chronic stroke.

Chronic phase: Low-frequency rTMS over the both sides of the brain vs. control conditions

Activities of daily living
Insufficient evidence
5

One pre-post study (Mally & Dinya, 2008) investigated the effect of rTMS on activities of daily living (ADLs) in patients with chronic stroke. This pre-post study divided participants into 4 groups. Group A consisted of patients who had movement in the paretic arm that could be evoked by a TMS pulse to either hemisphere of the brain. Group B consisted of patients who had no paretic arm movement evoked from either side of the brain; the pathway to the healthy arm was stimulated from where visible movement could be evoked. Patients in Group C had paretic arm movement that could only be evoked from the contralateral side of the brain, while patients in group D had paretic arm movement that could only be evoked from the ipsilateral side of the brain. Only patients in group B improved in functional activities (dressing, catching and walking as measured by a 4 point scale) following 1-week of low-frequency rTMS (where the region of the brain stimulated during treatment corresponded with the group to which the patient belonged).

Conclusion: There is insufficient scientific evidence (level 5) regarding the effect of low-frequency rTMS over the both sides of the brain on activities of daily living in patients with chronic stroke. However it should be noted that one pre-post study found a significant improvement in ADLs following low-frequency rTMS over the both sides of the brain in patients who had no initial paretic arm movement evoked from either side of the brain.

Lower extremity movement (either hemisphere)
Insufficient evidence
5

One pre-post study (Mally & Dinya, 2008) investigated the effect of rTMS on lower extremity movement in patients with chronic stroke. Participants were divided into 4 groups. Group A consisted of patients who had a movement in the paretic arm that could be evoked by a TMS pulse (low-frequency) to either hemisphere of the brain. Group B consisted of patients who had no paretic arm movement evoked from either side of the brain; the pathway to the healthy arm was stimulated from where visible movement could be evoked. Patients in Group C had paretic arm movement that could only be evoked from the contralateral side of the brain, while patients in group D had paretic arm movement that could only be evoked from the ipsilateral side of the brain. Patients in group B and C improved significantly in lower extremity movement (as measured by several 4 point scales) following a 1-week program of low-frequency rTMS (the region of the brain stimulated during treatment corresponded with the group to which the patient belonged).

Conclusion: While there is insufficient scientific evidence (level 5) that rTMS improves lower extremity movement in patients with chronic stroke, 1 pre-post study found that patients who received low-frequency rTMS to the motor cortex of either the unaffected or the affected hemisphere showed some improvements.

Spasticity of the hand
Insufficient evidence
5

One pre-post study (Mally & Dinya, 2008) investigated the effect of rTMS on hand spasticity in patients with chronic stroke. This pre-post study divided patients with chronic stroke into 4 groups. Group A consisted of patients who had a movement in the paretic arm that could be evoked by a TMS pulse (low-frequency) to either hemisphere of the brain. Group B consisted of patients who had no paretic arm movement evoked from either side of the brain; the pathway to the healthy arm was stimulated from where visible movement could be evoked. Patients in Group C had paretic arm movement that could only be evoked from the contralateral side of the brain, while patients in group D had paretic arm movement that could only be evoked from the ipsilateral side of the brain. Patients in group A, B and C improved significantly in finger spasticity (as measured by a 4-point scale), with group B improving the most, following a 1-week program of low-frequency rTMS where the region of the brain stimulated during treatment corresponded with the group to which the patient belonged.

Conclusion: There is insufficient scientific evidence (level 5) showing an effect of low-frequency rTMS over the both sides of the brain on spasticity in patients with chronic stroke, however 1 pre-post study found significant within-group improvements in spasticity when rTMS was applies to either the affected or unaffected hemisphere, especially when applied to the affected hemisphere of patients with no movement evoked potential of the paretic arm from TMS to the affected hemisphere.

Upper extremity movement (either hemisphere)
Insufficient evidence
5

One pre-post study (Mally & Dinya, 2008) investigated the effect of rTMS on overall upper extremity movement in patients with chronic stroke. Participants were divided into 4 groups. Group A consisted of patients who had a movement in the paretic arm that could be evoked by a TMS pulse (low-frequency) to either hemisphere of the brain. Group B consisted of patients who had no paretic arm movement evoked from either side of the brain; the pathway to the healthy arm was stimulated from where visible movement could be evoked. Patients in Group C had paretic arm movement that could only be evoked from the contralateral side of the brain, while patients in group D had paretic arm movement that could only be evoked from the ipsilateral side of the brain. Patients in group B and C improved significantly in upper extremity movement (as measured by several 4 point scales) following a 1-week program of low-frequency rTMS (the region of the brain stimulated during treatment corresponded with the group to which the patient belonged).

Conclusion: While there is insufficient scientific evidence (level 5) that rTMS improves overall upper extremity movement in patients with chronic stroke, 1 pre-post study found that patients who received low-frequency rTMS to the unaffected hemisphere, especially those who had no evoked movement from either hemisphere before treatment, showed some improvements.

Chronic phase: Low-frequency rTMS over the left prefrontal cortex vs. control conditions

Activities of daily
Not effective
1b

One high quality RCT (Kim et al., 2010) investigated the effect of rTMS on activities of daily living (ADLs) in patients with chronic stroke. This high quality RCT found no significant difference in ADLs (measured by the Barthel Index) at 2 weeks (immediately post-treatment) between low-frequency rTMS over the left prefrontal cortex, high-frequency rTMS over the left prefrontal cortex and sham rTMS.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that low-frequency rTMS over the left prefrontal cortex  is not more effective than sham rTMS in improving activities of living in patients with chronic stroke.

Cognitive impairment
Not effective
1b

One high quality RCT (Kim et al., 2010) investigated the effects of rTMS on cognitive impairment in patients with chronic stroke. This high quality RCT found no significant difference in cognitive impairment (measured by the Mini-Mental State Examination) at 2 weeks (immediately post-treatment) between low-frequency rTMS over the left prefrontal cortex, high-frequency rTMS over the left prefrontal cortex and sham rTMS.

Conclusion: There is moderate evidence (level 1b) that low-frequency rTMS over the left prefrontal cortex, is not more effective than sham rTMS in improving cognitive impairment in patients with chronic stroke.

Mood
Not effective
1b

One high quality RCT (Kim et al., 2010) investigated the effect of rTMS on mood in patients with chronic stroke. This high quality RCT found a significant difference in mood (measured by the Beck Depression Scale) at post-treatment (2 weeks) in favour of high-frequency rTMS over the left prefrontal cortex compared to low-frequency rTMS over the left prefrontal cortex or sham rTMS.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that low-frequency rTMS over the left prefrontal cortex or sham rTMS is less effective than high-frequency rTMS over the left prefrontal cortex in improving mood in patients with chronic stroke.

Chronic phase: Low-frequency rTMS over the right Broca's area

Aphasia
Insufficient evidence
5

One pre-post study (Naeser et al., 2005) investigated the effect of rTMS on patients with chronic stroke and chronic aphasia. The study found some short-term improvements in naming (as measured by the Snodgrass and Vanderwart) as well as some longer lasting improvement in naming (as measured by the Boston Naming test and the Boston Diagnostic Aphasia Exam) following 2 weeks of low-frequency rTMS over the anterior portion of the right Broca’s area.

Conclusion: While there is insufficient scientific evidence (level 5) that rTMS has an effect on aphasia in patients with chronic stroke, one pre-post study showed some improvements in naming ability following low-frequency rTMS to the right Broca’s area.

Chronic phase: Low-frequency rTMS over the unaffected motor cortex vs. control conditions

Manual dexterity
Effective
1b

One high quality RCT (Fregni et al., 2006) investigated the effect of rTMS on manual dexterity in patients with chronic stroke. This high quality RCT reported significant improvement on the Purdue Pegboard test and Jebsen-Taylor Hand Function Test for subjects who received 5 sessions over 5 days of low-frequency rTMS over the motor cortex of the unaffected hemisphere, compared to those who received sham rTMS.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that low-frequency rTMS over the motor cortex of the unaffected hemisphere  is more effective than sham rTMS for improving manual dexterity in patients with chronic stroke.

Mood
Insufficient evidence
5

One repeated measures study (Boggio et al., 2006) investigated the effect of rTMS on mood in patients with chronic stroke. This repeated measures study showed no improvement in mood (measured by a visual analogue scale) following low-frequency rTMS over the motor cortex of the unaffected hemisphere.

Conclusion: There is insufficient scientific evidence (level 5) regarding the effect of low-frequency rTMS over the contralateral hemisphere on mood in patients with chronic stroke, however it should be noted that 1 repeated measures study found no improvements following treatment.

Motor function (upper extremity)
Insufficient evidence
5

One pre-post study (Kakuda et al., 2011) investigated the effects of rTMS on motor function in patients with chronic stroke. Patients were divided based on Brunnstrom stage of recovery for hand-fingers into 3 groups: stage III, stage IV, & stage V. At 15 days, the study found an improvement in all groups on the Fugl-Meyer Assessment – upper extremity (FMA-UE) and Wolf Motor Function Test – upper extremity following low-frequency rTMS over the motor cortex of the unaffected hemisphere combined with occupational therapy. Patients in stage IV improved significantly more than the other 2 stages on the FMA, and patients in stage III improved significantly less than the other 2 stages on the WMFT. The authors concluded that rTMS appears to improve motor function, and that outcomes are influenced by baseline severity of upper limb hemi-paresis.
Note: This study did not compare the intervention to a control group; therefore results of this study were not used to inform levels of evidence. The study was included in this review, however, to note the effect of different baseline severity on outcome.

Conclusion: There is insufficient scientific evidence (level 5) regarding the effect of rTMS on upper extremity motor function in patients with chronic stroke.  However, 1 pre-post study found some improvement in motor function following low-frequency rTMS over the motor cortex of the unaffected hemisphere.

Pinch acceleration
Effective
1a

Two high quality RCTs (Takeuchi et al., 2005Takeuchi et al., 2009) investigated the effect of rTMS on pinch acceleration in patients with chronic stroke.

The first high quality RCT (Takeuchi et al., 2005) reported significantly greater pinch acceleration (measured by a monoaxial accelerometer) at post-treatment (single session) in favour of low-frequency rTMS over the motor cortex of the unaffected hemisphere compared to sham rTMS. However the between-group difference did not remain at 30 minutes post-intervention. Both groups also received motor training.

The second high quality RCT (Takeuchi et al., 2009) randomized patients into 3 groups: 1) low-frequency rTMS over the motor cortex of the unaffected hemisphere (low-rTMS) 2) high-frequency rTMS over the motor cortex of the affected hemisphere (high-rTMS), or 3) bilateral rTMS (bi-rTMS), which consisted of low-rTMS combined with hi-rTMS. All 3 groups also received motor training. At post-treatment (1 session) a significant between-group difference in pinch acceleration (measured by a monoaxial accelerometer) was found in favour of both bi-rTMS and low-rTMS compared to high-rTMS and these differences were maintained at 7-day follow-up.

Conclusion: There is strong evidence (level 1a) from 2 high quality RCTs that low-frequency rTMS over the motor cortex of the unaffected hemisphere is more effective than control conditions (sham rTMS, high-frequency rTMS) for improving pinch acceleration in patients with chronic stroke. It should be noted that one study demonstrated immediate effects only.

Pinch force
Not effective
1b

One high quality RCT (Takeuchi et al., 2005) investigated the effect of rTMS on pinch force in patients with chronic stroke. This high quality RCT found no significant difference in pinch force (measured by a pinch gauge) at post-treatment between 1 session of low-frequency rTMS over the unaffected motor cortex compare to sham rTMS. Both groups also received motor training.

Conclusion: There is moderate evidence (level 1b) from one high quality RCT that low-frequency rTMS over the motor cortex of the unaffected hemisphere is not more effective than sham rTMS in improving pinch force in patients with chronic stroke.

Range of motion of the hand
Insufficient evidence
5

One repeated measures study (Boggio et al., 2006) investigated the effect of rTMS on hand range of motion in patients with chronic stroke. This repeated measures study found a marked improvement in fingers and thumb range of motion (measured by angle of extension) following a single session of low-frequency rTMS over the motor cortex of the unaffected hemisphere and these improvements were maintained at the 4-month follow-up. No changes were found following sham rTMS.
Note: This study only involved 1 patient and did not do multiple baseline assessments beforehand; therefore results of this study were not used to inform levels of evidence.

Conclusion: There is insufficient scientific evidence (level 5) regarding the effect of rTMS on hand range of motion. However, 1 repeated measures study found some improvement motion following low-frequency rTMS.
Note:
This repeated measures study was deemed unqualified to inform levels of evidence.

Reaction time of the hand
Effective
1b

One high quality RCT (Fregni et al., 2006) investigated the impact of rTMS on reaction time and speed of the paretic hand in patients with chronic stroke. This high quality RCT reported significant improvement in simple reaction time and choice reaction time for subjects who received 5 sessions over 5 days of low-frequency rTMS over the motor cortex of the unaffected hemisphere compared to those who received sham rTMS.

Conclusion: There is moderate evidence (Level 1b) from 1 high quality RCT that suggests that low-frequency rTMS over the motor cortex of the unaffected hemisphere is more effective than sham rTMS  for improving reaction time of the paretic hand in patients with chronic stroke.

Spasticity of the hand
Insufficient evidence
5

One repeated measures study (Boggio et al., 2006) investigated the effect of rTMS on hand spasticity in patients with chronic stroke. This repeated measures study reported no effect of low-frequency rTMS over the motor cortex of the unaffected hemisphere on spasticity (measured by the Modified Ashworth Scale) in a 74-year-old woman with chronic stroke.
Note: This study only involved 1 patient and did not to multiple baseline assessments beforehand; therefore results of this study were not used to inform levels of evidence.

Conclusion: There is insufficient scientific evidence (level 5) showing an effect of low-frequency rTMS over the motor cortex of the unaffected hemisphere on spasticity in patients with chronic stroke, however 1 low quality repeated measures study found no improvement in spasticity following low-frequency rTMS to the unaffected hemisphere.

Chronic phase: Low-frequency rTMS over the unaffected parietal lobe vs. control conditions

Cognitive impairment
Insufficient evidence
5

One pre-post study (Shindo et al., 2006) investigated the effects of rTMS on cognitive impairment in patients with chronic stroke. This pre-post study found no change in cognitive impairment or dementia (measure by the Mini-Mental State Examination and the Revised Hasegawa Dementia Scale) following 2 weeks of low-frequency rTMS over the parietal cortex of the unaffected hemisphere.

Conclusion: There is insufficient scientific evidence (level 5) regarding the effect of low-frequency rTMS over the parietal cortex of the unaffected hemisphere on cognitive impairment in patients with chronic stroke. However, it should be noted that one pre-post study found no effect of treatment on cognitive impairment or dementia.

Chronic phase: High-frequency rTMS over the affected motor cortex vs. control conditions

Activities of daily living
Not effective
2b

One quasi-experimental study (Izumi et al., 2008) investigated the effect of rTMS on activities of daily living (ADLs) in patients with chronic stroke. This quasi-experimental study found no significant difference at 4 weeks (immediately post-treatment) in activities of daily living (measured by the Barthel Index) between high-frequency rTMS over the motor cortex of the affected hemisphere during maximum finger or thumb extension and sham rTMS.

Conclusion: There is limited evidence (level 2b) from one quasi-experimental study that high-frequency rTMS over motor cortex of the affective hemisphere is not more effective than sham rTMS for improving activities of daily living in patients with chronic stroke.

Hand function
Not effective
2b

One quasi-experimental study (Izumi et al., 2008) investigated the effect of rTMS on overall hand function in patients with chronic stroke. This study found no significant difference at 4 weeks (immediately post-treatment) in overall hand function, as measured by Brunnstrom’s protocol, the Manual Function Test, and the hand items of the Stroke Impairment Assessment Set, between high-frequency rTMS over the motor cortex of the affected hemisphere during maximum finger or thumb extension compared to sham rTMS (control). However a trend towards significance was found for the Manual Function Test in favour of the real rTMS group.
Note: This study only involved 9 subjects and thus may not have been powered to find significant results.

Conclusion: There is limited evidence (level 2b) from 1 quasi-experimental study showing that high-frequency rTMS over the motor cortex of the affected hemisphere, during maximum finger or thumb extension is not more effective than sham rTMS for improving overall hand function in patients with chronic stroke. It should be noted that this study may not have been powered to find significant results.

Manual dexterity
Effective
1b

One high quality cross-over study (Kim et al., 2006) investigated the effect of rTMS on manual dexterity in patients with chronic stroke. This high quality cross-over study showed significant improvement in movement accuracy and movement time of paretic fingers (as measured by a sequential motor task) with the application of 1 session of high-frequency rTMS over the motor cortex of the affected hemisphere compared to sham rTMS combined with the same movement tasks.
Note: The positive change in movement accuracy was related to increased cortical excitability following the real rTMS condition.

Conclusion: There is moderate evidence (level 1b), from 1 high quality crossover study that high-frequency rTMS over the motor cortex of the affected hemisphere is effective than sham rTMS for improving manual dexterity in patients with chronic stroke.

Range of motion of the hand
Insufficient evidence
5

One randomized cross-over study (Koganemaru et al., 2010) investigated the effect of rTMS on hand range of motion in patients with chronic stroke. This randomized crossover study randomized patients to receive, in random order: 1) high-frequency rTMS over the affected hemisphere (rTMS), 2) extensor motor training (EMT) and 3) both interventions combined (rTMS+EMT). At post-treatment (1 session), no within-group improvements were found for any of the 3 groups. However, when rTMS+EMT was continued for a further 8 weeks, a within-group improvement in hand range of motion (measurement tool not described) was found.
Note: This study did not compare rTMS to a control group; therefore results of this study were not used to inform levels of evidence.

Conclusion: There is insufficient scientific evidence (level 5) regarding the effect of rTMS on hand range of motion. However, 1 randomized crossover trial found some improvement motion following high-frequency rTMS.
Note:
This randomized crossover trial was deemed unqualified to inform levels of evidence.

Spasticity of the hand
Not effective
2b

One fair quality randomized cross-over study (Koganemaru et al., 2010) and one quasi-experimental study (Izumi et al., 2008) investigated the effect of rTMS on hand spasticity in patients with chronic stroke.

In the fair quality randomized crossover trial (Koganemaru et al., 2010), patients received (in random order) a single session of: 1) high-frequency rTMS over the motor cortex of the affected hemisphere (rTMS), 2) extensor motor training (EMT) and 3) both interventions combined (rTMS+EMT). No between-group comparisons were reported in this study*. However it should be noted that at post-treatment a significant improvement in hand spasticity (Modified Ashworth Scale) was found for the rTMS+EMT group only. In addition, patients continued receiving rTMS+EMT for 8 weeks. At the end of 8 weeks significant improvements were found for spasticity.
* Between-group comparisons were not reported; therefore results of this study were not used to inform levels of evidence.

The quasi-experimental study (Izumi et al., 2008) found no significant difference at 4 weeks (post-treatment) in paretic hand spasticity (measured by the Modified Ashworth Scale) between high-frequency rTMS over the motor cortex of the affected hemisphere during maximum finger or thumb extension vs. sham rTMS. However a tendency towards significance was found for wrist spasticity in favour of the real rTMS group.
Note: This study only involved 9 subjects and thus may not have been adequately powered to find significant results.

Conclusion: There is limited evidence (level 2b) from 1 quasi-experimental study that high-frequency rTMS over the motor cortex of the affected hemisphere, during maximum finger or thumb extension is not more effective than sham rTMS for improving spasticity in patients with chronic stroke. However, it should be noted that one randomized crossover study found a significant within-group improvement following high-rTMS over the motor cortex of the affected hemispherecombined with extensor motor training.

Stroke outcomes
Not effective
2b

One quasi-experimental study (Izumi et al., 2008) investigated the effects of rTMS on stroke severity and overall function in patients with chronic stroke. The study found no significant difference at 4 weeks (immediately post-treatment) in overall stroke impairment (measured by the Stroke Impairment Assessment Set) between high-frequency rTMS over the motor cortex of the affected hemisphere during maximum finger or thumb extension vs. sham rTMS (control).
Note: This study only involved 9 subjects and thus may not have been powered to find significant results.

Conclusion: There is limited evidence (level 2b) from one quasi-experimental study showing that high-frequency rTMS over the motor cortex of the affected hemisphere is not more effective than sham rTMS for improving overall stroke impairment in patients with chronic stroke.

Chronic phase: High-frequency rTMS over the left prefrontal cortex vs. control conditions

Activities of daily
Not effective
1b

One high quality RCT (Kim et al., 2010) investigated the effect of rTMS on activities of daily living (ADLs) in patients with chronic stroke. This high quality RCT found no significant difference in ADLs (measured by the Barthel Index) at 2 weeks (immediately post-treatment) between high-frequency rTMS over the left prefrontal cortex, low-frequency rTMS over the left prefrontal cortex and sham rTMS.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that both low-frequency rTMS over the left prefrontal cortex and high-frequency rTMS over the left prefrontal cortex are not more effective than sham rTMS in improving activities of daily living in patients with chronic stroke.

Cognitive impairment
Not effective
1b

One high quality RCT (Kim et al., 2010) investigated the effects of rTMS on cognitive impairment in patients with chronic stroke. This high quality RCT found no significant difference in cognitive impairment (measure by the Mini-Mental State Examination) at 2 weeks (immediately post-treatment) between high-frequency rTMS over the left prefrontal cortex, low-frequency rTMS over the left prefrontal cortex and sham rTMS.

Conclusion: There is moderate evidence (level 1b) that both low-frequency rTMS over the left prefrontal cortex, and high-frequency rTMS over the left prefrontal cortex are not more effective than sham rTMS in improving cognitive impairment in patients with chronic stroke.

Mood
Effective
1b

One high quality RCT (Kim et al., 2010) investigated the effect of rTMS on mood in patients with chronic stroke. This high quality RCT found a significant difference in mood (measured by the Beck Depression Scale) at post-treatment (2 weeks) in favour of high-frequency rTMS over the left prefrontal cortex compared to low-frequency rTMS over the left prefrontal cortex or sham rTMS.

Conclusion: There is moderate evidence (level 1b) from 1 high quality RCT that high-frequency rTMS over the left prefrontal cortex is more effective than low-frequency rTMS over the left prefrontal cortex or sham rTMS in improving mood in patients with chronic stroke.

Chronic phase: High-frequency rTMS over the unaffected motor cortex vs. control conditions

Safety of rTMS
Insufficient evidence
5

One pre-post study (Carey et al., 2007) investigated the safety of rTMS on patients with chronic stroke. The study found no significant impairment of overall function after high-frequency rTMS over the motor cortex of the unaffected hemisphere as measured by the Wechsler Adult Intelligence Scale-third edition, Beck Depression Inventory-Second edition or the NIH Stroke Scale at post treatment or follow-up. Interviews with the patients on treatment day showed some tiredness, headache, anxiety and nausea. There was a significant impairment shown by the HVLT-R (Hopkins Verbal Learning Test-Revised) for word memory at post-test, but the score returned to normal at follow-up over the next 5 days. As well, there was no significant impairment of the fingers motor control of the normal and paretic hand with the finger-tracking performance test at post-test and follow-up.

Conclusion: While there is insufficient scientific evidence (level 5) describing whether or not rTMS is safe for patient with chronic stroke, one pre-post study concluded that high-frequency rTMS over the unaffected hemisphere does not cause any profound negative impact on daily function. Although some minor impairments were found immediately post treatment in this study, the problems faded at subsequent follow-up tests.

Pediatric - chronic phase: Low-frequency rTMS over the unaffected motor cortex vs. control conditions

Grip strength
Effective
1b

One high quality RCT (Kirton et al., 2008) studied the effects of rTMS on grip strength in children with chronic stroke. The study reported a significant between-group difference at 1-day follow-up and 7-day follow-up for grip strength (measured by a dynamometer) in favour of 8 days of low-frequency rTMS over the motor cortex of the unaffected hemisphere vs. sham rTMS.

Conclusion: There is moderate evidence (level 1b) from one high quality RCT that low-frequency rTMS over the motor cortex of the unaffected hemisphere is more effective than sham rTMS for improving grip strength in children with chronic stroke.

Upper extremity motor function
Effective
1b

One high quality RCT (Kirton et al., 2008) studied the effects of rTMS on upper extremity motor function in children with chronic stroke. The results showed a significant improvement at a 1-day follow-up in upper extremity motor function (measured by the Melbourne Assessment of Upper Extremity Function) in favour of 8 days of low-frequency rTMS over the motor cortex of the unaffected hemisphere vs. sham rTMS, however the difference was no longer significant at a 1-week follow-up.

Conclusion: There is moderate evidence (level 1b) from one high quality RCT that low-frequency rTMS over the motor cortex of the unaffected hemisphere is more effective than sham rTMS for improving upper extremity motor function at 1-day follow-up in children with chronic stroke. However, this difference was no longer significant at 1-week follow-up.

References

Boggio P.S., Alonso-Alonso M., Mansur C.G., Rigonatti S.P., Schlaug G., Pascual-Leone A., & Fregni F. (2006). Hand Function Improvement with Low-Frequency Repetitive Transcranial Magnetic Stimulation of the Unaffected Hemisphere in a Severe Case of Stroke, American Journal of Physical Medicine & Rehabilitation, 85 (11), 927-930. http://www.ncbi.nlm.nih.gov/pubmed/17079967

Brighina F., Bisiach E., Oliveri M., Piazza A., La Bua V., Daniele O., & Fierro B. (2003). 1 Hz repetitive transcranial magnetic stimulation of the unaffected hemisphere ameliorates contralesional visuospatial neglect in humans, Neuroscience Letters, 336,131-133. http://www.ncbi.nlm.nih.gov/pubmed/12499057

Carey J.R., Evans C.D., Anderson D.C., Bhatt E., Nagpal A., Kimberley T.J., & Pascual-Leone A. (2007). Safety of 6-Hz Primed Low-Frequency rTMS in Stroke. The American Society of Neurorehabilitation, 22. http://www.ncbi.nlm.nih.gov/pubmed/17876070

Chang W, Kim Y, Bang OW et al. (2010). Long-Term Effects of rTMS on Motor Recovery in Patients after Subacute Stroke. J Rehabil Med, 42, 758–764. http://www.ncbi.nlm.nih.gov/pubmed/20809058

Dafotakis M., Grefkes C., Eickhoff S.B., Karbe H., Fink G.R., Nowak D.A. (2008). Effects of rTMS on grip force control following subcortical stroke. Experimental Neurology, 211, 407-412. http://www.ncbi.nlm.nih.gov/pubmed/18395715

Emara, T.H., Moustafa, R.R., Elnahas, N.M., Elganzoury, A.M., Abdo, T.A., Mohamed S.A. & ElEtribi, M.A. (2010). Repetitive transcranial magnetic stimulation at 1Hz and 5Hz produces sustained improvement in motor function and disability after ischaemic stroke. European Journal of Neurology. 17(9), 1203-9. http://www.ncbi.nlm.nih.gov/pubmed/20402755

Fregni F., Boggio P.S., Valle A.C., Rocha R.R., Duarte J., Ferreira M.J.L., Wagner T., Fecteau S., Rigonatti S.P., Riberto M., Freedman S.D. , & Pascual-Leone A. (2006). A sham-Controlled Trial of a 5-Day Study Course of Repetitive Transcranial Magnetic Stimulation of the Unaffected Hemisphere in Stroke Patients. American Heart Association, 37(8), 2115-2122. http://www.ncbi.nlm.nih.gov/pubmed/16809569

Izumi S., Kondo T., & Shindo K. (2008). Transcranial magnetic stimulation synchronized with maximal movement effort of the hemiplegic hand after stroke: a double-blinded controlled pilot study. J Rehabil Med, 40, 49-54. http://www.ncbi.nlm.nih.gov/pubmed/18176737

Kakuda, W., Abo, M., Kobayashi, k., Takagishi, T., Momosaki, R., Yokoi, A., Fukuda, A., Ito, H. & Tominaga, A. (2011). Baseline severity of upper limb hemiparesis influences the outcome of low-frequency rTMS combined with intensive occupational therapy in patients who have had a stroke. The Journal of Injury, Function and Rehabilitation. 3(11), 993-1078. http://www.ncbi.nlm.nih.gov/pubmed/21665163

Khedr E.M., Ahmed M.A., Fathy N. & Rothwell J.C. (2005). Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke. Neurology, 65, 466-468. http://www.ncbi.nlm.nih.gov/pubmed/16087918

Khedr, E.M., & Abo-Elfetoh, N. (2010). Therapeutic role of rTMS on recovery of dysphagia in patients with lateral medullary syndrome and brainstem infarction. Journal of Neurology, Neurosurgery & Psychiatry. 81(5), 495-9.
http://www.ncbi.nlm.nih.gov/pubmed/19828479

Kim Y.H., You S.H., Ko M.H., Park J.W., Lee K.H., Jang S.H., Yoo W., & Hallett M. (2006). Repetitive transcranial magnetic stimulation induced corticomotor excitability and associated motor skill acquisition in chronic stroke. Stroke, 37:1471-1476. http://www.ncbi.nlm.nih.gov/pubmed/16675743

Kim, B.R., Kim, D.Y., Chun, M.H., Yi, J.H., & Kwon, J.S. (2010). Effect of repetitive transcranial magnetic stimulation on cognition and mood in stroke patients: a double-blind, sham-controlled trial. American Journal of Physical Medicine & Rehabilitation. 89(5), 362-368. http://www.ncbi.nlm.nih.gov/pubmed/20407301

Kirton A., Chen R., Friefeld S., Gunraj C., Pontigon A., & deVeber G. (2008). Contralesional repetitive transcranial magnetic stimulation for chronic hemiparesis in subcortical paediatric stroke: a randomised trial. Lancet Neurol, 7, 507-13. http://www.ncbi.nlm.nih.gov/pubmed/18455961

Koganemaru, S., Mima, T., Thabit, M., Ikkaku, T., Shimada, K., Kanematsu, M., Takahashi,K., Fawi, G., Takahashi, R., Fukuyam, H. & Domen, K. (2010). Recovery of upper-limb function due to enhanced use-dependent plasticity in chronic stroke patients. Brain, 133(11), 3373-3384. http://www.ncbi.nlm.nih.gov/pubmed/20688810

Lieperta J., Zittel S., & Weiller C. (2007). Improvement of dexterity by single session low-frequency repetitive transcranial magnetic stimulation over the contralesional motor cortex in acute stroke: A double-blind placebo-controlled crossover trial. Restorative Neurology and Neuroscience, 25(5-6), 461-465. http://www.ncbi.nlm.nih.gov/pubmed/18334764

Lim J, Kang EK, Paik N. (2010). Repetitive Transcranial Magnetic Stimulation For Hemispatial Neglect In Patients After Stroke: An Open-Label Pilot Study. J Rehabil Med, 42, 447–452. http://www.ncbi.nlm.nih.gov/pubmed/20544155

Mally J., & Dinya E. (2008). Recovery of motor disability and spasticity in post-stroke after repetitive transcranial magnetic stimulation (rTMS). Brain Research Bulletin, 76, 388-395. http://www.ncbi.nlm.nih.gov/pubmed/18502315

Mansur, C. G., Fregni, F., Boggio, P. S., Riberto, M., Gallucci-Neto, J., Santos, C. M., Wagner, T., Rigonatti, S. P., Marcolin, M. A., & Pascual-Leone, A. (2005). A sham stimulation-controlled trial of rTMS of the unaffected hemisphere in stroke patients. Neurology, 64, 1802-1804. http://www.ncbi.nlm.nih.gov/pubmed/15911819

Naeser M.A., Martin P.I., Nicholas M., Baker E.H., Seekins H., Kobayashi M., Theoret H., Fregni F., Maria-Tormos J., Kurland J., Doron K.W., Pascual-Leone A. (2005). Improved picture naming in chronic aphasia after TMS to part of right Broca’s area: an open-protocol study. Brain and Language, 93, 95-105. http://www.ncbi.nlm.nih.gov/pubmed/15766771

Pomeroy V. M., Cloud G., Tallis R.C., Donaldson C., Nayak V., & Miller S. (2007). Transcranial Magnetic Stimulation and Muscle Contraction to Enhance Stroke Recovery: A Randomized Proof-of-Principle and Feasibility Investigation. Neurorehabillitation and Neural Repair, 21(6), 509-517. http://www.ncbi.nlm.nih.gov/pubmed/17409389

Shindo K., Sugiyama K., Huabao L., Nishijima K., Kondo T., Izumi S-I. (2006). Long-term effect of low-frequency repetitive transcranial magnetic stimulation over the unaffected posterior parietal cortex in patients with unilateral spatial neglect. Journal of Rehabilitation Medicine, 38, 65-67. http://www.ncbi.nlm.nih.gov/pubmed/16548090

Takeuchi N., Chuma T., Matsuo Y., Watanabe I., Ikoma K. (2005). Repetitive Transcranial Magnetic Stimulation of Contralesional Primary motor Cortex Improves Hand Function after Stroke. Stroke: Journal of the American Heart Association, 26, 2681-2686. http://www.ncbi.nlm.nih.gov/pubmed/16254224

Takeuchi, N., Tada, T., Toshima, M., Matsuo, Y., & Ikoma, K. (2009). Repetitive transcranial magnetic stimulation over bilateral hemispheres enhances motor function and training effect of paretic hand in patients after stroke. Journal of Rehabilitative Medicine, 41, 1049-1054. http://www.ncbi.nlm.nih.gov/pubmed/19894000

Talelli P., Greenwood R.J., Rothwell J.C. (2007). Exploring Theta Burst Stimulation as an intervention to improve motor recovery in chronic stroke, Clinical Neurophysiology, 118, 333-342. http://www.ncbi.nlm.nih.gov/pubmed/17166765

Weiduschat, N., Thiel, A., Rubi-Fessen, I., Hartmann, A., Kessler, J., Merl, P., Kracht, L., Rommel, T. & Heiss, W.D. (2010). Effects of Repetitive Transcranial Magnetic Stimulation in Aphasic Stroke A Randomized Controlled Pilot Study. Stroke, 42(2), 409-15. http://www.ncbi.nlm.nih.gov/pubmed/21164121

We need your feedback