Background: Repetitive transcranial magnetic stimulation (rTMS) is a promising intervention to promote upper limb recovery after stroke. We aimed to identify differences in the efficacy of rTMS treatment on upper limb function depending on the onset time post-stroke.Methods: We searched PubMed, Embase, and the Cochrane Library to identify relevant RCTs from their inception to February 2018. RCTs on the effects of rTMS on upper limb function in adult patients with stroke were included. Study quality and risk of bias were assessed independently by two authors. Meta-analyses were performed for outcomes on individual upper limb outcome measures (function or activity) and for function and activity measures jointly, categorized by timing of treatment initiation. Timing of treatment initiation post-stroke was categorized as follows: acute to early subacute (<1 month), early subacute (1–3 months), late subacute (3–6 months), and chronic (>6 months).Results: We included 38 studies involving 1,074 stroke patients. Subgroup analysis demonstrated benefit of rTMS applied within the first month post-stroke [MD = 9.31; 95% confidence interval (6.27–12.34); P < 0.0001], but not in the early subacute phase (1–3 months post-stroke) [MD = 1.14; 95% confidence interval (−5.32 to 7.59), P = 0.73) or chronic phase (>6 months post-stroke) [MD = 1.79; 95% confidence interval (−2.00 to 5.59]; P = 0.35), when assessed with a function test [Fugl-Meyer Arm test (FMA)]. There were no studies within the late subacute phase (3–6 months post-stroke) that used the FMA. Tests at the level of function revealed improved upper limb function after rTMS [SMD = 0.43; 95% confidence interval (0.02–0.75); P = 0.0001], but tests at the level of activity did not, independent of rTMS onset post-stroke [SMD = 0.17; 95% confidence interval (−0.09 to 0.44); P = 0.19]. Heterogeneities in the results of the individual studies included in the main analyses were large, as suggested by funnel plot asymmetry.Conclusions: Based on the FMA, rTMS seems more beneficial only when started in the first month post-stroke. Tests at the level of function are likely more sensitive to detect beneficial rTMS effects on upper limb function than tests at the level of activity. However, heterogeneities in treatment designs and outcomes are high. Future rTMS trials should include the FMA and work toward a core set of outcome measures.

IntroductionMany patients with stroke have moderate to severe long-term sensorimotor impairments, often including inability to execute movements of the affected arm or hand. Limited recovery from stroke may be partly caused by imbalanced interaction between the cerebral hemispheres, with reduced excitability of the ipsilesional motor cortex while excitability of the contralesional motor cortex is increased. Non-invasive brain stimulation with inhibitory repetitive transcranial magnetic stimulation (rTMS) of the contralesional hemisphere may aid in relieving a post-stroke interhemispheric excitability imbalance, which could improve functional recovery. There are encouraging effects of theta burst stimulation (TBS), a form of TMS, in patients with chronic stroke, but evidence on efficacy and long-term effects on arm function of contralesional TBS in patients with subacute hemiparetic stroke is lacking.Methods and analysisIn a randomised clinical trial, we will assign 60 patients with a first-ever ischaemic stroke in the previous 7–14 days and a persistent paresis of one arm to 10 sessions of real stimulation with TBS of the contralesional primary motor cortex or to sham stimulation over a period of 2 weeks. Both types of stimulation will be followed by upper limb training. A subset of patients will undergo five MRI sessions to assess post-stroke brain reorganisation. The primary outcome measure will be the upper limb function score, assessed from grasp, grip, pinch and gross movements in the action research arm test, measured at 3 months after stroke. Patients will be blinded to treatment allocation. The primary outcome at 3 months will also be assessed in a blinded fashion.Ethics and disseminationThe study has been approved by the Medical Research Ethics Committee of the University Medical Center Utrecht, The Netherlands. The results will be disseminated through (open access) peer-reviewed publications, networks of scientists, professionals and the public, and presented at conferences.Trial registration numberNTR6133

Supplementary material for this article is available on the Neurorehabilitation & Neural Repair website along with the online version of this article.