DISCUSSION
Headache, anxiety, disability and dependency, stroke, pain, headache/nausea, poststroke
ADVERSE EVENTS, STROKE
Patients who received active cTBS showed greater improvement in upper limb recovery as measured with the ARAT at 3 months poststroke compared with patients who received sham cTBS. The mean additional improvement of 9.5 points (17% of the maximum ARAT score) on the ARAT is clinically meaningful and exceeds the previously established minimal clinically important difference of 5.7 points (10% of the maximum ARAT score).Patients who received active cTBS showed more improvement on metrics of disability and dependency (mRS) and quality of life (upper limb section of the stroke impact scale ) at 1 month posttreatment and at 3 months poststroke, compared with patients who were treated with sham stimulation. The EuroQol-5D was a quality of life metric that did not show a treatment effect, presumably due to involvement of factors that are not directly related to an improvement in upper limb recovery, such as pain and anxiety. In addition to a treatment effect on these metrics, the length of stay in the rehabilitation center, an indicator of independency, was 18 days shorter in patients treated with active cTBS compared with patients who received sham cTBS. These findings suggest that patients who received active cTBS were able to independently perform activities of daily living and participate in society at an earlier stage compared with patients who received sham cTBS.Equally important to efficacy, the investigated cTBS treatment was safe and tolerable, as no serious adverse events were reported. Headache was more prevalent in the active cTBS group, but overall mild side-effects (headache/nausea) were uncommon (<4% of cases).We did not detect an effect of active cTBS on contralesional M1 excitability, although a trend toward long-lasting (days) inhibition of the contralesional M1 could be observed. We speculate that active cTBS leads to a short-lasting reduction (<2 hours) in contralesional M1 excitability, which has dissipated the next day, but which facilitates the effects of upper limb therapy directly following cTBS. Unfortunately, the acute effect of cTBS could not be measured as the cTBS treatments were directly followed by upper limb therapy. Our findings are in line with a recent meta-analysis that showed that contralesional inhibitory rTMS improves upper limb recovery on the FMA arm score with a similar mean difference of 9 points at 3 months poststroke.Earlier meta-analyses of effects of rTMS treatment within the first months poststroke were based (almost) exclusively on inhibition with conventional LF rTMS.A third of the screened patients did not meet the inclusion criteria because the treatment could not be started within 3 weeks after stroke onset. Extension of the treatment time window would have increased the number of eligible patients, but posed the risk of reducing the treatment efficacy, as a previous meta-analysis demonstrated efficacy for treatment only when started within the first month poststroke.