Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Tung, 2019

SR and meta-analysis of  RCTs

Literature search up to January 2019

A: Wang, 2012
B: Lin, 2015
C: Gu, 2016

Study design:

A: RCT
B: RCT
C: RCT

Setting and Country:

Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei

Source of funding and conflicts of interest:

The author(s) received no financial support for the

research, authorship, and/or publication of this article. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Inclusion criteria SR:

1) the patients were diagnosed with stroke; (2) the outcomes included the effects of rTMS on 1104 Clinical Rehabilitation 33 lower limb motor function; and (3) they were randomized controlled trials.

Exclusion criteria SR:

We excluded articles with only protocols and non-peer-reviewed articles, such as conference papers and letters to the editor. Randomized controlled trials that investigated the effect of combined treatments, where the effects of rTMS could not be isolated, were also excluded.

3 studies included

Important patient characteristics at baseline:

N, mean age

A: 28 patients, 63.9 yrs.
B: 32 patients, 60,3 yrs.
C: 24 patients, 58.2 yrs

Groups comparable at baseline?

Yes

Describe intervention:

A: 10 10-minute sessions of rTMS + 30-minute task-oriented training
B: 15 sessions of 15-minute rTMS + 45 min physical therapy
C: 5 5-minute session of rTMS + movement therapy

Describe  control:

A: 10 10-minute sessions of sham rTMS + 30-minute task-oriented training
B: 15 sessions of 15-minute sham rTMS +45 minutes physical therapy
C: 5 5-minute sessions of sham rTMS + movement therapy

End-point of follow-up:

A: Posttreatment
B: Posttreatment
C: Posttreatment

For how many participants were no complete outcome data available?

(intervention/control)

A: 2/2
B: 0/1
C: 0/0

≤ 3 months

Walking
n.r.

Maintaining standing balance
n.r.

Muscle power/synergies
Defined by FM-LE test score (0-34)

Effect measure: median, (IQR):
LF-rTMS
A: n.r.
B: I: 21 (6.8)
C: 20 (8.0)

HF-rTMS
C: n.r.

Sitting balance
n.r.

Transferring oneself
Defined by the number of patients who finished the TUG test within 2 minutes.

Effect measure: RR (95% CI):
LF-rTMS
A: n.r.
B: 2.75 (1.11 – 6.84)

HF-rTMS
C: n.r.

Walking long distances
n.r.

Walking speed
n.r.

Falling
n.r.

> 3 months

Walking
Defined by the FAC score (0-5)

Effect measure: MD (95% CI)
LF-rTMS
A: n.r.
B: n.r.

HF-rTMS
C: 0.20 (-0.24 – 0.64)

Maintaining standing balance
n.r.

Muscle power/synergies
Defined by the FM-LE test score (0-34)

Effect measure: SMD (95% CI)

LF-rTMS
A: 0.16 (-0.64 – 0.96)
B: n.r.

HF-rTMS
C: 0.38 (-0.43 – 1.19)

Sitting balance
n.r.

Transferring oneself
n.r.

Walking long distances
n.r.

Walking speed
Defined by the gait speed (cm/s)

Effect measure: MD (95% CI)

LF-rTMS
A: 17.17 (-0.45 – 34.79)
B: n.r.

HF-rTMS
C: 0.38 (-0.43 – 1.19)

Falling
n.r.

Author’s conclusion

In conclusion, rTMS may exhibit short-term beneficial effects on the lower limbs of patients with stroke, and it is safe for application. The long-term effects of rTMS on the lower limbs could not be discerned from this meta-analysis. Therefore, additional high-quality, large-scale randomized controlled trials are required to clarify both the long-term effects of and standard protocols for rTMS on the lower limbs of patients with stroke.

Van Lieshout, 2019

SR and meta-analysis of  RCTs and cross-over studies.

Literature search up to February 2018

A: Cha, 2016
B: Conforto, 2012
C: Du, 2016
E: Hosomi, 2016
F: Khedr, 2009
G: Lai, 2015
H: Lüdemann-Podubecka, 2015
I: Seniow, 2012
J: Khedr, 2010
K: Theilig, 2011
L: Wang, 2014
M: Zheng, 2015

Study design:

A: RCT
B: RCT
C: RCT
E: RCT
F: RCT
G: RCT
H: RCT
I: RCT
J: RCT
K: RCT
L: RCT
M: RCT

Setting and Country:

Department of Radiology and Imaging Institute of Rehabilitation and Development of Brain Function, The Second Clinical Medical College of North Sichuan Medical College Nanchong Central Hospital, Nanchong, China

Source of funding and conflicts of interest:

The authors declare that they have no conflicts of interest.

Inclusion criteria SR:

In adult patients (>18 years) with stroke (population), does rTMS aimed at improvement of upper limb function (intervention) as compared with sham rTMS or no rTMS (comparison) improve function or activity of the upper limb (outcome)

Exclusion criteria SR:

Studies were excluded if rTMS was part of a coupling/primingprotocol or if it was bilateral; if there was no upper limb outcome or stroke severity scale measurement (e.g.,NIHSS score) as outcome assessment; or if information required to perform a meta-analysis (e.g., mean scores, standard deviations) was missing.

38 studies included

Important patient characteristics at baseline:

N, mean age

A: 30, 63.7 yrs
B: 30, 55.8 yrs
C: 69, 55.7 yrs
E: 39, 62,8 yrs
F: 36, 57.9 yrs
G: 38, 62.2 yrs
H: 40, 67.0 yrs
I: 40, 63.5 yrs
J: 48, 58.3 yrs
K: 24, 61.0 yrs
L: 44, 64.5 yrs
M: 112, 65.8 yrs

Groups comparable at baseline?

No

Describe intervention:

A: 1Hz, 90% RMT, 1,200 pulses, 20 sessions Right hemisphere, P3 10/20 EEG system.
B: 1Hz, 90% RMT, 1,500 pulses, 10 sessions, UH M1
C: LF: 1Hz, 110–120% RMT, HF: 3Hz, 80–90% RMT, both: 1,200 pulses, 5 sessions, UH, AH M1
E: 5Hz, 90% RMT, 500 pulses, 10 sessions, AH M1
F: (LF: 1Hz, 100% RMT, 900 pulses HF: 3Hz, 130% RMT, 900 pulses, both: 5 Sessions, UH, AH M1
G: iTBS, 80% AMT, 600 pulses, 10 sessions, AH M1
H: 1Hz, 100% RMT, 900 pulses, 15 sessions, UH M1
I: 1Hz, 90% RMT, 1,800 pulses, 15 sessions, UH M1
J: (1): 3Hz, 130% RMT, (2): 10Hz, 100% RMT, both: 750 pulses, 5 sessions, AH M1
K: 1Hz, 100% RMT, 900 pulses, 10 sessions
L: cM1/cPMd: 1Hz, 600 pulses, 90% RMT, 20 sessions, UH M1/PMd
M: 1Hz, 90% RMT, 1,800 pulses, 24 sessions, UH M1

Describe  control:

A: Sham coil
B: Tilted coil
C: Tilted coil
E: Tilted coil
F: Tilted coil
G: Sham coil
H: 0% RMT
I: Sham coil
J: Titled coil
K: 0% RMT
L: Sham coil
M: Sham coil

End-point of follow-up:

A: After treatment (4 wk)
B: After treatment and one month follow-up
C: After treatment and three months follow-up
E:  After treatment (12 days), and 17 days follow-up
F: After treatment and after 1/2/3 months follow-up.
G: After treatment
H: After treatment and after 6 months follow-up
I: After treatment and after 3 months follow-up
J: After treatment and after 1/2/3/12 months follow-up
K: After each intervention
L: After treatment
M: 4wks after treatment

For how many participants were no complete outcome data available?

(intervention/control)

A: n.r.
B: 0/1
C: n.r.

E: 2/0
F: n.r.
G: n.r.
H: n.r.
I: n.r.
J: n.r.
M: n.r.

≤ 3 months

Upper limb capacity
Effect measure: standardized mean difference (95% CI):

LF-rTMS
A: n.r.
B: 0.01 (-0.71 – 0.72)
C: n.r.
E: n.r.
F: 2.90 (1.38 – 4.23)
G: n.r.
H: 0.06 (-0.56 0 0.68)
I: -0.00 (-0.62 -0.62)
J: n.r.
K: n.r.
L: n.r.
M: 0.52 (-0.09 – 0.81)

Pooled effect (random effects model): 0.45 (95% CI -0.17 to 1.07) favouring rTMS. Heterogeneity (I²): 88%

HF-rTMS
A: n.r.
B: n.r.
C: n.r.
D: n.r.
E: n.r.
F: 2.0 (0.77 – 3.22)
G: n.r.
H: n.r.
I: n.r.
J: n.r.
K: n.r.
L: n.r.
M: n.r.

Total pooled effect (random effects model): 0.68 (95% CI 0.02 to 1.35) favoring rTMS. Heterogeneity (I²): 77%

Upper limb muscle synergies
Effect measure: standardized mean difference (95% CI):

LF-rTMS
A: n.r.
B: 0.25 (-0.47 – 0.96)
C: n.r.
E: 0.08 (-0.55 – 0.71)
F: n.r.
G: n.r.
H: n.r.
I: 0.03 (-0.59 – 0.65)
J: n.r.
K: n.r.
L: n.r.
M: 1.38 (0.96 – 1.79)

Pooled effect (random effects model): 0.46 (95% CI -0.29 to 1.21) favoring rTMS
Heterogeneity (I²): 85%

HF-rTMS
A: n.r.
B: n.r.
C: n.r.
E: 0.10 (-0.53 – 0.73)
F: n.r.
G: n.r.
H: n.r.
I: n.r.
J: n.r.
K: n.r.
L: n.r.
M: n.r.

Total pooled effect (random effects model): 0.39 (95% CI -0.23 to 1.02) favouring rTMS
Heterogeneity (I²): 82%

Strength
Effect measure: standardized mean difference (95% CI):

LF-rTMS
A: n.r.
B: 0.07 (-0.64 – 0.79)
C: n.r.
E: n.r.
F: 0.88 (-0.15 – 1.91)
G: n.r.
H: n.r.
I: n.r.
K: n.r.
L: n.r.
M: n.r.

Pooled effect (random effects model): 0.39 (95% CI -0.39 to1.16) favouring rTMS
Heterogeneity (I²): 37%

HF-rTMS
A: n.r.
B: n.r.
C: n.r.
E: 0.27 (-0.36 – 0.90)
F: 1.83 (0.64 – 3.02)
G: n.r.
H: n.r.
I: n.r.
J: 0.56 (-0.14 – 1.27)
K: n.r.
L: n.r.
M: n.r.

Pooled effect (random effects model): 0.74 (95% CI -0.02 to1.49) favouring rTMS
Heterogeneity (I²): 61%

Total pooled effect (random effects model): 0.58 (95% CI -0.09 to1.07) favouring rTMS
Heterogeneity (I²): 45%

Activities of daily living
Effect measure: standardized mean difference (95% CI):

LF-rTMS
A: n.r.
B: n.r.
C: n.r.
E: n.r.
F: 4.89 (2.83 – 6.94)
G: n.r.
H: n.r.
I: n.r.
J: n.r.
K: n.r.
L: n.r.
M: 1.11 (0.71 – 1.51)

Pooled effect (random effects model model): 2.86 (95% CI -0.84 to 6.55) favouring rTMS
Heterogeneity (I²): 92%

HF-rTMS
A: n.r.
B: n.r.
C: n.r.
E: Not estimable
F: 0.48 (-0.52 – 1.47)
G: n.r.
H: n.r.
I: n.r.
J: n.r.
K: n.r.
L: n.r.
M: n.r.

Total pooled effect (random effects model model): 1.79 (95% CI: 0.24 to 3.35) favouring rTMS
Heterogeneity (I²): 86%

>3 months

Upper Limb Capacity
Effect measure: standardized mean difference (95% CI)

LF-rTMS
A: n.r.
B: n.r.
C: n.r.
E: n.r.
F: n.r.
G: n.r.
H: n.r.
I: n.r.
J: n.r.
K: -1.01 (-1.87 - -0.15)
L: 0.92 (-0.77 – 0.91)
M: n.r.

Pooled effect (random effects model model): -0.02 (95% CI: -1.91 to 1.87) favouring sham
Heterogeneity (I²): 92%

iTBS
A: n.r.
B: n.r.
C: n.r.
E: n.r.
F: n.r.
G: 0.64 (-0.02 – 1.29)
H: n.r.
I: n.r.
J: n.r.
K: n.r.
L: n.r.
M: n.r.

Total pooled effect (random effects model model): 0.22 (95% CI: -0.50 to 0.94) favouring rTMS
Heterogeneity (I²): 85%

Upper limb muscle synergies
Effect measure: mean difference (95% CI):

LF-rTMS
A: n.r.
B: n.r.
C: n.r.
E: n.r.
F: n.r.
G: n.r.
H: n.r.
I: n.r.
J: n.r.
K: n.r.
L: 7.89 (5.34 – 10.45)
M: n.r.

Strength
n.r.

Activities of daily living
n.r.

Facultative:

rTMS treatment within the first month after stroke seems more beneficial in increasing upper limb function than after 1–3 months or in the chronic phase post-stroke (>6 months). Improvements after rTMS can most likely be detected with outcome measures assessing body functions, like the FMA score, than tests at the level of activity (e.g., JTT, ARAT). However, rTMS treatment studies in stroke patients are highly heterogeneous, with varying outcome measures and relatively small sample sizes. Another source of uncertainty is that we are unable to identify whether improved outcomes were primarily caused by rTMS per se or by rTMS in combination with an additional therapy (of a certain intensity). Further research and international cooperation should be undertaken to develop a standardized, core set of measurements for testing upper limb function. We recommend to conduct measurements at the different levels of function, activity (and participation). Future studies should incorporate these standardized tests, include a follow-up measurement at 3months after stroke onset (if the trial starts within 1-month post-stroke), and report their findings in a uniform manner (e.g., using final scores or change scores, and subtest scores).

High heterogeneity and wide confidence intervals of effect sizes were found for some analyses on activity outcome measures, which could also account for the absence of rTMS effects in activity.

Bucur, 2019

SR and meta-analysis of RCTs

Literature search up to February 2019

A: Hu, 2018

C: Seniow, 2013

D: Tsai, 2014

E: Waldowski, 2012

F: Wang, 2014

Study design:

A: RCT

C: RCT (pilot)

D: RCT

E: RCT

F: RCT

Setting and Country:

A:

B:

C:

D: Taiwan

E: Poland

F: Taiwan

Source of funding and conflicts of interest:

n.r.

Inclusion criteria SR:

interventions designed for adults with post-stroke aphasia; rTMS or tDCS stimulation studies (alone or combined with other therapies); rTMS or tDCS were specified as the main intervention/ treatment,

; cephalic stimulation designs only (at least one electrode was positioned on the scalp, the

reference electrode could be extra-cephalic, such as on a shoulder); minimum 4 weeks (1 month) of follow-up; at least four aphasic participants; peer-reviewed publications; only RCTs or crossover designs; published in English; when several articles derived from the same study, either with increased recruitment or extended

follow-up evaluations, we chose the one with the higher number of participants and the most

complete data reported at follow-up.

Exclusion criteria SR:

interventions designed for other types of post-stroke disorders or aphasia not due to stroke; other types of brain stimulations such as transcranial random noise stimulation, electroconvulsive

therapy, et cetera.; open-label studies, e.g. (55–57);  studies involving less than 3 stimulation sessions over the same cortical region per patient; extra-cephalic stimulation sites, e.g.; a short follow-up period (less than one month), e.g. ; case reports and research studies with less than four participants; articles from the gray literature (i.e., literature that is not formally published in sources such as

books or journal articles, e.g., unpublished Ph.D. thesis); presentations from international meetings with no specific data provided, perspective and

opinion publications, case reports, series of cases, previous reviews or meta-analyses; studies not published in or translated into English; studies that did not provide adequate information to analyse treatment effects (i.e., when we could not extract useful quantitative data) and we got no reply from the authors.

16 studies included

Important patient characteristics at baseline:

N, mean age

A:

C: 40,

D: 56, 62.5y

E: 26, 61.2y

F: 30, 60.9y

Sex:

A: % Male

C:

D: 26.8% Male

E: 50% Male

F: 90% Male

Groups comparable at baseline?

Describe intervention:

A: a high-frequency rTMS (HF-rTMS) group (10 Hz), a low-frequency rTMS (LF-rTMS) group (1 Hz)

C: 3-week aphasia rehabilitation protocol in combination with real rTMS

D: Group A (n = 33), who underwent 10 sessions of 1-Hz rTMS over the contralesional pars triangularis

(PTr)

E: speech and language therapy combined with real rTMS

F: the TMSsyn

group and underwent synchronous picture-naming training together with contralesional 1 Hz-rTMS for 10 daily sessions.

Describe control:

A:  sham stimulation group

C: 3-week aphasia rehabilitation protocol in combination with sham rTMS

D: Group B (n = 23), who received sham 1-Hz stimulation

E: speech and language therapy combined with sham rTMS

F: the TMS sham group

received concurrent naming task along with the sham 1 Hz-rTMS.

End-point of follow-up:

A: post treatment and 2 months post-treatment

C: Immediately after therapy, and 15 weeks after completing treatment.

D: on the day after the

10th session (post 1), and at 3 months after the last intervention

session (post 2)

E: after treatment

F: immediately, and after 3 months of the intervention

For how many participants were no complete outcome data available?

(intervention/control)

A:

B:

C:

D: 2/1

E: 0/0

F: 0/1

≤ 3 months

Functional communication
Effect measure: standardized mean difference (95% CI):

LF-rTMS
A: n.r.
B: n.r.
C: n.r.
E: 2.57 (149 – 3.66)
F: n.r.

Verbal comprehension

n.r.

Expressive naming
Effect measure: standardized mean difference (95% CI):

LF-rTMS
A: n.r.
B: n.r.
C: n.r.
E: 0.36 (-0.41 – 1.14)
F: n.r.

>3 months

Functional communication
n.r.

Verbal comprehension
n.r.

Expressive naming

Defined by the picture naming test.

Effect measure: mean difference (95% CI):

LF-rTMS

A: n.r.
B: n.r.
C: n.r.
D: 12.10 (-3.54 – 27.74)
E: n.r.
F: 18.90 (5.06 – 26.41)

Total pooled effect (random effects model model): 15.73 (95% CI: -5.06 to 26.41) favouring rTMS
Heterogeneity (I²): 0%

Conclusion

In conclusion, each technique has advantages and disadvantages: rTMS seems more effective but also

more expensive and with a higher safety risk, while tDCS appears less effective but is user-friendly and

could be applied at home with a relatively small cost. For these reasons, further evaluation of the utility

of these methods for aphasia rehabilitation should combine efficacy and feasibility data, making a cost benefit

analysis possible. Still, in the future the most important challenge will be to collect clear evidence

of the long-term efficacy in the everyday life of these methods.

Risk of bias

A: Moderate (sequence allocation, loss to follow-up, selective outcome reporting, trial ended early)

C: High (all domains)

D: High (all domains)

E: High (all domains)

F: High (all domains)

Van Lieshout, 2019

SR and meta-analysis of  RCTs, cross-over design trials, case studies and mixed design studies.

Literature search up to January 2018

A: Cha, 2016

B: Lu, 2015

Study design:

A: RCT
B: RCT

Setting and Country:

A: Korea
B: China

Source of funding and conflicts of interest:

The authors declared no potential conflicts of interest with respect

to the research, authorship, and/or publication of this article. The authors disclosed receipt of the following financial support

for the research, authorship, and/or publication of this article: This

work was supported by the Netherlands Organization for Scientific

Research (VICI 016.130.662).

Inclusion criteria SR: 1) patients

with ischaemic or haemorrhagic stroke; (2) age ≥ 18 years;

(3) the use of NIBS (TMS, TBS, or tDCS); (4) objective,

standardized tests or test batteries for assessment of cognitive

function; and (5) baseline measurement and posttreatment

measurement(s)

Exclusion criteria SR:

(1) nonhuman

studies and (2) studies that only tested effects on motor, language

functions and perception.

2 studies included

Important patient characteristics at baseline:

N, mean age

A: 30 patients, 63.7 yrs

B: 40 patients, 44.9 yrs

Sex:

A: 53.3% Male

B: 62.5% Male

Stroke
A: 60% ischaemic

B: n.r.

comparable at baseline?

Yes

Describe intervention:

A: LF rTMS + PT (5/wk x 4 weeks)

B: LF rTMS + comp.-assisted cognitive training, 10 min. x 20 sessions, x5/wk x 4 weeks

Describe  control:

A: PT, 5/wk x 4 weeks

B: sham rTMS + comp.-assisted cognitive training, 10 min. x 20 sessions, x5/wk x 4 weeks

End-point of follow-up:

A: post-intervention

B: 3 days and 2 months post treatment.

For how many participants were no complete outcome data available?

(intervention/control)

A: 0

B: 0

≤ 3 months

Visual and spatial attention

Defined by the line bisection test (A¹) and Albert Test (A²).
Effect measure: mean difference (95% CI):

LF-rTMS
A¹: 8.00 (5.27 – 10.73)

A²: 15.27 (11.25 – 19.29)

B: n.r.

Global cognitive functioning

Defined by the MoCA test.

Effect measure: mean difference (95% CI):

LF-rTMS
A: n.r.
B: 2.31 (1.07 – 3.55)

Memory

Defined by the RBMT
Effect measure: standardized mean difference (95% CI):

LF-rTMS
A: n.r.
B: 2.81 (1.50 – 4.12)

Executive functioning

n.r.

>3 months

Visual and spatial attention
n.r.

Global cognitive functioning
n.r.

Memory

n.r.

Executive functioning

n.r.

Author’s conclusion:

Our review suggests that NIBS is

able to alleviate neglect after stroke. However, the results are still inconclusive and preliminary for the effect of NIBS on

other cognitive domains. A standardized core set of outcome measures of cognition, also at the level of daily life activities

and participation, and international agreement on treatment protocols, could lead to better evaluation of the efficacy of

NIBS and comparisons between studies.

Risk-of-bias:

A:

B: publication bias (funding)

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Choi, 2016

Type of study:

Cross-over study design

Setting and Country: Department of Rehabilitation Medicine, Gwangju Veterans Hospital, Gwangju, Korea.

Funding and conflicts of interest:
No potential conflict of interest relevant to this article was reported.

Inclusion criteria:

(1) brain lesion detectable by magnetic resonance imaging or computed tomography which were taken at the onset of the symptom; (2) the location of subcortical lesion was in middle cerebral artery (MCA) territory; (3) the time gap between enrollment in the present study and occurrence of cerebral infarct was a minimum of 6 months and a maximum of 10 years; (4) mild to moderate balance impairment (score of Berg Balance Scale (BBS) was ≥20 and ≤46; and (5) Korean version of Mini-Mental State Examination score was ≥24, indicative of cognitive ability, which was sufficient to understand the nature of study.

Exclusion criteria:
(1) having other neurologic problems, which can affect balance ability; (2) intake of drugs that can affect balance function; and (3) presence of contraindications for rTMS (pacemaker, cochlear implants, metal in the brain or skull, or history of epilepsy).

N total at baseline:
Intervention: 15
Control: 15

Important prognostic factors²:

Age: mean (SD)
I: 67.1 ± 3.8
C: 68.7 ± 5.2

Sex (% Male):
I: 93,3%
C: 86.7%

Groups comparable at baseline?
Yes

The rTMS cycles were composed of 10 sessions each administered over two weeks, and separated by a 4-week washout period.

Real rTMS was delivered at 10 Hz and 90% of RMT for 5 seconds with 25-second inter-train interval. A total of 1,000 pulses were delivered over a period of 10 minutes.

The sham rTMS cycles were composed of 10 sessions each administered over two weeks, and separated by a 4-week washout period.

For sham rTMS, the treatment cycles were same as that of real rTMS; however, sham coil (MCF-P-B70, MagVenture) which provides sound and the sensation of scalp similar to the real rTMS coil, but does not induce a magnetic field was used.

Length of follow-up:
One day after treatment and one month after treatment.

Loss-to-follow-up (3 months)

N=3
Reasons: occurrence of latest cerebral infarction, occurrence of benign paroxysmal positional vertigo, worsening of general condition.

Incomplete outcome data:
n.r.

Walking
n.r.

Maintaining standing balance
Defined by the BBS test score

Effect measure: MD (95% CI)
1.0 (-3.98 – 5.98)

Muscle power/synergies
n.r.

Sitting balance
n.r.

Transferring oneself
n.r.

Walking long distances
n.r.

Walking speed
n.r.

Falling
n.r.

In conclusion, to the best of our knowledge, this is the first study to investigate the therapeutic effects of rTMS over the trunk motor cortex on balance function in stroke patients. Our results show that high frequency rTMS may be used as one of the strategies for treating chronic stroke patients with balance impairment. Further studies are required to assess not only underlying mechanisms but also detailed protocol.

Forogh, 2017

Type of study:
randomized double blind clinical trial

Setting and Country: Neuromusculoskeletal Research Center, Firoozgar Hospital, Tehran, Iran.

Funding and conflicts of interest:
All authors certify that this manuscript has neither been
published in whole nor in part nor being considered for
publication elsewhere. The authors have no conflicts of interest to declare.

Inclusion criteria:

stroke patient with subacute and chronic ischaemic and hemiplegic stroke documented by Computed Tomography (CT) or MRI; at least one month has elapsed from stroke; first-ever cerebral infarction; ability to perform 3-step command (3 points); no cognitive impairment, impaired patient’s balance and gait; the ability to walk with or without support; and with Functional Ambulation Categories more than one.

Exclusion criteria:

Patients were not included in the study if they had: a second stroke, bilateral weakness; the cerebel-lum or brain stem involvement, proprioception impairment, hemianopsia or another visual impairment, vestibular dysfunction, neurologic comorbidity other than stroke like neuropathy, severe postural instability, orthopedic problems, significant cognitive problem, receptive aphasia, epilepsy or seizures after stroke, and pathological conditions referred as contraindica-tions of rTMS (presence of a metallic implant inside the eye or the brain, the external fixator, cardiac pacemaker).

N total at baseline:
26

Important prognostic factors²:

Age: range
53 – 79 yrs

Sex (% Male):
61.5%

Groups comparable at baseline?
n.r.

Treatment was carried in 5 consecutive days, with 1 Hz rTMS in contralateral brain hemisphere over the primary motor area for 20 minutes (1200 pulses), in sitting position. Low-frequency rTMS was administered by a 70-mm figure-8 coil connected to Magstim R30 stimulator (MagVenture, Denmark). The optimal site and intensity of stimulation was deter-mined based on proposed method of Kondo et al., (2013).

for Sham stimulation, we recorded the sound of stimulator. A small speaker was installed on the stimulation coil handle. The coil was placed on the head, adjustments were done on the rTMS monitor, but speaker was activated by a switch behind the patient. A sound mimicking the real rTMS was played for the patient.

Length of follow-up:

Directly after treatment, 3 weeks and 3 months thereafter.

Loss-to-follow-up (3 months)

After treatment: 0
3 weeks: 0
3 months: 11

Reasons: Study withdrawal

Incomplete outcome data:
n.r.

Walking
n.r.

Maintaining standing balance
Defined by the BBS test score (0-56)

Effect measure: MD (95% CI)
1.80 (-0.77 – 4.37)

Muscle power/synergies
Defined by the FM-LE test score (0-34)

Effect measure: SMD (95% CI)
-1.02 (-1.88 - -0.16)

Sitting balance
n.r.

Transferring oneself
n.r.

Walking long distances
n.r.

Walking speed
n.r.

Falling
n.r.

The present study showed that rTMS as an adjuvant therapy may improve the static postural stability, falling risk, coordination, motor recovery, and muscle strength in patients with stroke. These effects could persist up to 3 months. Further research should be conducted with larger sample size.

Huang, 2018

Type of study:
A Randomized Controlled Trial

Setting and Country: From the Neuroscience Research Center and Department of Neurology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan (Y-ZH).

Funding and conflicts of interest:
This study was supported by grants from Wan Fang Hospital, Taipei Medical University (104-wf-eva-11), the Ministry of Science and Technology (MOST-102-2314-B-182-030-MY3), and the Chang Gung Medical Foundation (CMRPD3E0112 and BMRP844). Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.

Inclusion criteria:

(1) first-ever supratentorial stroke in the past 10–90 days, (2) an age of 18–80 yrs, and (3) displaying substantial leg disabilities and inability to complete a Timed Up and Go (TUG) test within 2 mins independently even with orthosis.

Exclusion criteria:

Patients were excluded if they had contraindications to (r)TMS,21 had reported walking impairment before the stroke, or had no recordable motor evoked potentials (MEPs) from the quadriceps of M1CL in the pretreatment assessment.

N total at baseline:
Intervention: 18
Control: 20

Important prognostic factors²:

Age: mean ± SD
I: 62.2 ± 10.4
C: 61.2 ± 9.4

Sex (% Male):
I: 55.6%
C: 65%

Groups comparable at baseline?
n.r.

One-Hertz rTMS was produced by a Magstim Rapid2 stimulator with a double-cone coil. A stimulus intensity at 120% of the aMTwas adopted. The aMTand stimulation location (hot spot) were determined during the TMS procedure in the pretreatment assessment. Group E received real rTMS. Interventions included 15 daily sessions of 15 mins of 1-Hz rTMS (900 pulses, either real or sham) immediately followed by 45 mins of regular PT by physical therapists who were blinded to the treatment assignment. The preceding rTMS could potentially prime functional networks for the following physical intervention and lead to superior outcomes17 probably through the mechanism of metaplasticity. The routine PT program was customized and based on the participant's performance. All the participants also received occupational therapy, and some of them had speech therapy. However, only rTMS and PTwere provided in sequence.

One-Hertz rTMS was produced by a Magstim Rapid2 stimulator with a double-cone coil. A stimulus intensity at 120% of the aMTwas adopted. The aMTand stimulation location (hot spot) were determined during the TMS procedure in the pretreatment assessment. Group C group C received sham rTMS using a customized sham coil. included 15 daily sessions of 15 mins sham immediately followed by 45 mins of regular PT by physical therapists who were blinded to the treatment assignment. The preceding rTMS could potentially prime functional networks for the following physical intervention and lead to superior outcomes17 probably through the mechanism of metaplasticity. The routine PT program was customized and based on the participant's performance. All the participants also received occupational therapy, and some of them had speech therapy. However, only rTMS and PTwere provided in sequence.

Length of follow-up:
Directly after treatment and 3 months thereafter.

Loss-to-follow-up (3 months)

After treatment: 0/1
3 months: 1/2

Reasons: refused to continue, loss of contact, rejection of the assessment.

Incomplete outcome data:
n.r.

Walking
n.r.

Maintaining standing balance
n.r.

Muscle power/synergies
n.r.

Sitting balance
n.r.

Transferring oneself
Defined by the number of patients who finished the TUG test within 2 minutes.

Effect measure: RR (95% CI)
1.33 (0.49 – 3.63)

Walking long distances
n.r.

Walking speed
n.r.

Falling
n.r.

The present study found insufficient evidence that contralesional priming with 1-Hz rTMS improves ambulatory and other motor functions among patients with a severe leg dysfunction in subacute stroke.

Koch, 2019

Type of study:
randomized clinical trial.

Setting and Country: Santa Lucia Foundation IRCCS

Funding and conflicts of interest:
n.r.

Inclusion criteria:

(1) first ever chronic ischaemic stroke (i.e., at least 6 months after the stroke event); (2) hemiparesis due to left or right subcortical or cortical lesion in the territory of the middle cerebral artery; and (3) residual gait and balance impairment.

Exclusion criteria:

(1) history of seizures; (2) severe general impairment or concomitant diseases; (3) patients older than 80 years; and (4) treatment with benzodiazepines, baclofen, and antidepressants.

N total at baseline:
Intervention: 18
Control: 18

Important prognostic factors²:

Age: mean ± SD
I: 63.4 ± 11.1
C: 64.9 ± 11.9

Sex (% Male):
I: 76.5%
C: 58.8%

Groups comparable at baseline?
Yes

Each patient performed 1 session per day of conventional PT. Physiotherapy consisted of exercises designed to promote recovery of voluntary motor and balance functions, including muscle stretching, active-assisted mobilizations, progressive neuromuscular facilitation training balance exercises, and gait training,21 lasting 90 minutes including rest periods between exercises. During gait training, the therapist (A.M.C.) was positioned behind the patient to support hip and trunk stability. Cerebellar intermittent θ-burst stimulation was carried out using a Magstim Rapid magnetic biphasic stimulator connected with a figure-8 coil with a 70-mm diameter (Magstim Company). Before each daily PT session, 2 runs of CRB-iTBS were applied over the contralesional lateral cerebellum, spaced by an interval of 5 minutes.12 For each stimulation session, in total, we delivered 1200 pulses over the lateral cerebellum, contralateral to the affected hemisphere.13,14,15,16 Cerebellar intermittent θ-burst stimulation intensity was set at 80% of the active motor threshold,22 adjusted according to the individual scalp-to-cortex distance.23 The coil was positioned tangentially to the scalp, with the handle pointing superiorly.24 A neuronavigation system (SofTaxic; EMS) coupled with a Polaris Vicra infrared camera was used to ensure that in each patient, CRB-iTBS was applied over the same spot across different sessions.

sham iTBS

Length of follow-up:
After 3 weeks of treatment (T1) and 3 weeks after the end of treatment (T2)

Loss-to-follow-up

T1: 0/0
T2: 1/1

Reasons: Discontinued intervention (pneumonia / depression)

Incomplete outcome data:
n.r.

Walking
n.r.

Maintaining standing balance
Defined by the BBS test score

Effect measure: MD (95% CI)
7.3 (4.54 – 10.06)

Muscle power/synergies
n.r.

Sitting balance
n.r.

Transferring oneself
n.r.

Walking long distances
n.r.

Walking speed
n.r.

Falling
n.r.

In conclusion, we provide novel evidence that combining CRB-iTBS with traditional PT is an effective strategy to promote gait and balance recovery by engaging successful cerebello-cortical reorganization in patients with ischaemic stroke.

Chiu, 2020

Type of study:

A

phase 1/2a randomized trial

Funding and conflicts of interest:

This study was funded by grants

from the Translational Research Initiative of the Houston

Methodist Research Institute and Seraya Medical, LLC to

Drs. Helekar and Chiu. We thank Dr. Susan Xu, Ph.D. of

Houston Methodist Research Institute for conducting statistical

analysis of the data. Dr. Helekar is listed as an inventor on U.S. patent numbers 9456784, 10398907 and 10500408 covering the device used in this study. The patent is licensed to Seraya Medical, LLC. On behalf of all other authors, the corresponding author states that they do not have a conflict of interest.

Inclusion criteria

1) Chronic stable ischaemic

stroke (>3 months from acute event); 2) Persistent unilateral

weakness involving at least the upper extremity verified by clinical neurological examination; and 3) Age 18 to 80 years.

Exclusion criteria:
1) Seizure history or epileptogenic activity on screening electroencephalogram; 2)

Any active unstable medical condition; 3) Pregnancy, schizophrenia, bipolar disorder, alcoholism, or substance

abuse; 4) Any condition precluding MRI; and 5) Botulinum toxin use within 2 months.

N total at baseline:

Intervention: 16

Control: 15

Important prognostic factors²:

There were no significant treatment group differences in

baseline physical and demographic characteristics including

age, gender, race, affected side, cortical versus subcortical

lesion location, time since stroke, and pre-treatment

fMRI profile (Supplemental Table S1).

TRPMS microstimulators were attached (using Velcro)

to a neoprene cap (Fig. 2) resembling in appearance and

feel to a modified diving or swimming cap. On the contralesional

side, two microstimulators were placed on primary motor cortical (PMC) sites 1 cm and 4 cm lateral

to midline. Contralesional PMC was identified by locating

the activation of the hand motor area in the precentral

gyrus in an fMRI scan involving gripping movements of

the normal hand. On the ipsilesional side, microstimulators

were placed on the lateral premotor cortical (LPC)

site 5 cm anterior to the international 10 20 system electroencephalographic

(EEG) electrode locus C3 or C4, and

the supplementary motor cortical (SMC) site 15% of the

nasion-to-inion distance anterior to EEG locus Cz.21 In

addition, two microstimulators were placed on ipsilesional

sites surrounding the infarct lesion on the PMC and

the postcentral gyrus 4 cm apart. In subjects who had a

subcortical infarct and intact PMC, the microstimulator

pair was placed over the MRI-localized precentral gyrus

1 cm and 4 cm lateral to midline. The stimulus protocol

was programmed to a Bluetooth-enabled microcontroller

operated by smartphone. Treatment consisted of 40-minute

sessions of TRPMS stimulation each day 5 times per

week for a total of 20 sessions over 4 weeks. The subject

sat in a relaxed position during stimulation. Stimulus

pulse duration was 100 msec and frequency 0.2 Hz on the

contralesional side. Stimulus duration and frequency on

the ipsilesional side (perilesional/PMC, LPC and SMC)

were 25 ms and 5 Hz respectively. The strength of the stimuli was the maximum generated by the TRPMS

device prototype and known to modulate muscle activity

and cortical excitability upon stimulation of the motor

representation of the muscle.

Sham stimulation.

Length of follow-up:

After treatment.

Loss-to-follow-up:

Intervention: 1

Control: 0

Reasons: Early termination.

Incomplete outcome data:

n.r.

≤ 3 months

Upper Limb Capacity
n.r.

Upper limb muscle synergies
n.r.

Strength
n.r.

Activities of daily living
n.r.

>3 months

Upper limb capacity
Effect measure: standardized mean difference (95% CI):

TRPMS
0.22 (-0.50 – 0.94)

Upper limb muscle synergies
Effect measure: mean difference (95% CI):

TRPMS
5.80 (-23.51 – 35.11)

Strength
Effect measure: standardized mean difference (95% CI):

TRPMS
-0.00 (-0.72 – 0.71)

Activities of daily living
n.r.

Multifocal bilateral

TRPMS was safe and showed significant fMRI changes suggestive of functional

reorganization of cortical circuits in patients with chronic ischaemic stroke. A larger

randomized clinical trial is warranted to verify recovery of motor function.

Ren, 2019

Type of study:

A Randomized

Sham-Controlled Study

Setting and country:

Department of Neurological Rehabilitation, Wuxi Tongren Rehabilitation Hospital of NanjingMedical University,

Wuxi, Jiangsu Province, China

Funding and conflicts of interest:

The authors declare that there are no conflicts of interest

regarding the publication of this paper. The authors thank all those who participated in the trial. This work was supported by the National Natural Science

Foundation of China (Grant number 1501949). Contributor Shuyuan Wu participated in the treatment of participants.

Inclusion criteria:

1) a first-ever leftsidedmiddle

cerebral artery (MCA) strokewith the lesion site verified by magnetic resonance imaging (MRI); (2) the time between 4 and 12 weeks after suffering from the stroke; (3) global aphasia defined by WAB-AQ scores; and (4) written informed consent from all subjects who participated in the study.

Exclusion criteria:

(1) vision and hearing disabilities that might interfere with diagnostic and therapeutic treatment; (2) medications altering the level

of cortical excitability (e.g., antiepileptics, neuroleptics or benzodiazepines); (3) a history of substance abuse, premorbid dementia or any neuropsychiatric diseases; and (4) contraindications for rTMS according to the safety guidelines.

N total at baseline:

rTMS-w: 18

rTMS-b: 13

Sham: 15

Important prognostic factors²:

Age: mean ± SD

rTMS-w: 65.95 ± 8.53

rTMS-b: 62.46 ± 10.95

Sham: 63.60 ± 16.71

Sex:

rTMS-w: 66.7%

rTMS-b: 53.8%

Sham: 60.0%

Groups comparable at baseline?

All three groups were balanced at baseline with respect to the severity of aphasia,

time since onset, participant age, gender and concomitant diseases (P>0.05)

Those receiving real inhibiting rTMS on the right pars triangularis

of the pIFG, which is the homolog of the left Broca’s area (the

rTMS-b group); those receiving real inhibiting rTMS on the right pSTG, which is the homolog of the left Wernicke’s area

(the rTMS-w group); and those receiving sham rTMS (the sham group), all in combination with SLT. The allocations

were stored in sealed, numbered envelopes. The subjects did not know whether they were receiving real or sham

rTMS. The language therapist assessed speech and language

abilities and was blinded to the patients’ group assignments. All subjects, investigators (except the investigator responsible for rTMS application), clinicians, speech, and language

therapists were blinded to patient assignment to real or sham rTMS.

The therapeutic procedure consisted of rTMS sessions and SLT. Subjects in all three groups underwent SLT sessions for 30 minutes immediately after finishing rTMS treatment

from Monday to Friday for 3 weeks. The speech and language training mainly focused on the comprehension and

expression of spoken language. The rehabilitation program

focused on specific training to stimulate various aspects of

the language system (e.g., semantic, phonological, syntactic

or motor).

The sham group was given sham rTMS, also incombination with SLT.

Length of follow-up:

After treatment and 3 weeks of follow-up.

Loss-to-follow-up:

rTMS-w: 0
rTMS-b: 3

Sham: 2

Reasons: Complications

Incomplete outcome data:

rTMS-w: 0
rTMS-b: 2

Sham: 1

Reasons: Discontinued intervention (refusal).

≤ 3 months

Functional communication

Effect measure: mean difference (95% CI) in WAB-AQ:

rTMS-w

0.72 (-0.14 – 1.58)

rTMS-b

0.75 (0.21 – 1.70)

Verbal comprehension

Effect measure: mean difference (95% CI) in standardized z-scores of the comprehension test:

rTMS-w

1.02 (0.13 – 1.91)

rTMS-b

0.77 (-0.18 – 1.73)

Expressive naming

Effect measure: mean difference (95% CI) in WAB naming score:

LF-rTMS-w

0.01 (-0.82 – 0.84)

LF-rTMS-b

0.41 (-0.52 – 1.34)

> 3 months

n.r.

Many studies have reported that low frequency rTMS is

beneficial for rehabilitating patients with aphasia, but the

ideal stimulation sites for rTMS are not known. Lowfrequency

rTMS applied to the right pIFG and pSTG can be assumed to be an effective treatment for global aphasia

following subacute stroke. Even immediately after the 15-day treatment, LF-rTMS inhibited the right pSTG and promoted significantly increased gains in auditory comprehension and

repetition, whereas LF-rTMS inhibited the right pIFG and

apparently caused changes in spontaneous speech and repetition.

Further investigations are necessary to explore the

neural mechanisms that underlie the differences in functional recovery observed between the different stimulation sites in this study.

Rubi-Fessen, 2015

Type of study:

A Randomized Controlled Study

Setting and country:

Neurologic rehabilitation hospital, Germany.

Funding and conflicts of Suppliers

a. Magstim Rapid2 stimulator; The Magstim Company Ltd.

b. SPSS version 20; IBM Corp.

Inclusion criteria:

1) subacute aphasia with testability for the

Aachen Aphasia Test (AAT)30; (2) poststroke period up to 16 weeks (but most were 4e6wk poststroke); (3) right handedness as

measured by the Laterality Questionaire31; (4) German as the first language; and (5) age between 55 and 85 years. other neurological disease.

Exclusion criteria:

1) prior symptomatic cerebrovascular accidents; (2) neurodegenerative or psychiatric disease; (3) epilepsy; and (4)

auditory or visual deficits that might impair testing.

N total at baseline:

Intervention: 15

Control: 15

Important prognostic factors²:

For example

age ± SD:

I: 67.9 ± 8.12

C: 69.6 ± 6.67

Sex:

I: 33.3% M

C: 60% M

Groups comparable at baseline?

independent-sample t tests did not reveal any significant group differences with respect to age, disease duration, lesion size and aphasia severity.

The rTMS group received 20 minutes of 1-Hz rTMS over the right triangular part of the inferior frontal gyrus (center of

Brodmann area 45),

Both groups were given an intensity of 90% of the individual resting

motor threshold. The resting motor threshold was defined as the

minimum stimulator output that elicited a visible contraction on

the first dorsal interosseus muscle of the unaffected hand in more than 5 of 10 stimulation trials. Stimulation parameters were in accordance with the guidelines suggested by Wassermann.36

Before stimulation, T1-weighted, diffusion-weighted, and T2

fluid-attenuated inversion recovery MRI images were obtained to

locate the optimal coil position. The respective brain areas were

stimulated using a Magstim Rapid2 stimulatora with a double 70-mm coil. The stimulation point was determined using reference lines defined on the reconstruction of the respective patient’s head from the MRIs, which were then transferred to the patient’s head

(For details, see Weiduschat et al37). This method has an accuracy of 10mm when compared with neuronavigated methods.

The sham group) received the same stimulation over the vertex. Both

groups were given an intensity of 90% of the individual resting

motor threshold. The resting motor threshold was defined as the

minimum stimulator output that elicited a visible contraction on the first dorsal interosseus muscle of the unaffected hand in more

than 5 of 10 stimulation trials. Stimulation parameters were in

accordance with the guidelines suggested by Wassermann.36

Before stimulation, T1-weighted, diffusion-weighted, and T2 fluid-attenuated inversion recovery MRI images were obtained to

locate the optimal coil position. The respective brain areas were

stimulated using a Magstim Rapid2 stimulatora with a double 70- mm coil. The stimulation point was determined using reference

lines defined on the reconstruction of the respective patient’s head

from the MRIs, which were then transferred to the patient’s head

(For details, see Weiduschat et al37). This method has an accuracy

of 10mm when compared with neuronavigated methods.

Length of follow-up:

After treatment (10 sessions) and after 2 weeks follow-up

Loss-to-follow-up:

Intervention: 0

Control: 0

Incomplete outcome data:

Intervention: 0

Control: 0

≤ 3 months

Functional communication

Effect measure: mean difference (95% CI) in ANELT-A scale

LF-rTMS

0.09 (-0.62 – 0.81)

Verbal comphrehension

Effect measure: mean difference (95% CI) in Token Test

LF-rTMS

-0.09 (-0.82 – 0.62)

Expressive naming

Effect measure: mean difference (95% CI) in the accuracy of the naming screening test:

LF-rTMS

-0.07 (-0.78 – 0.65)

> 3 months

n.r.

The present study delivers further evidence that combining 1-Hz

rTMS with SLT leads to significant add-on treatment effects in the subacute stage of aphasia. As indicated by the results, the outcome of behavioral therapy is enhanced not only for a variety of basic linguistic skills but also for functional communication. Longitudinal

studies are required to evaluate the long-term stability of

these benefits.

Zumbansen, 2020

Type of study:

three-armed sham-controlled blinded prospective

proof-of-concept study

Setting and country:

Jewish General Hospital, Lady Davis Institute for Medical Research,

Department of Neurology & Neurosurgery, McGill University, Montreal,

Quebec

Funding and conflicts of interest:

The author(s) disclosed receipt of the following financial support

for the research, authorship, and/or publication of this

article: This trial was supported by research grants from the

Canadian Institutes for Health Research (CIHR,

MOP#125954), W.-D. Heiss Foundation, and the Lady

Davis Institute at the JGH (CLIPP#2014). AZ was funded

by a CIHR postdoctoral fellowship.

The author(s) declared no potential conflicts of interest with

respect to the research, authorship, and/or publication of this

article.

Inclusion criteria:

stroke patients presenting with speech or

language problems.

Exclusion criteria:

Withdrawal of consent, patients with very severe aphasia (who most likely

exclusively depend on the right hemisphere) were excluded from the study.

N total at baseline:

Intervention: 20

Control: 19

Important prognostic factors²:

For example

age ± SD:

I: 66.7 ± 9.8

C: 67.4 ± 11.7

Sex:

I: 50% M

C: 36.8% M

Groups comparable at baseline?

Yes

rTMS was applied over the non-affected right hemisphere

(pars triangularis of the right inferior frontal

gyrus) using a figure-of-eight coil at 1Hz for 900

pulses (15min) at 90% resting motor threshold

(RMT). RMT was determined prior to each treatment

session over the right primary motor area.13 ST sessions

were given immediately following the rTMS procedure

to ensure treatment within the period of

maximum rTMS after-effect (about 45 min).14

For sham-stimulation, the coil was placed over the interhemispheric

fissure at the vertex, and stimulation was

applied with 10% RMT.

Length of follow-up:

After treatment and after one month follow-up.

Loss-to-follow-up (after treatment)

Intervention: 2

Control: 1

Reasons: Withdrew before starting treatment and off before starting treatment.

Incomplete outcome data:

n.r.

≤ 3 months

Functional communication

n.r.

Verbal comprehension

Effect measure: mean difference (95% CI) in standardized Z-scores of the comphrehension test

LF-rTMS
-0.13 (-0.76 – 0.50)

Expressive naming
Effect measure: mean difference (95% CI) in standardized Z-scores of the Boston Naming Test

LF-rTMS
0.15 (-0.47 – 0.78)

> 3 months

n.r.

Contralesional NIBS is a safe add-on therapy for poststroke

aphasia. Low frequency rTMS improved

naming recovery one month after a 10-day treatment

course. tDCS effect was not significantly different

from sham stimulation. Our results raise the possibility

that inhibitory NIBS over the right pars triangularis may have negative effects in patients where Broca’s

Area is affected, supporting the view that NIBS presently

should not be applied outside clinical trials.

Future trials should specifically investigate individual

factors for patient stratification (e.g., lesion location)

and include longer-term follow-up outcome measures

(>6months).

Iwánski, 2020

Type of study:

RCT

Setting and country:

Inpatient inpatient or outpatient ward of the Neurorehabilitation Unit of the Institute of Psychiatry

and Neurology, Poland.

Funding and conflicts of interest:

This work was supported by the National Science

Center, grant number: UMO-2012/07/N/NZ7/01138.

The authors declare that there is no conflict of interest.

Inclusion criteria:

1) MRI or CT (in case

of contraindications to MRI) confirming a first-ever stroke in the right hemisphere; 2) time after onset 2–12 weeks (early subacute stroke; Bernhardt et al., 2017); 3) severe to moderate VSN recognized in a neuropsychological assessment; 4) age 18–75 years; 5) signed informed consent by the patient.

Exclusion criteria:

1) severe cognitive impairment; 2) a history of premorbid dementia, substance abuse, or any neuropsychiatric disease; 3) medications altering the level of cortical excitability (e.g., anti-epileptics, neuroleptics, or benzodiazepines); 4) contraindications for rTMS (intracranial metallic objects, implanted stimulator devices, or a history of seizures or epilepsy).

N total at baseline:

Intervention: 14

Control: 14

Important prognostic factors²:

age ± SD:

I: 65  ± 87.5

C: 64.6 ±  7.7

Sex:

I: 78.6 % M

C: 78.% M

Stroke type:
I: 7.1% haemorrhagic stroke

C: 7.1% haemorrhagic stroke

Groups comparable at baseline?

Yes

Stimulation was applied at 90% of the RMT at

1Hz frequency. A total of 1800 pulses were generated

during a 30-min session.

 All the participants underwent comprehensive cognitive training five days a week for four weeks. During the long-lasting rTMS, the accuracy of stimulation was constantly monitored by neuronavigation, while coil position error was recorded every 10 pulses. Deviation of up to four millimetres from the target was considered acceptable. For every participant, the percentage of pulses “in target” was estimated for each session.

VSN therapy was focused mainly on visuospatial

scanning with active and purposeful direction

of sight to the left visual field in cognitive tasks

performed in two computer programs. Additionally, paper-and-pencil tasks to improve visual scanning were used. Patients were asked to draw, copy, and analyze complex visual stimuli. The visual-scanning training was guided by verbal instruction, contralesional cues (e.g., visual stimuli), and the therapist’s feedback to orientate attention to

the neglected part of space.

The control group

received sham stimulation performed with a sham

coil that looked and sounded similar to real stimulation.

VSN therapy was focused mainly on visuospatial

scanning with active and purposeful direction

of sight to the left visual field in cognitive tasks

performed in two computer programs. Additionally, paper-and-pencil tasks to improve visual scanning were used. Patients were asked to draw, copy, and analyze complex visual stimuli. The visual-scanning training was guided by verbal instruction, contralesional cues (e.g., visual stimuli), and the therapist’s feedback to orientate attention to

the neglected part of space.

Length of follow-up:

End of treatment

Loss-to-follow-up:

0 (0%)

Incomplete outcome data:

0 (0%)

≤ 3 months

Visual and spatial attention

Effect measure: mean difference (95% CI) in behavioral inattention test

LF-rTMS

3.50 (-5.56 – 12.56)

Global cognitive functioning

n.r.

Memory

n.r.

Executive functioning

n.r.

> 3 months

n.r.

Our study did not confirm the efficacy of focused

low frequency (1 Hz) rTMS over the left angular gyrus as a  therapeutic method to ameliorate VSN in early subacute stroke patients (up to three months).

Future studies should explore the efficacy of more extensive rTMS targeted to neural substrates of visuospatial

attention.

Liu, 2020

Type of study:

RCT

Setting and country:

Inpatient rehabilitation hospital.

Funding and conflicts of interest:

The author(s) disclosed receipt of the following financial

support for the research, authorship, and/or publication

of this article: This work was supported by the National

Natural Science Foundation of China (Grant Number:

81871847), the National Natural Science Foundation of

China (Grant Number: 81672261), the National Natural

Science Foundation of China (Grant Number: 81702232),

the Natural Science Foundation of Guangdong Province

(Grant Number: 2017A030313493) and the Medical

Science and Technology Foundation of Guangdong

Province (Grant Number: A2016251).

The author(s) declared no potential conflicts of interest

with respect to the research, authorship, and/or publication

of this article.

Inclusion criteria:

Patient with a clear history of stroke who had

imaging data showing clear lesions, sudden aggravation

or ladder-like progression of attention dysfunction,

or definite time between attention

dysfunction and stroke or causality were included

in the study. Patients with attention dysfunction

screened by Mini-Mental State Examination and

Cancellation Test, those with a stable condition and

good motor function of the upper extremities of the

habitual hand were also included. Besides, the

patients had to have first onset of the disease

(course of disease; 6–12 months) and aged between

40 and 75 years old.

Exclusion criteria:

Patients with metal implants in the body or

those with a history of seizures or family history,

severe cardiopulmonary disease and multiple organ

failure, malignant tumors, and severe mental illness

were excluded from the study. We also

excluded patients with a previous history of

encephalitis, brain trauma, Alzheimer’s disease

and dementia, those with severe visual, hearing or

communication impairment as well as those who

had received TMS treatment.

N total at baseline:

Intervention: 31

Control: 31

Important prognostic factors²:

age ± SD:

I: 58.6 ± 6.2

C: 57.7 ±  7.3

Sex:

I: 34.5 % M

C: 55.2% M

Stroke type:
I: 69% infarction

C: 51.7% infarction

Groups comparable at baseline?

Yes

Patients in the TMS group received 10 Hz, 700 pulses of TMS for four weeks. TMS was applied

using a magnetic stimulation device (CCY-IA

Wuhan Yiruide Co., Ltd.), connected to a focal

figure-of-eight shape coil (each loop had a diameter

of 3.5 cm) cooled in liquid nitrogen. The “8”-shaped coil, was placed at the F3 point-left dorsolateral prefrontal cortex according to the 10– 20 electroencephalogram coordinate system, and

the coil was at a tangent with the F3 point. We only

targeted the left dorsolateral prefrontal cortex for stimulation, irrespective of the lesion hemisphere.

 All the participants underwent comprehensive cognitive training five days a week for four weeks.

The patients in the sham

group were treated with sham TMS, and the coil

was held at a 90°angles to the scalp using the

parameters as described for the TMS group.

Length of follow-up:

End of treatment

Loss-to-follow-up:

Intervention: 2 (6.5%)

Reasons: Did not receive allocated overall intervention due to discharge or withdrawal of consent.

Control: 2 (6.5%)

Reasons: Did not receive allocated overall intervention due to discharge or surgery.

Incomplete outcome data:

n.r.

≤ 3 months

n.r.

> 3 months

Visual and spatial attention

Effect measure: mean difference (95% CI) on digit symbol test

HF-rTMS
3.28 (1.39 – 5.17)

Global cognitive functioning

Effect measure: mean difference (95% CI) on the MMSE.

HF-rTMS

2.11 (0.23 – 3.99)

Memory

n.r.

Executive functioning

Effect measure: mean difference (95% CI) in TMT-A (errors and time in seconds)

HF-rTMS

Errors: 1.73 (0.81 – 2.65)

Time: 67.34 (6.90 – 167.78)

In summary, this study suggests that TMS might

be effective in improving the performance in the

activities of daily living and attention function of

stroke patients. The treatment parameters of TMS in our study is safe and does not cause brain tissue

damage. Our findings, thus support the inclusion of

the specific intervention programs in clinical practice. Further studies are necessary to evaluate

the underlying mechanism of TMS for the performance

of the activities of daily living and attention

function after stroke.

Tsai, 2020

Type of study:

RCT

Setting and country:

Taiwan.

Funding and conflicts of interest:

This work was supported by the Taipei Veterans General

Hospital Grant (V104C058). No conflicts of interests declared.

Inclusion criteria:

left hemispheric ischaemic or haemorrhagic

stroke more than 3 months previously with cognitive impairment,

defined by a Repeatable Battery for the Assessment

of Neuropsychological Status (RBANS)24 score below

85; no seizure history; no intracranial occupying lesion,

including

arteriovenous malformation or brain tumour,

according

to imaging results; and no concurrent use of antidepressants

or neurostimulators.

Exclusion criteria:

unstable cardiac dysrhythmia, fever, infection, hyperglycemia,

epilepsy or previous administration of tranquilizers,

neurostimulators or other medication that significantly

affected

the cortical motor threshold.25 We excluded patients

with metallic intracranial devices, pacemakers or

other electronic devices in their bodies. The rTMS protocols

used in the current study were in accordance with the safety

guidelines for rTMS applications.

N total at baseline:

rTMS: 14

iTBS: 15

Sham: 15

Important prognostic factors²:

For example

age ± SD:

r: 47.45 ± 12.3
i: 60.13 ± 14.1
S: 56.23 ± 12

Sex:

r: 81.8% Male

i: 73.3% Male
S: 86.7% Male

Stroke type:
r: 27.3% ischaemic
i: 46.7% ischaemic
S: 66.7% ischaemic

Groups comparable at baseline?

Each patient received 10 days of rTMS treatment, administered in the morning from Monday to Friday for 2 consecutive

weeks. The left dlPFC (F3 point) was stimulated according to the international 10/20 electroencephalography (EEG) recording system to stimulate the left prefrontal cortex.11 The intensity for the 5 Hz rTMS and iTBS groups was set at 80%

of the resting motor threshold.

The iTBS treatment consisted of 3 pulses of 50 Hz bursts repeated

at 5 Hz (2 s on and 8 s off) for a total of 190 seconds

(600 pulses). The 5 Hz rTMS protocol was applied at an intensity of 80% of the resting motor threshold, with 2 s trains (10 pulses) at an intertrain interval of 8 seconds, repeated

Every 10 seconds for a total of 10 minutes (600 pulses).

The sham condition involved similar procedures, except that a sham coil was used. We used a placebo coil (Magstim) for the sham stimulation, which delivered less than 5% of the  magnetic output with an audible click on discharge.

Length of follow-up:

Loss-to-follow-up:

rTMS: 3 (20%)

Reasons: withdrawal because of commuting difficulties.

iTBS: 0 (0%)
Sham: 0 (0%)

Incomplete outcome data:

n.r.

≤ 3 months

n.r.

> 3 months

Visual and spatial attention

n.r.

Global cognitive functioning

Effect measure: mean difference (95% CI) on the RBANS

LF-rTMS

11 (0.73 – 21.27)

Memory

n.r.

Executive functioning

n.r.

Our results demonstrated that both 5 Hz rTMS and iTBS were effective for poststroke cognitive impairment in terms of global cognition,

attention and memory function; the domain of attention was susceptible to 5 Hz modulation. Treatment with 5 Hz rTMS may slow

cognitive decline, representing both a pivotal process in poststroke cognitive impairment and an aspect of neuroplasticity that contributes

to disease-modifying strategies.

Yin (2020)

Type of study:

Randomized Clinical Trial.

Setting and country:

China

Funding and conflicts of interest:

This work was supported by the National Natural Science Foundation of China (81871847, 81672261, 1601979, 81702232, and 81972151), the Science and Technology Planning Key Project of Guangzhou (201803010119), Guangdong Basic and Applied Basic Research Foundation (2019A1515011106), and the Natural Science Foundation of Guangdong Province of China

(2017A030313493).

All authors listed have made a substantial, direct and intellectual

contribution to the work, and approved it for publication.

Inclusion criteria:

(1) stroke patients in accordance with the diagnostic criteria established by the fourth National Cerebrovascular Disease Academic Conference in 1995 confirmed by a brain CT or MRI; (2) first-ever stroke, course of stroke between 1 and 6 months; (3) right-handed; (4) aged 30– 75 years; (5) the presence of cognitive impairments (Montreal

Cognitive Assessment, MoCA < 26); (6) no severe aphasia and able of accomplishing cognitive tests; (7) stable vital signs, no progression of neurological symptoms; (8) normal cognitive functions before stroke; (9) capable of tolerating MRI scan; (10) voluntary participation and signed the informed consent.

Exclusion criteria:

The exclusion criteria were as follows: (1) non-first stroke;

(2) complete left prefrontal cortex injury confirmed by CT/MRI; (3) transcranial surgery or skull defect; (4) metal or cardiac pacemaker implants; (5) history of brain tumor, brain trauma, seizures, and risks of seizures; (6) cognitive function recession before stroke; (7) any neuropsychiatric comorbidity and affective disorder that could influence the test outcomes; (8) any other factors that could affect cognitive assessments and treatments.

N total at baseline:

Intervention: 16

Control: 18

Important prognostic factors²:

age ± SD:

Intervention: 56.69 ± 12.92
Control: 58.17 ± 11.27

Sex:

Intervention: 87.5% male

Control: 88.9% male

Stroke type:
Intervention: 68.8% ischaemic

Control: 66.7% ischaemic

Groups comparable at baseline?

Yes

For rTMS group,

the stimulating coil was placed tangentially to the surface of the skull.

All patients received treatments once a day, 5 days per week for 4 weeks. After rTMS treatments, patients received a 30-min computer assisted

cognitive rehabilitation referring to attention, executive function, memory, calculation, language and visuospatial

skills, et cetera. Therapists were blinded to assignments. Besides, during  hospitalization, patients received conventional drug

treatments recommended by the 2016 American Heart

Association/American Stroke Association recommendation

(Winstein et al., 2016).

For the no-stim control group, the coil was placed perpendicularly to the surface of the skull inducing no magnetic field. All patients received treatments once a day, 5 days per week for 4 weeks. After rTMS treatments, patients received a 30-min computer assisted

cognitive rehabilitation referring to attention, executive function, memory, calculation, language and visuospatial

skills, et cetera. Therapists were blinded to assignments. Besides, during  hospitalization, patients received conventional drug

treatments recommended by the 2016 American Heart

Association/American Stroke Association recommendation

(Winstein et al., 2016).

Length of follow-up:

After treatment (4 weeks)

Loss-to-follow-up:

rTMS: 2 (11%)

Reasons: Discontinued rTMS intervention (complained of scalp pain)

control: 0 (0%)

Incomplete outcome data:

n.r.

≤ 3 months

Visual and spatial attention

n.r.

Global cognitive functioning

Effect measure: mean difference (95% CI) n the MoCA test

HF-rTMS

7.00 (3.30 – 10.70)

Memory

Effect measure: mean difference (95% CI) on the RBMT

HF-rTMS

1.00 (-2.37 – 4.37)

Executive functioning

Effect measure: mean difference (95% CI) on the coloured dots trail/neutral words trail/incongruent coloured words in time (seconds) and errors words (n)

HF-rTMS

Errors: 0.00 (-2.17 – 2.17)/ 0.00 (-1.05 – 1.05)/ 2.00 (-0.14 – 4.14)

Time: -5.00 (-16.81 – 6.81)/ -5 (-38.16 – 28.16)//45 (15.85 – 74.35)

> 3 months

n.r.

In summary, our results suggest that high frequency rTMS

applied on the left DLPFC could improve cognitive function for

stroke patients with cognitive impairment, with accompanying

changes in the left medial prefrontal cortex.

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?⁶

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁷

Yes/no/unclear

Potential risk of publication bias taken into account?⁸

Yes/no/unclear

Potential conflicts of interest reported?⁹

Yes/no/unclear

Tung, 2019

Yes

Yes

No

Yes

Not applicable

Yes

Yes

Yes

Yes

Van Lieshout, 2019

Yes

Yes

Yes

Yes

Not applicable

Yes

No

Yes

Yes

Bucur, 2019

Yes

Yes

Yes

Yes

Not applicable

Yes

Yes

Yes

Unclear

Van Lieshout, 2019

Yes

Yes

Yes

Yes

Not applicable

Yes

Yes

Yes

Yes

Study reference

(first author, publication year)

Was the allocation sequence adequately generated? ^a

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?^b

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?^c

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?^d

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?^e

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?^f

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure^g

LOW

Some concerns

HIGH

Choi, 2016

Probably yes;

Reason: Patients were randomly divided into two groups considering their treatment order.

Definitely yes;

Reason: The subjects were randomized by other healthcare professional who did not participate in this study.

Probably no;

Reason: For sham rTMS, the treatment

cycles were same as that of real rTMS; however, sham coil (MCF-P-B70, MagVenture) which provides sound and the sensation of scalp similar to the real rTMS

coil, but does not induce a magnetic field was used. In addition, the patients were not allowed to recognize

whether it is the sham rTMS or not.

No information;

Reason: Loss to follow-up was not reported.

Definitely no;

Reason: All relevant outcomes were reported.

Definitely yes;

Reason: No other problems reported.

LOW

Forogh, 2017

No information;

Reason: No information was provided.

No information;

Reason: No information was provided.

Probably yes;

Reason: A sound mimicking the real rTMS was played for the patient, but no information was provided about the blinding of outcome assessors and data analysts.

Probably no;

Reason: Loss to follow-up was frequent, but balanced (5 and 6 from the 22 patients). 

Definitely yes;

Reason: All relevant outcomes were reported.

Definitely yes;

Reason: No other problems reported.

Some concerns (lack of information about the randomization and blinding)

Huang, 2018

Definitely yes;

Reason: With stratification regarding the stroke duration (10–30 and 31–90 day), patients were randomly allocated at a 1:1 ratio (with a block of 2) into experimental group (E) or control group (C).

No information;

Reason: No information was provided.

Definitely yes;

Reason: Patients and

the outcome measurement assessors were blinded to the treatment

assignment.

Probably yes:

Reason: loss to follow-up was infrequent and balanced 1 and 2 from the 38 patients).

Definitely yes;

Reason: All relevant outcomes were reported.

Definitely yes;

Reason: No other problems reported.

LOW

Koch, 2019

Definitely yes;

Reason: Patients were randomly assigned to 2 age-matched groups treated either with CRB-iTBS treatment or sham iTBS. The randomization algorithm used the minimal sufficient balancing method to prevent imbalances in baseline age and stroke severity

No information;

Reason: No information was provided.

Definitely yes;

Reason: Each evaluation was performed by a clinician or by a neurophysiologist who was blinded to the experimental condition of the patient.

Probably yes;

Reason: loss to follow-up was infrequent (2 patients discontinued treatment from the 36 in total).

Definitely yes;

Reason: All relevant outcomes were reported

Probably no;

Reason: The sample included patients with stroke in both hemispheres, which could have influenced literality.

Li, 2016

Definitely yes;

Reason: Patients were equally and randomly divided into three groups according to the consecutive order of admission using a random number table.

Probably yes;

Reason: Patients were equally and randomly divided into three groups according to the consecutive order of admission using a random number table.

Probably yes;

Reason: The paper was double-blinded.

Definitely yes;

Reason: The remaining 127 patients completed the trial and were included in statistical analyses

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: No other problems noted.

LOW

Volz, 2016

Probably yes;

Reasons: All subsequent patients were matched

to the most similar patient regarding the randomization factors

(1–3) and accordingly assigned to the other treatment group.

Definitely yes;

matching of patients was performed by an experimenter

(C.G.) not involved in the behavioural, electrophysiological, or neuroimaging

assessment of patients to exclude any selection bias.

Definitely no;

Reasons: We used a sham-controlled, pseudo-randomized, single-blinded

between-subject design.

Definitely yes;

Reasons: All patients completed the intervention protocol without adverse

events.

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: No other problems noted.

Some concerns (grip strength)

Long, 2018

Probably yes:

Reasons: The participants were randomized

into three groups.

Probably yes:

Reasons: The participants were randomized

into three groups.

Definitely yes;

Patients, healthcare providers and outcome assessors were blinded to the study.

Definitely yes;

All patients included underwent the intervention.

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: No other problems noted.

LOW

Ke, 2020

Definitely yes;

Reasons: The study participants were

randomly assigned to three HF-rTMS

groups using a randomization distribution

table, generated by a computer.

Definitely yes;

Reasons: The study participants were

randomly assigned to three HF-rTMS

groups using a randomization distribution

table, generated by a computer.

Definitely yes;

Reasons: These clinical outcome assessments were performed by a neurologist with experience in these scales who was blinded to the study assignment at baseline, after rTMS, and at follow-up.

Probably yes;

Reasons: Four patients were lost during follow-up: two patients in the sham group and one patient in each of the short and long ITI rTMS groups.

Definitely yes;

Reasons: All relevant outcomes were reported

Probably yes;

Reasons: No other problems noted.

Some concerns

Kim, 2020

Probably yes;

Reasons: This study was an outcome-assessor-blinded, single-center, randomized controlled pilot clinical

trial with a 1:1:1:1 allocation ratio.

Probably yes;

Reasons: This study was an outcome-assessor-blinded, single-center, randomized controlled pilot clinical

trial with a 1:1:1:1 allocation ratio.

Probably no;

Reasons: We had no choice but to adopt a single-outcome-assessor blinding approach because sham treatment was impossible due to the nature of SA, which included scalp penetration. During the study, the assessor was blinded to group assignments, and data analysts without conflicts of interest were

involved in this study.

Probably yes;

Reasons: Three did not complete treatment in the control group. One exited the study due to

orthopaedic surgery, four did not complete treatment, and two were lost to follow-up in the rTMS group.

Definitely yes;

Reasons: All relevant outcomes were reported

Probably yes;

Reasons: we did not explore the long-term additional effects on cognitive function, dysphagia, and walking and could not exclude any biasing effect of pain.

Some concerns

Harvey, 2018

Probably yes;

Reasons: This was a multicentre randomized, blinded, sham-controlled pivotal

trial comparing NBT comprising 1 Hz rTMS to noninjured hemisphere versus sham stimulation, delivered before upper limb rehabilitation

therapy. Random assignment of participants occurred at 12

sites in the United States in a 2:1 ratio of experimental treatment to

sham. An imbalanced randomization provided adequate subject exposure

to therapeutic NBT for assessment of safety.

Probably yes;

Reasons: This was a multicentre randomized, blinded, sham-controlled pivotal

trial comparing NBT comprising 1 Hz rTMS to noninjured hemisphere versus sham stimulation, delivered before upper limb rehabilitation

therapy. Random assignment of participants occurred at 12

sites in the United States in a 2:1 ratio of experimental treatment to

sham. An imbalanced randomization provided adequate subject exposure

to therapeutic NBT for assessment of safety.

Probably no;

Blinding to group

assignment included all participants and study staff except for the

NBT device operator.

Probably yes;

Reasons: Loss- to follow-up was equal in both groups.

Definitely yes;

Reasons: All relevant outcomes were reported.

Probably no;

Reasons: Although the target sample

size was achieved, follow-up was not completed after

the Data Safety Monitoring Board reported on February 26,

2016, that the second interim analysis met statistical futility

for the intervention.

LOW

Chen, 2019

Definitely yes;

Reasons: The flow diagram of the randomization procedure

and the study design are illustrated in Figs. 1 and 2, respectively.

Definitely yes;

Reasons: The flow diagram of the randomization procedure

and the study design are illustrated in Figs. 1 and 2, respectively.

Probably yes;

Reasons: The raters (occupational therapists who were only in contact with the patients during assessment), blinded to group assignment, were trained to administer outcome

measures by senior therapists prior to the experiment, and

passed a written competency and reliability test.

Definitely yes;

Reasons: One patient was lost to follow-up in the intervention group due to unavailability for intervention.

Definitely yes;

Reasons: All relevant outcomes were reported.

Probably yes;

Reason: No other problems noted

LOW

Chiu, 2020

Probably yes;

Reasons: Randomization of 30 subjects

1:1 to active and sham groups was planned.

Probably yes;

Reasons: Randomization of 30 subjects

1:1 to active and sham groups was planned.

Definitely yes;

Reasons: Certified physical therapist, were

blinded to treatment assignment. Blinding of subjects was successfully maintained.

Definitely yes;

Reasons: One patient was lost to follow-up in the intervention group due to early termination.

Definitely yes;

Reasons: All relevant outcomes were reported.

Probably yes;

Reason: No other problems noted

LOW

Ren, 2019

Probably yes;

Reason: The

patients were randomly assigned to three groups.

Definitely yes;

Reason: The allocations

were stored in sealed, numbered envelopes. The subjects

did not know whether they were receiving real or sham rTMS.

Definitely yes;

Reason: The language therapist assessed speech and language

abilities and was blinded to the patients’ group assignments.

All subjects, investigators (except the investigator responsible

for rTMS application), clinicians, speech, and language

therapists were blinded to patient assignment to real or sham rTMS.

Probably yes;

Reason: Loss to follow-up was 9.3%.

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: No other problems noted.

LOW

Rubi-Fessen, 2015

Definitely yes;

Reasons: Allocation to either real or sham stimulation was performed by a computer-generated allocation sequence

Definitely yes;

Reasons: The allocation sequence was concealed by means of consecutively

numbered sealed envelopes.

Definitely yes;

Reasons: All therapy plans were developed by the same experienced

speech and language therapist, who was blinded to group allocation

and not involved in conducting the treatment.

Definitely yes;

Reasons: Ten persons discontinued the study

during initial magnetic resonance imaging (MRI) or withdrew after enrolment

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: No other problems noted.

LOW

Zumbansen, 2020

Probably yes:

Reasons: Computer-generated, non-restricted randomization by

site was performed through an online system located at

the Department of Clinical Epidemiology at the JGH (Montreal).

Probably yes:

Reasons: Data and eligibility were entered by each study site coordinator into a web-based data capturing system. Only the technician performing the stimulation

had access to the randomization information when logging into the study platform, on the first day of treatment.

Definitely yes;

Reasons: Patients, therapist, principal investigators and

research personnel assessing clinical outcomes were

blinded to the treatment assignment. Therapists did

not attend rTMS sessions and had no access to the

tDCS device settings.

Probably yes;

Reasons: 4 patients withdrew from the study before starting treatment, 7 patients discontinued intervention and 4 patients were lost at post evaluation.

Definitely yes;

Reason: All relevant outcomes were reported

Probably no;

Reason: Imprecision and multiplicity of analyses, violation of intention-to-treat analysis.

LOW

Liu, 2020

Definitely yes;

Reasons: A computer-generated randomization table with a 1:1 ratio, created by a statistician not involved in the study, was used to randomly allocate patients into the TMS group or the sham group.

Definitely yes;

Reasons:
Group allocations were assigned  confidentiality through sealed opaque envelopes, and the envelopes were kept in a central, locked closet by independent researchers who were not involved in the study.

Definitely yes;

Reasons:
patients and healthcare providers were blinded. No information was provided about the blinding of data collectors, outcome assessors and data analysists.

Definitely yes;

Reasons:
Loss to follow-up was infrequent.

Definitely yes;

Reasons: All relevant outcomes were reported

Probably yes;

Reasons: No other problems noted.

LOW

Tsai, 2020

Definitely yes;

Reasons: Randomization order was computer generated and concealed in sequentially numbered opaque envelopes by an independent statistician.

Probably yes;

Reasons: Therapists were blinded to group allocation.

Probably yes;

Reasons: The study was double-blinded.

Probably no;

Reasons: Three patients in the 5 Hz rTMS group withdrew from the intervention sessions because of commuting difficulties

Definitely yes;

Reasons: All relevant outcomes were reported

Probably yes;

Reasons: No other problems noted.

LOW

Yin, 2020

Definitely yes;

Reasons: total of 34 PSCI patients were recruited for the present study between August 2017 and August 2019, which were subdivided for rTMS (n = 16) and no-stim control (n = 18) treatment groups using a computer-generated list of random numbers.

Probably yes;

Reasons: No information was provided about the blinding of the randomization process.

Probably yes:

Reasons: Therapists were blinded to assignments, but no information was provided about the blinding of patients, data collectors and outcome assessors.

Definitely yes;

Reasons: Loss to follow-up was infrequent.

Definitely yes;

Reasons: All relevant outcomes were reported.

Probably no;

Reasons: Only two female patients were included in each group. It is undeniable that the findings were more suitable explaining for male patients.

LOW

Iwanski, 2020

Definitely yes;

Reasons: Patients were randomly assigned (via a bespoke computer program) to either an experimental (rTMS),

or control group (sham).

Probably yes;

Reasons: Group assignments were known to the researchers who administered rTMS (ML and KP), while the neuropsychologist responsible for the

cognitive assessment and leading therapy (SI) was blind to all patient treatment allocation.

Definitely yes;

Reasons: Group assignments were known to the researchers who administered rTMS (ML and KP), while the neuropsychologist responsible for the

cognitive assessment and leading therapy (SI) was blind to all patient treatment allocation. All participants

had never experienced rTMS before, and were

unaware whether they were receiving real or sham stimulation.

Definitely yes;

Reasons: Loss to follow-up was infrequent.

Definitely yes;

Reasons: All relevant outcomes were reported.

Probably yes;

Reasons: No other problems noted.

LOW