Effects of concomitant neuromuscular electrical stimulation during repetitive transcranial magnetic stimulation before repetitive facilitation exercise on the hemiparetic hand

Abstract

BACKGROUND:

Repetitive transcranial magnetic stimulation (rTMS) and Repetitive facilitative exercise (RFE) improves motor impairment after stroke.

OBJECTIVE:

To investigate whether neuromuscular electrical stimulation (NMES) can facilitate the effects of rTMS and RFE on the function of the hemiparetic hand in stroke patients.

METHODS:

This randomized double-blinded crossover study divided 20 patients with hemiparesis into two groups and provided treatment for 4 weeks at 5 days/week. NMES-before-sham group and NMES-following-sham group performed NMES sessions and sham NMES sessions for each 2 weeks. Patients received NMES or sham NMES for the affected extensor muscle concurrently with 1 Hz rTMS for the unaffected motor cortex for 10 min and performed RFE for 60 min. The Fugl-Meyer Assessment (FMA), Action Research Arm Test (ARAT), Box and Block Test (BBT) and Modified Ashworth Scale (MAS) were used for evaluation.

RESULTS:

FMA and ARAT improved significantly during both sessions. The gains in the BBT during an NMES session were significantly greater than those during a sham NMES session. MAS for the wrist and finger significantly decreased only during an NMES session.

CONCLUSIONS:

NMES combined with rTMS might facilitate, at least in part, the beneficial effects of RFE on motor function and spasticity of the affected upper limb.

Keywords

Neuromuscular electrical stimulation hemiparesis repetitive facilitative exercise repetitive transcranial magnetic stimulation stroke

1 Introduction

Repetitive facilitative exercise (RFE) combines a high repetition rate and neurofacilitation. It is a recently developed approach to the rehabilitation of limb impairment in stroke patients (Kawahira, 2010; Shimodozono, 2013). RFE provides physical stimulation using stretch or skin– muscle reflexes elicited immediately before movements to elevate the level of excitation of injured descending motor tracts. This allows patients to induce intended movements. RFE may be more effective than conventional rehabilitation in lessening impairment and improving upper limb motor function during the subacute phase of stroke (Shimodozono, 2013).

Neuromuscular electrical stimulation (NMES) of the hemiparetic arm has been used to improve movement affected by central neuron lesions. NMES over the hemiparetic upper limb can facilitate excitation of the affected motor areas and enhance the recovery of motor dysfunction in hemiparetic stroke patients (Powell, 1999; Chipchase, 2011). NMES can be used by patients with hemiparesis who do not have sufficient residual movement to take part in volitional, active repetitive movement therapy (Chae, 2008). RFE under NMES is also feasible in clinical settings and may be more effective than conventional rehabilitation for lessening arm impairment after sub-acute stroke (Shimodozono, 2014).

On the other hand, downregulation of the contralesional motor cortex by 1 Hz repetitive transcranial magnetic stimulation (rTMS) might decrease transcallosal inhibition from the contralesional to the ipsilesional motor cortex, and thus facilitate recovery after stroke (Murase, 2004; Ward, 2004; Takeuchi, 2005; Lefaucheur, 2014). In a previous report, the group that received rTMS before physical therapy (PT) showed robust and stable improvements and the group that received PT before rTMS showing a slight decline over time (Avenanti, 2012). In our previous study, multiple sessions of 4 min of 1 Hz rTMS also facilitated the beneficial effects of RFE on motor function of the affected upper limb, but did not change spasticity (Etoh, 2013).

A previous study suggested that NMES combined with rTMS may improve motor function of the hemiparetic upper limb using a pre-/post-test design (Koyama, 2014). However, in a randomized control trial (RCT) study that included an NMES+rTMS+PT group, an rTMS+PT group and a PT group, there were no statistically significant differences in clinical outcome scores between groups (Tosun, 2017). Thus, the effects of NMES combined with rTMS on functional recovery of the hemiparetic upper limb remain unclear. We hypothesized that NMES combined with rTMS may facilitate the effect of RFE. The purpose of this study was to explore the effect of concomitant NMES during rTMS before RFE on functional recovery of the upper limb in strokepatients.

2 Methods

2.1 Subjects

Twenty stroke patients were enrolled in this crossover study. The mean age was 56.7 (standard deviation (SD), 9.0) years and the mean duration after onset was 45.9 (SD, 41.0) months. The inclusion criteria were as follows: adults (>18 years of age) who experienced a first or second unilateral stroke, chronic stroke (≧4 months duration); mild-to-moderate motor upper-limb deficits (Brunnstrom proximal upper-limb stage ≥III); and the ability to comprehend the tasks required for the intervention. The exclusion criteria were as follows: clinically unstable medical disorders; seizures; intracranial metallic implants; severe sensory disturbance, pain and contracture of the upper limb, and severe aphasia that made it impossible to follow the verbal instructions of the therapist. All subjects gave their written informed consent, and the study protocol was approved by the local ethics committee of Kagoshima University Hospital, Japan (26–151).

2.2 Experimental design

Patients were randomly assigned to two groups: an NMES-before-sham group (n = 10), which performed NMES sessions for 2 weeks followed by sham NMES sessions for 2 weeks, and an NMES-following-sham group (n = 10), which performed sham NMES sessions for 2 weeks followed by NMES sessions for 2 weeks. During NMES sessions, patients received NMES to the extensor digitorum communis (EDC) of the affected side with 1 Hz rTMS on the contralesional motor cortex for 10 min. We selected the EDC muscle for NMES because stimulation induces finger extension which is related to preshaping before a pinching movement. NMES was simultaneously applied during 1 Hz rTMS. NMES was delivered using a surface neuromuscular stimulator (Trio ES-515, Ito Co., Ltd., Tokyo). The stimulation pulse was a triangular waveform with a pulse width of 50μs. Patients received NMES at 1 Hz with a burst of 7 pulses. The intensity of the electrical current was adjusted to produce slight contraction of the target muscle (16–38.5 mA, peak voltage 150 V) while the subject remained at rest and wassubjectively comfortable. During sham NMES sessions, patients received weak NMES (1 mA) to the EDC with 1 Hz rTMS for 10 min. 1 Hz NMES and 1 Hz rTMS were not synchronized. rTMS was applied using a 70-mm figure-of-eight coil and a Magstim Rapid stimulator (Magstim Co., Dyfed, UK). rTMS was applied for 10 min, and consisted of 600 pulses over the motor cortex of the unaffected hemisphere at a frequency of 1 Hz and a stimulus intensity of 90% of the resting motor threshold (rMT). When the subject felt pain, the stimulus intensity was decreased until the subject did not feel pain, which was at 60–85% of the rMT in 7 cases. The coil was placed tangentially over the motor cortex at the optimal site for the unaffected abductor pollicis brevis (APB) muscle. This was defined as the location where stimulation at a slightly suprathreshold intensity elicited the largest MEPs in the APB. This position was marked on the scalp and used throughout the experiment. Electromyographic activity was recorded using silver– silver chloride electrodes positioned in a belly-tendon montage on the skin overlying the APB. The signal was amplified and filtered (20–5000 Hz) for on-line analysis (Neuropack MEB-2200; Nihon Koden, Tokyo). The rMT was defined as the lowest stimulator output that could produce MEPs with a peak-to-peak amplitude of >50μV in ≥50% of the 10 trials. The protocols were in accordance with the safety guidelines for rTMS application to the motor cortex (Rossi, 2009).

RFEs were performed for 60 min after NMES or sham NMES sessions. Patients underwent NMES or sham NMES sessions once daily for 5 days a week. Neural block in the upper limb was not administered during the study period. The dose of muscle relaxant was not changed during the study period.

2.3 Clinical evaluations

The popular Fugl-Meyer Assessment (FMA) was used to evaluate motor impairment (Fugl-Meyer, 1975). The motor score for the upper extremity includes 33 items and ranges from 0 to 66. The Action Research Arm Test (ARAT) and Box and Block Test (BBT) were used to assess the ability to manipulate objects. The ARAT is a commonly used, validated and reliable measure of upper-extremity function that has four subsections: grip, grasp, pinch and gross movement (Yozbatiran, 2008). The maximum summed ARAT score is 57. In BBT, the number of wooden blocks (2.5×2.5×2.5 cm) that can be transported from one compartment of a box to another within 1 min is counted. This test is simple to conduct and easy to undertake for stroke patients (Platz, 2005). The Modified Ashworth Scale (MAS) score was used to evaluate spasticity in the elbow, wrist and finger flexors of the affected upper limb (Bohannon, 1987). To facilitate data analysis, MAS scores (0, 1, 1+, 2 and 3) were assigned numerical values (0, 1, 2, 3 and 4, respectively).The FMA, ARAT, BBT and MAS scores were assessed immediately before the first sessions, and immediately after the first and second 2-week sessions, respectively. All patients were blinded to the NMES conditions. RFEs were carried out by therapists blinded to the group allocation. The FMA, ARAT, BBT and MAS scores were evaluated by a therapist blinded to the group allocation.

2.4 Data analysis

The FMA, ARAT, BBT and MAS during the combined first and second 2-week sessions of NMES were compared with those of sham NMES in all patients. Data analyses were performed using the Wilcoxon t-test. All significance tests were two-tailed, and P values <0.05 were deemed statistically significant. FMA, ARAT, BBT and MAS scores are presented as the median and range. Analysis was performed using SPSS version 24.0 for Windows.

3 Results

The subjects did not report any adverse effects during the course of the study. The characteristics of the patients in the two groups are shown in Table 1. Table 2 presents the combined data of changes in motor impairment, motor function and spasticity for the 10 patients in each group. The increases in FMA and ARAT did not differ between the NMES sessions and the sham NMES sessions. The FMA and ARAT scores of the hemiparetic upper limbs increased significantly during the 2 weeks of NMES and sham NMES sessions. The increase in the BBT scores during the NMES sessions was significantly greater than that during the sham NMES sessions. The BBT scores of the hemiparetic upper limbs increased significantly during the NMES sessions, but not during the sham NMES sessions. The decrease in MAS did not differ between the NMES sessions and sham NMES sessions. The MAS scores of the elbow flexors showed significant improvement during sham NMES sessions, but not during NMES sessions. The MAS scores for the wrist and finger flexors showedsignificant improvement during the NMES sessions and did not change during the sham NMES sessions.

Table 1
Clinical characteristics of post-stroke patients

No. Age/Sex Duration (months) Paretic side FMA ARAT BBT MAS Type Lesion site

elbow wrist finger

NMES-before-sham group

1 33/F 45 R 27 5 0 2 2 3 infarction putamen

2 40/M 4 L 36 9 1 2 2 2 hemorrhage thalamus

3 52/M 52 R 53 38 21 2 1 0 hemorrhage thalamus

4 56/M 155 L 7 0 0 4 3 3 hemorrhage putamen

5 57/M 24 L 16 4 0 2 2 3 infarction corona radiate, putamen

6 58/F 84 R 47 35 9 2 1 1 hemorrhage putamen

7 62/M 18 R 24 4 2 2 3 3 hemorrhage thalamus

8 63/F 46 R 11 3 0 2 2 3 infarction internal capsule

9 64/M 24 R 40 25 8 3 2 1 infarction MCA, ACA

10 74/M 145 L 34 26 11 2 1 2 infarction MCA

NMES-following-sham group

1 48/F 11 L 18 4 0 3 2 2 hemorrhage putamen corona radiate

2 53/M 57 R 62 42 27 0 1 1 hemorrhage putamen

3 53/M 26 R 29 11 5 2 1 1 infarction pons

4 55/M 26 R 25 8 1 1 0 0 infarction corona radiate

5 58/M 53 R 53 35 12 1 0 0 hemorrhage thalamus

6 59/M 18 R 44 33 28 2 1 1 infarction thalamus, corona radiate

7 60/F 4 L 9 0 0 2 2 2 infarction corona radiate

8 61/M 25 L 13 3 0 4 2 1 hemorrhage corona radiate, internal capsule

9 62/M 50 R 45 52 28 2 1 1 hemorrhage thalamus

10 65/M 50 L 39 11 11 4 3 3 hemorrhage putamen, corona radiate

No.	Age/Sex	Duration (months)	Paretic side	FMA	ARAT	BBT	MAS			Type	Lesion site
NMES-before-sham group
1	33/F	45	R	27	5	0	2	2	3	infarction	putamen
2	40/M	4	L	36	9	1	2	2	2	hemorrhage	thalamus
3	52/M	52	R	53	38	21	2	1	0	hemorrhage	thalamus
4	56/M	155	L	7	0	0	4	3	3	hemorrhage	putamen
5	57/M	24	L	16	4	0	2	2	3	infarction	corona radiate, putamen
6	58/F	84	R	47	35	9	2	1	1	hemorrhage	putamen
7	62/M	18	R	24	4	2	2	3	3	hemorrhage	thalamus
8	63/F	46	R	11	3	0	2	2	3	infarction	internal capsule
9	64/M	24	R	40	25	8	3	2	1	infarction	MCA, ACA
10	74/M	145	L	34	26	11	2	1	2	infarction	MCA
NMES-following-sham group
1	48/F	11	L	18	4	0	3	2	2	hemorrhage	putamen corona radiate
2	53/M	57	R	62	42	27	0	1	1	hemorrhage	putamen
3	53/M	26	R	29	11	5	2	1	1	infarction	pons
4	55/M	26	R	25	8	1	1	0	0	infarction	corona radiate
5	58/M	53	R	53	35	12	1	0	0	hemorrhage	thalamus
6	59/M	18	R	44	33	28	2	1	1	infarction	thalamus, corona radiate
7	60/F	4	L	9	0	0	2	2	2	infarction	corona radiate
8	61/M	25	L	13	3	0	4	2	1	hemorrhage	corona radiate, internal capsule
9	62/M	50	R	45	52	28	2	1	1	hemorrhage	thalamus
10	65/M	50	L	39	11	11	4	3	3	hemorrhage	putamen, corona radiate

Abbreviations: FMA, Fugl-Meyer Assessment; ARAT, Action Research Arm Test; BBT, Box and Block Test; MAS, Modified Ashworth Scale; NMES, Neuromuscular electrical stimulation; M, male; F, female; L, left; R, right; MCA, middle cerebral artery; ACA, anterior cerebral artery.

Table 2

Pre- and post-treatment FMA, ARAT, BBT and MAS scores^a

	NMES session (2 weeks)			sham NMES session (2 weeks)			P value
	Pre	Post^b	Gain^c	Pre	Post^b	Gain^c	(Gain)
FMA	34 (7–64)	39(8–64)^**	3 (–1–11)	35.5(8–62)	37(9–64)^**	2 (0–7)	0.34
ARAT	12 (0–54)	15 (3–55)^**	1 (–1–18)	11 (0–52)	13.5 (3–54)^*	1.5 (–5–12)	0.82
BBT	3.5 (0–34)	7.5 (0–38)^**	2 (0–7)	5 (0–28)	4 (0–34)	0 (–8–6)	0.02^*
MAS
Elbow	2 (0–4)	2 (0–4)	0 (–1–1)	2 (0–4)	2 (0–4)^*	0 (–1–0)	0.4
Wrist	1 (0–3)	1 (0–3)*	0 (–1–0)	1 (0–3)	1 (0–3)	0 (–1–0)	0.16
Finger	2 (0–3)	1 (0–3)*	0 (–2–0)	1 (0–3)	1 (0–3)	0 (–1–2)	0.15

Abbreviations: NMES, Neuromuscular electrical stimulation; FMA, Fugl-Meyer Assessment; ARAT, Action Research Arm Test; BBT, Box and Block Test. MAS, Modified Ashworth Scale; ^aValues are given as median (range). ^bComparison of pre- and post-treatment values in each group according to the Wilcoxon t-test: ^*P < 0.05, ^**P < 0.01. ^cP values indicate the significance level of between-group differences in gain according to the Wilcoxon t-test.

4 Discussion

Multiple sessions of NMES combined with rTMS facilitated, at least in part, the beneficial effects of RFE on motor function and spasticity of the affected upper limb in chronic stroke patients. The improvement in the BBT score during NMES sessions was significantly greater than that during sham NMES sessions. The BBT and MAS scores of the wrist and finger joint of the affected side improved significantly during NMES sessions, but not during sham NMES sessions. The combination of NMES for the affected forearm and 1 Hz rTMS for the unaffectedmotor cortex with RFE produced significantly greater improvement. These results demonstrated that NMES combined with rTMS enhanced the improvement of the affected hand function through a motor-training effect in chronic patients after stroke.

A previous study reported that NMES combined with rTMS improved FMA, Wolf Motor Function Test (WMFT) and BBT with a pre-/post-test design in patients with chronic stroke (Koyama, 2014). In a previous RCT study, patients were divided into 3 groups (NMES+rTMS+PT, rTMS+PT, PT). Most of the clinical outcome scores, such as the Brunnstrom recovery stage, FMA, Motricity Index, and Barthel Index improved significantly in all groups, but no statistically significant difference was found between groups in the paretic hand of patients with acute/subacute ischemic stroke (Tosun, 2017). Our study extends the findings of these previous studies. Although the improvements in FMA and ARAT during NMES sessions were not different than those during sham NMES sessions, the improvements in BBT scores in NMES sessions were significantly greater than those in sham NMES sessions in our study. The MAS scores for the wrist and finger flexor only improved in NMES sessions. These results demonstrate the efficacy of the combination of NMES with rTMS in chronic stroke patients.

In a previous study, NMES parameters were a stimulation cycle of 500 ms on and 500 ms off and synchronous onset with 1 Hz rTMS (Koyama, 2014). We also tried to synchronize 1 Hz NMES with 1 Hz rTMS, but were unable to do so because the NMES stimulator could not input a trigger signal. The combination of central and peripheral stimulation with an appropriate timing as in paired associative stimulation (PAS) (Stefan, 2000) seems to be important for changing cortical and spinal excitability and inducing plasticity. Synchronized NMES with rTMS under an appropriate timing might produce a better effect for functional recovery.

The duration of NMES, rTMS and number of sessions in previous studies were 15 min and 24 sessions (Koyama, 2014) and 20 min and 20 sessions (Tosun, 2017). In our study, these values were 10 min and 10 sessions. Despite the shorter duration of stimulation and smaller number of therapeutic sessions, this study showed an enhancing effect of NMES with rTMS. NMES combined with rTMS was considered to be sufficient for enhancing the effect of RFE, because RFE can facilitate and directly repeat isolated movements in the hemiparetic upper limb over a relatively short time period. RFE can repeat and improve target movements, such as elbow extension, finger extension and thumb abduction. The combinationof NMES with rTMS and RFEs might facilitate use-dependent plasticity.

In the present result, the BBT scores and the MAS scores for the wrist and finger flexor improved significantly only in NMES and rTMS sessions. The BBT score seems to be influenced by the function of a distal joint (wrist and finger joint) rather than a proximal joint (shoulder and elbow joint) of the upper limb. The improvement of the BBT and MAS scores for the wrist and finger joint might depend on the improvement of the function and spasticity of the distal portion of the upper limb. This may be due to the target muscles of NMES and rTMS, which are the EDC and APB, respectively. The MAS score for the elbow flexor as a proximal muscle improved only in sham NMES sessions, perhaps because the elbow flexor was not the target muscle of NMES or rTMS. Cortical and peripheral stimulation and repeated voluntary movement of the target muscle might be important for functional recovery of the hemiparetic upper limb.

Some limitations of the current study should be noted. First, it might be underpowered to show a difference in FMA or ARAT. A statistically significant benefit of adding concomitant NMES to rTMS was noted by measures of dexterity (BBT) and spasticity (MAS), but not by “whole-upper-limb” measures of motor impairment (FMA) and motor function (ARAT). Further, although the between-group difference in the increase in BBT was statistically significant, the crude median difference was only 2 blocks. This might not be clinically significant, because the minimum detectable change for the BBT is 5.5 blocks in acute and chronic stroke patients (Chen, 2009). Similarly, although the MAS for the wrist and finger flexor significantly improved in NMES sessions, the gains were small. The small size of the study group prevented us from showing a clear difference in FMA, ARAT, BBT and MAS. Second, our study might be biased with respect to the patient age and the type of stroke, and there was no follow-up evaluation. The mean age of the patients in this study was 56.7 years, which is relatively young; in 2005, the mean age of stroke onset in the US was 69.2 years (Kissela, 2012). On the other hand, 11 of 20 patients (55%) in this study had hemorrhagic stroke, which is less common and usually has a better prognosis in terms of functional recovery. About 10% of all strokes in the US are due to hemorrhage. Further research will be needed to confirm the effectiveness of combining NMES and rTMS before RFE. We would have to perform a larger study with ischemic stroke patients, and test for improvements measured by BBT and MAS at post-training follow up sessions. Third, we did not measure neurophysiological data. We were unable to investigate whether NMES and rTMS decreased excitability in the intact hemisphere and increased excitability in the affected hemisphere.

In conclusion, we showed that multiple sessions of NMES for the affected upper limb facilitated, at least in part, the effects of 1 Hz rTMS for the unaffected motor cortex and RFE on hemiparetic upper-limb function in chronic stroke patients.

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Footnotes

Acknowledgments

This work was supported in part by JSPS KAKENHI Grant Number 25350605.

References

Avenanti,

, Coccia,

, Ladavas,

, Provinciali,

, & Ceravolo,

M. G.

(2012). Low-frequency rTMS promotes use-dependent motor plasticity in chronic stroke: A randomized trial. Neurology, 78, 256-264.

Bohannon,

R. W.

, & Smith,

M. B.

(1987). Interrater reliability of a modified Ashworth scale of muscle spasticity. Physical Therapy, 67, 206-207.

Chae,

, Sheffler,

, & Knutson,

(2008). Neuromuscular electrical stimulation for motor restoration in hemiplegia. Topics in Stroke Rehabilitation, 15, 412-426.

Chen,

H. M.

, Chen,

C. C.

, Hsueh,

I. P.

, Huang,

S. L.

, & Hsieh,

C. L.

(2009). Test-retest reproducibility and smallest real difference of 5 hand function tests in patients with stroke. Neurorehabil Neural Repair, 23, 435-440.

Chipchase,

L. S.

, Schabrun,

S. M.

, & Hodges,

P. W.

(2011). Peripheral electrical stimulation to induce cortical plasticity: A systematic review of stimulus parameters. Clinical Neurophysiology, 122, 456-463.

Etoh,

, Noma,

, Ikeda,

, Jonoshita,

, Ogata,

, Matsumoto,

, Shimodozono,

, & Kawahira,

(2013). Effects of repetitive transcranial magnetic stimulation on repetitive facilitation exercises of the hemiplegic hand in chronic stroke patients. Journal of Rehabilitation Medicine, 45, 843-847.

Fugl-Meyer,

A. R.

, Jääskö,

, Leyman,

, Olsson,

, & Steglind,

(1975). The post-stroke hemiplegic patient. 1. a method for evaluation of physical performance. Scandinavian Journal of Rehabilitation Medicine, 7, 13-31.

Kawahira,

, Shimodozono,

, Etoh,

, Kamada,

, Noma,

, & Tanaka,

(2010). Effects of intensive repetition of a new facilitation technique on motor functional recovery of the hemiplegic upper limb and hand. Brain Injury, 24, 1202-1213.

Kissela,

B. M.

, Khoury,

J. C.

, Alwell,

, Moomaw,

C. J.

, Woo,

, Adeoye,

, Flaherty,

M. L.

, Khatri,

, Ferioli,

, De Los Rios La Rosa,

, Broderick,

J. P.

, & Kleindorfer,

D. O.

(2012). Age at stroke: Temporal trends in stroke incidence in a large, biracial population. Neurology, 79, 1781-1787.

10.

Koyama,

, Tanabe,

, Warashina,

, Kaneko,

, Sakurai,

, Kanada,

, Nagata,

, & Kanno,

(2014). NMES with rTMS for moderate to severe dysfunction after stroke. Neuro Rehabilitation, 35, 363-368.

11.

Lefaucheur,

J. P.

, André-Obadia,

, Antal,

, Ayache,

S. S.

, Baeken,

, Benninger,

D. H.

, Cantello,

R. M.

, Cincotta,

, de Carvalho,

, De Ridder,

, Devanne,

, Di Lazzaro,

, Filipović,

S. R.

, Hummel,

F. C.

, Jääskeläinen,

S. K.

, Kimiskidis,

V. K.

, Koch,

, Langguth,

, Nyffeler,

, Oliviero,

, Padberg,

, Poulet,

, Rossi,

, Rossini,

P. M.

, Rothwell,

J. C.

, Schönfeldt-Lecuona,

, Siebner,

H. R.

, Slotema,

C. W.

, Stagg,

C. J.

, Valls-Sole,

, Ziemann,

, Paulus,

, & Garcia-Larrea,

(2014). Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clinical Neurophysiology, 125, 2150-2206.

12.

Murase,

, Duque,

, Mazzocchio,

, & Cohen,

L. G.

(2004). Influence of interhemispheric interactions on motor function in chronic stroke. Annals of Neurology, 55, 400-409.

13.

Platz,

, Pinkowski,

, van Wijck,

, Kim,

I. -H.

, di Bella,

, & Johnson,

(2005). Reliability and validity of arm function assessment with standardized guidelines for the Fugl-Meyer Test, Action Research Arm Test and Box and Block Test: A multicentre study. Clinical Rehabilitation, 19, 404-411.

14.

Powell,

, Pandyan,

A. D.

, Granat,

, Cameron,

, & Stott,

D. J.

(1999). Electrical stimulation of wrist extensors in poststroke hemiplegia. Stroke, 30, 1384-1389.

15.

Rossi,

, Hallett,

, Rossini,

P. M.

, & Pascual-Leone

, Safety of TMS Consensus Group. (2009). Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clinical Neurophysiolgy, 120, 2008-2039.

16.

Shimodozono,

, Noma,

, Nomoto,

, Hisamatsu,

, Kamada,

, Miyata,

, Matsumoto,

, Ogata,

, Etoh,

, Basford,

J. R.

, & Kawahira,

(2013). Benefits of a repetitive facilitative exercise program for the upper paretic extremity after subacute stroke: A randomized controlled trial. Neurorehabilitation and Neural Repair, 27, 296-305.

17.

Shimodozono,

, Noma,

, Matsumoto,

, Miyata,

, Etoh,

, & Kawahira,

(2014). Repetitive facilitative exercise under continuous electrical stimulation for severe arm impairment after sub-acute stroke: A randomized controlled pilot study. Brain Injury, 28, 203-210.

18.

Stefan,

, Kunesch,

, Cohen,

L. G.

, Benecke,

, & Classen,

(2000). Induction of plasticity in the human motor cortex by paired associative stimulation. Brain: A Journal of Neurology, 123, 572-584.

19.

Takeuchi,

, Chuma,

, Matsuo,

, Watanabe,

, & Ikoma,

(2005). Repetitive transcranial magnetic stimulation of contralesional primary motor cortex improves hand function after stroke. Stroke, 36, 2681-2686.

20.

Tosun,

, Türe,

, Askin,

, Yardimci,

E. U.

, Demirdal,

S. U.

, Kurt

Incesu, T.

, Tosun,

, Kocyigit,

, Akhan,

, & Gelal,

F. M.

(2017). Effects of low-frequency repetitive transcranial magnetic stimulation and neuromuscular electrical stimulation on upper extremity motor recovery in the early period after stroke: A preliminary study. Topics in Stroke Rehabilitation, 24, 361-367.

21.

Ward,

N. S.

, & Cohen,

L. G.

(2004). Mechanisms underlying recovery of motor function after stroke. Archives of neurology. 61, 1844-1848.

22.

Yozbatiran,

, Der-Yeghiaian,

, & Cramer,

S. C.

(2008). A standardized approach to performing the action research arm test. Neurorehabilitation and Neural Repair, 22, 78-90.