Effects and safety of combined rTMS and action observation for recovery of function in the upper extremities in stroke patients: A randomized controlled trial

Abstract

Background:

Repetitive transcranial magnetic stimulation (rTMS) modulates cortical excitability and facilitates motor learning to improve motor recovery after stroke. Action observation (AO) therapy effectively facilitates physical training for motor memory formation.

Objective:

To compare the effectiveness of rTMS alone with that of combined rTMS and AO for the functional recovery of upper extremity function in subacute stroke patients and to verify the safety of the interventions.

Methods:

The present study was a prospective, randomized controlled trial involving subacute unilateral stroke patients. In total, 22 patients were randomly assigned to 2 groups: the trial group (rTMS with AO) and the control group (rTMS alone). Both groups received 1 Hz rTMS (intensity: 120% of resting motor threshold; rMT) over the contralesional primary motor cortex for 20 minutes on 10 consecutive days. Trial group received rTMS while watching a video of 5 different complex hand movements. The functional parameters were the Brunnstrom stage, Fugl-Meyer assessment (FMA) score of the upper extremity, Manual Function Test (MFT) score, and grip power. The following motor evoked potential (MEP) parameters were recorded from the abductor pollicis brevis muscle: rMT, latency, and amplitude. Both parameters were measured before and after the 2 week intervention.

Results:

After the 2 week trial, the total FMA and MFT scores were significantly improved in both groups, but the MFT subscores of hand motor function and grip power were significantly improved in the combination therapy group only. In contrast, the changes (Δ) of FMA, MFT, grip power test, and MEP outcomes were not significantly different between the 2 groups. No adverse events or complications were reported.

Conclusions:

Distal upper extremity function, as measured by MFT and grip power, was improved after rTMS and AO in combination. The combination of rTMS with AO may be applied safely to improve upper extremity function after stroke.

Keywords

Transcranial magnetic stimulation stroke hemiplegia stroke rehabilitation recovery of function

1. Introduction

Stroke is the leading cause of physical disability worldwide (Ward, 2005). About one-third of stroke survivors suffer severe motor deficits in the acute stage, and half are left with some degree of physical impairment (Bonita & Beaglehole, 1988). Characteristics of motor impairment across patients are diverse and include a range of functional ability and recovery (Carey, Abbott, Egan, Bernhardt, & Donnan, 2005). Weaknesses can affect all muscle groups in the upper extremities, or may be selective, affecting some muscle groups more than others. Previous research has shown that no consistency in proximal-to-distal or flexor-to-extensor weakness gradient exists (Raghavan, 2015; Tyson, Chillala, Hanley, Selley, & Tallis, 2006).

To treat motor weakness after stroke, various neuro-rehabilitative therapies have been suggested. For example, previous researchers have found that the motor areas of the human brain are recruited by mental rehearsal or simple observation, as well as by actual execution (Jeannerod, 2001). Thus, action observation (AO) therapy facilitates physical training for motor memory formation (Celnik, Webster, Glasser, & Cohen, 2008). AO is based on mirror neurons, which were first described in monkeys (Gallese, Fadiga, Fogassi, & Rizzolatti, 1996; Rizzolatti, Fadiga, Gallese, & Fogassi, 1996). Gallese et al. described a set of F5 neurons in monkeys that became active both when the animal performed a specific action and when it watched a similar action being performed by a human. The researchers named these “mirror neurons.” Thereafter, homologous F5 neurons have been sought in the human brain. One study using brain functional magnetic resonance imaging (fMRI) suggested that 1 mirror neuron circuit in humans is located in the inferior parietal lobule, a posterior part of the inferior frontal gyrus and adjacent premotor cortex (Buccino et al., 2004). Measured motor evoked potentials (MEPs) showed significant modulation of the observers’ corticospinal system while they watched a man lifting an object. The response differed depending on the objects’ weight and grip patterns indicating that the effect on the brain may depend on the extent of observation and the content being observed (Lapenta, Ferrari, Boggio, Fadiga, & D’Ausilio, 2018; Senot et al., 2011). Furthermore, AO with a fixed point-of-gaze facilitated higher MEP amplitudes than free viewing; thus, directing the observers’ gaze during AO may optimize acquisition (D’Innocenzo, Gonzalez, Nowicky, Williams, & Bishop, 2017).

Brain areas may undergo maladaptive plasticity after stroke, affecting both neural activation and motor behavior. In this regard, rTMS may modulate cortical excitability, and thus, facilitate motor learning and improve motor recovery (Du et al., 2016; Le, Qu, Zhu, Tao, & Li, 2013; Tosun et al., 2017). This non-invasive technique applies focused magnetic stimulation to the skull to target a particular brain area. In healthy adults, low-frequency (<1 Hz) rTMS can suppress cortical excitability, resulting in an inhibiting motor cortex, whereas at higher frequencies (>5 Hz), rTMS can induce long-term potentiation facilitating it (Askin, Tosun, & Demirdal, 2017). Therapeutic utility of TMS has been explored in many conditions with varying degrees of success for psychiatric disorders, such as major depressive disorder, drug addiction, eating disorders, or obesity; neurologic diseases such as Parkinson’s disease or epilepsy; rehabilitation of aphasia or dysphagia after stroke; and pain associated diseases, such as neuropathic pain or migraine (Dosenovic et al., 2017; Ilkhani, Shojaie Baghini, Kiamarzi, Meysamie, & Ebrahimi, 2017; Lefaucheur et al., 2014; Loo & Mitchell, 2005; Nardone et al., 2017; Noohi & Amirsalari, 2016; Song, Zilverstand, Gui, Li, & Zhou, 2018; Stilling, Monchi, Amoozegar, & Debert, 2019; Tarameshlu, Ansari, Ghelichi, & Jalaei, 2019; Yang et al., 2018).

Recently extensive literature has analyzed the effects of AO with rTMS in healthy participants. Continuous theta burst stimulation to the left inferior parietal lobule before mental rehearsal of motor tasks decreased reaction time for the implicit and random sequences in healthy participants (Kraeutner, Keeler, & Boe, 2016). Furthermore, inhibitory rTMS on the left dorsal premotor cortex decreased the success rate of action prediction in healthy participants (Brich, Bachle, Hermsdorfer, & Stadler, 2018). However, few studies have addressed the effect of combined rTMS and AO in subacute stroke patients.

In the present study, we hypothesized that the brain modulating effects of the conventional inhibitory rTMS protocol (usually 20 minutes) and AO are amplified and facilitated when combined. Therefore, we investigated whether combined rTMS and AO therapy is superior to rTMS therapy alone in terms of alleviating motor impairment in subacute stroke patients, as measured using standard functional scales and MEP parameters. We also recorded any adverse events during the study.

2. Materials and methods

2.1. Participants

This single-center, prospective, randomized controlled study was conducted in subacute stroke survivors who were referred to subacute rehabilitation units after acute stroke between September 2012 and August 2013.

The inclusion criteria were as follows: (1) age 18 years or older, (2) first ever stroke, (3) unilateral vascular stroke lesion in the cerebral hemisphere, as confirmed by computed tomography (CT) or magnetic resonance imaging (MRI), (4) mild-to-moderate unilateral hemiparesis secondary to cerebrovascular accident (finger movements of more than fair grade and individual finger movement possible), (5) ability to follow simple verbal commands or instructions (no severe deficit in visual, attentional, or language comprehension), (6) MEP response test performed in the paralyzed hand (patients were excluded when a TMS of 100% intensity failed to induce MEP response). The exclusion criteria were as follows: (1) bilateral cerebral hemisphere lesion, (2) brain stem lesion, (3) known history of previous stroke, (4) cognitive impairment that prevented compliance with test instructions, (5) presence of unstable medical conditions, (6) peripheral neuropathy that could have affected MEP response, and (7) contraindications to TMS (seizure, cardiac pacemaker, or coil embolization).

The G^*Power program (v3.1.9.2; Franz Faul, Kiel University, Germany) was used to calculate the necessary sample size of the test subjects. Based on a previous study using 1 Hz rTMS on the paretic hand of patients who had suffered chronic stroke, an effect size of 0.97 was selected (Takeuchi et al., 2008; L. Zhang, Xing, Fan, et al., 2017). In the Mann-Whitney U test, a α-error of 0.05 and a β of 0.20 (power level of 0.80) were used. The results showed that the control and experimental groups required at least 10 patients each. Assuming a dropout rate of 10%, at least 11 patients were needed in each group.

A total of 122 stroke survivors were admitted to the rehabilitation unit of the Department of Physical Medicine and Rehabilitation at Korea University Anam Hospital during the study period. They were screened for eligibility using the inclusion criteria. A CONSORT diagram (Fig. 1) shows the study flow chart. Two patients declined to continue the study, citing economic reasons and a mild headache during the pre-interventional MEP study. Therefore, 22 patients were assigned to the trial group (n = 11) and the control group (n = 11).

Fig. 1

Flowchart of participant selection. Abbreviations: rTMS, repetitive transcranial magnetic stimulation; AO, action observation.

The study was approved by Clinical Research Information Service (CRIS) (KCT0003200) and the Institutional Review Board of Korea University Anam Hospital (AN12030-002). All patients submitted written informed consent for study participation. The current study was conducted in accordance with the Declaration of Helsinki.

2.2. Study design

Patients were identified by a number assigned by a centralized computer-generated randomization code. The patients were randomly allocated to 1 of the following 2 groups: (1) combined rTMS and AO group (trial group) or (2) rTMS alone (control group). All subjects underwent conventional physical and occupational therapy, including range of motion and strengthening exercises, gait and balance training, manual dexterity exercises, and activities of daily living (ADL) training for 1 hour twice a day (5 days/week).

2.3. Motor evoked potentials (MEP) study

Before and after the 2 week rTMS treatment, MEPs were recorded in the abductor pollicis brevis (APB) muscle by a blinded rater. The resting motor threshold (rMT) was assessed using the method described in the study by Rossini et al., which was used in previous studies (Khedr, Ahmed, Fathy, & Rothwell, 2005; Rossini et al., 1994). An elastic cap was put on each patient’s head and placed using standard anatomical markers along the nasion-to-inion line and the interaural line. The coil was kept tangential to the scalp and maintained at 45° to the mid-sagittal line. The “hot spot” was defined as the point at which the MEP amplitude, elicited with supramaximal threshold intensity in the APB muscle, was the highest. MEP amplitude was measured between the 2 largest peaks of opposite polarity (Day et al., 1987; Rothwell, Day, Berardelli, & Marsden, 1984). If no opposite polarity was detected, we considered it unobtainable. Once the optimal scalp location (“hot spot”) had been determined, a single TMS pulse was delivered to the location to identify the rMT, defined as the minimum intensity capable of producing at least 5 MEPs of > 50μV in 10 consecutive trials. The stimulation was delivered using a figure-of-eight coil and a MagPro×100 magnetic stimulator (MagVenture Ltd., Reading, United Kingdom).

2.4. Repetitive transcranial magnetic stimulation

The magnetic stimulus protocol and stimulation intensity of rTMS were the same as reported in a study by Emara, and the stimulation duration was 20 minutes (Emara et al., 2010). Both groups received 1 Hz rTMS (intensity: 120% of rMT) over the contralesional “hot spot”, the hand area of the motor cortex on 10 consecutive weekdays. The duration of the trains of rTMS was within the safe range described by the Safety of TMS Consensus Group (Rossi, Hallett, Rossini, & Pascual-Leone, 2009). The rTMS intervention was performed just before the subjects underwent conventional occupational therapies. Subjects were instructed to sit in a comfortable chair in a relaxed position, with both hands placed on its armrests, and to stay awake during the procedure. The stimulation induced a response in the APB muscle, which manifested as a muscle twitch that was recorded as an MEP using surface electromyography in the affected upper extremity. The rTMS was delivered using the same MagPro ×100 magnetic stimulator as mentioned above.

2.5. Action observation

To perform AO, videos were prepared featuring an able-bodied individual. Trial group received rTMS intervention while watching the video on a 19 inch monitor positioned 1 meter in front of them in a quiet room. The video displayed 5 different complex hand movements: 1) lifting up a white baseball by about 10 cm with the fingers spread out and then the subsequent downward motion, 2) moving 5 gray cans 1 by 1 in line with the fence on the table, 3) flipping yellow cards (15 cm horizontal, 10 cm vertical) over vertically 1 by 1, 4) stacking button-shaped objects 4 cm in length and 1 cm in height vertically, 5) and putting small objects (2 clips, bottle caps and coins) into a large can. These actions were derived from the evaluation items from the Jebsen Hand Function Test. Each video clip was 2 minutes long, and all videos were repeated in sequence for a total running time of 20 minutes. Control group received rTMS treatment but were not provided with any visual materials. The rTMS and AO interventions were delivered by a physiatrist who was otherwise uninvolved in the present study.

2.6. Outcome measures

The outcome measures were upper extremity motor function and neurophysiologic parameters representing motor cortical excitability, as determined using MEP. These were measured before and after completion of the 2 week treatment by an assessor who was otherwise uninvolved in the present study. To assess upper extremity function, we determined the Brunnstrom stage and the Fugl-Meyer assessment (FMA) score of the upper extremity; we also carried out the Jebsen Hand Function test, manual function test (MFT), and grip power test using a dynamometer. The Jebsen Hand Function test results were ultimately excluded from the analysis because many patients failed to perform the test items. The manual function test (MFT) evaluates arm and hand function; its validity and reliability have been verified in stroke patients (H. J. Kim et al., 2017; Miyamoto, Kondo, Suzukamo, Michimata, & Izumi, 2009; Sone et al., 2015). The MFT has 4 items that evaluate the function of the shoulder as the proximal part of the upper limb (forward elevation of the upper limb, lateral elevation of the upper limb, touching the occiput with the palm, and touching the back with the palm) and 4 items that evaluate the hand as the distal part of the upper limb (grasping, pinching, carrying cubes, and manipulating a pegboard). The total possible MFT score across the 8 tasks is 32 (0 indicates severely impaired function and 32 indicates full function).

The neurophysiological parameters measured by MEP were rMT, latency, and amplitude; 120% of the rMT intensity was used to evoke motor responses in the APB, and the onset latency and peak-to-peak amplitude of the motor response were measured for analysis.

2.7. Statistical analysis

Independent t test and Fisher’s exact test were used to compare parametric and nonparametric data at baseline between the 2 groups. The Shapiro-wilt test was used to test normality of the data. Nonparametric statistics were used because the measures did not follow a normal distribution. The before-and after-treatment results of the clinical outcomes and MEP parameters were analyzed using the Wilcoxon signed-rank test in each group. Changes in functional outcome and MEP parameters at the 2-week follow-up evaluation were compared between the 2 groups using the Mann–Whitney U test. All statistical analyses were performed using SPSS version 22.0 for Windows (SPSS Inc., Chicago, IL, USA). All p-values <0.05 were considered statistically significant. For reducing the risk of Type-I error in the statistical analyses, adjustments were made using the Bonferroni method for multiple comparisons between the trial and control groups.

3. Results

Table 1 summarizes the baseline clinical characteristics. Ten men and 12 women participated in the present study. The mean age of the subjects was 65.2 years (range: 32–86 years). At baseline, there were no significant differences between the 2 groups in terms of age, type or side of stroke lesion, post-onset duration, or cognitive function (K-MMSE). No adverse events or complications were reported by any of the participants, and all participants completed the trial.

Table 1
Baseline characteristics of participants

Variables	Trial group (rTMS + AO)	Control group (rTMS alone)	p-value
Number	11	11
Age (years)	66.45±12.27	57.45±14.98	0.133
Sex, M/F	4/7	6/5	0.670
Lesion type (infarct/hemorrhage)	10/1	8/3	0.586
Lesion side (right/left)	5/6	5/6	1.000
Time post-onset (days)	31.36±16.87	22.63±7.00	0.270
K-MMSE	18.54±7.72	21.27±8.90	0.410

Abbreviations: rTMS, repetitive transcranial magnetic stimulation; AO, action observation; M, male; F, female; K-MMSE, Korea mini mental state examination.

After the 2 week rTMS intervention, both groups demonstrated significant gains in upper extremity functional parameters, as measured by FMA and MFT (Fig. 2). The total MFT score, as well as the proximal limb subscore, was significantly improved in both groups. However, the subscore of the distal limb was significantly improved in the trial group only (Fig. 2). Similarly, grip power showed significant improvement in the control group. No significant changes were noted in all the MEP parameters after rTMS intervention, except for increase in rMT in the control group (Table 2).

Fig. 2

Fugl-Meyer assessment, manual function test (total), and manual function test (distal) results of each participant and its average before and after intervention. X axis represents the participant number while Y axis represents the test results. Abbreviations: rTMS, repetitive transcranial magnetic stimulation; AO, action observation; FMA, Fugl-Meyer assessment; MFT, manual function test; ^*,<0.05; -, score of zero.

Table 2

Before-and after-treatment results of the clinical outcomes and MEP parameters in trial and control groups

Variables	Group	Mean±SD (Median, IQR)		p-value
Variables	Group	Before	After	p-value
Functional parameters
Brunnstrom (proximal)	Trial	3.45±1.63(4, 3)	3.81±1.47 (4, 3)	0.180
	Control	3.09±1.37 (3, 2)	3.54±1.29 (3, 3)	0.025^*
Brunnstrom (distal)	Trial	3.18±1.88 (4, 4)	3.81±1.72(4, 7)	0.096
	Control	2.36±1.56 (2, 3)	2.63±1.50 (2, 3)	0.180
FMA	Trial	28.45±21.20 (27, 40)	39.63±22.79 (42, 44)	0.008^*
	Control	20.63±18.50 (13, 28)	31.27±20.61 (22, 37)	0.005^*
MFT (total)	Trial	11.54±10.61(11, 20)	15.81±9.89 (20, 17)	0.012^*
	Control	8.81±7.80 (10, 12)	12.00±8.20 (13, 14)	0.011^*
MFT (proximal)	Trial	8.64±7.16 (11, 16)	2.91±4.11(15, 10)	0.041^*
	Control	6.82±5.10 (8, 2)	9.18±5.27 (10, 10)	0.017^*
MFT (distal)	Trial	2.91±4.11 (0, 4)	4.73±3.93 (4, 7)	0.017*
	Control	2.00±3.38 (0, 4)	2.82±3.74 (1, 3)	0.109
Grip power test	Trial	4.62±13.11 (0, 0)	7.96±14.73 (1.17, 12.08)	0.027*
	Control	1.71±3.87(0, 1.83)	2.17±3.57 (0, 3.30)	0.500
MEP parameters
rMT (contralesional) (%)	Trial	69.63±7.37 (70, 14)	70.54±6.86 (69, 13)	0.372
	Control	66.81±9.68 (61, 18)	73.45±10.38 (68, 20)	0.004*
Latency (contralesional) (msec)	Trial	22.20±2.46 (23.40, 4.10)	21.77±2.22 (22.00, 3.30)	0.373
	Control	22.18±1.71 (21.90, 1.90)	22.39±1.23 (22.20, 2.50)	0.507
Amplitude (contralesional) (mV)	Trial	0.68±0.52 (0.50, 1.00)	0.80±0.47 (0.70, 0.50)	0.635
	Control	0.63±0.38 (0.60, 0.50)	0.61±0.49 (0.50, 0.70)	0.824

Abbreviations: SD, standard deviation; IQR, interquartile range; FMA, Fugl-Meyer assessment; MFT, manual function test; MEP, motor evoked potential; rMT, resting motor threshold; ^*, p < 0.05.

Table 3 and Fig. 3 compare the changes (Δ) in clinical and MEP parameters between the trial group and the control group. The changes in clinical outcomes showed no significant difference between the groups. Similarly, MEP parameters (rMT, latency, amplitude) did not differ significantly between the 2 groups (p > 0.05/10) (Table 3).

Fig. 3

Change in clinical and motor evoked potential parameters for individual participants between the trial and control groups. (A) Fugl-Meyer assessment (B) Manual function test (C) Grip power test (D) Resting motor threshold (contralesional) Abbreviations: rTMS, repetitive transcranial magnetic stimulation; AO, action observation; MEP, motor evoked potential; FMA, Fugl-Meyer assessment; MFT, manual function test; rMT, resting motor threshold.

Table 3

Differences in variables between trial and control groups

Variables		Mean±SD (Median, IQR)		p-value
Variables		Trial group (rTMS+AO)	Control group (rTMS alone)	p-value
Functional parameters
Brunnstrom (proximal)	Before	(4, 3)	(3, 2)	0.606
	After	(4, 3)	(3, 3)	0.652
	Δ	0.36±0.50 (0, 1)	0.45±0.52 (0, 1)	0.748
Brunnstrom (distal)	Before	(4, 4)	(2, 3)	0.438
	After	(4, 7)	(2, 3)	0.133
	Δ	0.63±0.92 (0, 1)	0.27±0.64 (0, 0)	0.332
FMA	Before	(27, 40)	(13, 28)	0.438
	After	(42, 44)	(22, 37)	0.401
	Δ	11.18±13.19 (10, 13)	10.63±6.81 (10, 13)	0.478
MFT (total)	Before	(11, 20)	(10, 12)	0.562
	After	(20, 17)	(13, 14)	0.243
	Δ	4.27±5.10 (2, 9)	3.18±2.92 (2, 7)	0.898
MFT (proximal)	Before	(11, 16)	(8, 2)	0.332
	After	(15, 10)	(10, 10)	0.797
	Δ	2.45±3.36 (0, 5)	2.36±2.73 (2, 5)	0.748
MFT (distal)	Before	(0, 4)	(0, 4)	0.217
	After	(4, 7)	(1, 3)	0.217
	Δ	1.81±2.09 (1, 3)	0.82±1.47 (0, 2)	0.171
Grip power test	Before	(0, 0)	(0, 1.83)	0.438
	After	(1.17, 12.08)	(0, 3.30)	0.557
	Δ	11.82±25.69 (0.83, 2.70)	0.32±1.80 (0, 3.00)	0.061
MEP parameters
rMT (contralesional) (%)	Before	(70, 14)	(61, 18)	0.365
	After	(69, 13)	(68, 20)	0.652
	Δ	0.90±3.75 (1, 3)	6.63±5.06 (5, 8)	0.013
Latency (contralesional) (msec)	Before	(23.40, 4.10)	(21.90, 1.90)	0.562
	After	(22.00, 3.30)	(22.20, 2.50)	0.606
	Δ	–0.43±1.10 (– 0.30, 1.60)	0.20±1.29 (0.30, 1.80)	0.243
Amplitude (contralesional) (mV)	Before	(0.50, 1.00)	(0.60, 0.50)	0.847
	After	(0.70, 0.50)	(0.50, 0.70)	0.300
	Δ	0.11±0.56 (0.0, 0.73)	–0.02±0.46 (– 0.10, 0.80)	0.606

Abbreviations: IQR, interquartile range; rTMS, repetitive transcranial magnetic stimulation; AO, action observation; FMA, Fugl-Meyer assessment; MFT, manual function test; MEP, motor evoked potential; rMT, resting motor threshold. A value of p < 0.005 (corresponding to p < 0.05 after adjusting for 10 independent tests by the Bonferroni correction) was considered significant.

4. Discussion

The present study investigated whether the combined AO and traditional inhibitory rTMS protocol is superior to the rTMS protocol alone in terms of functional improvements in the upper extremities of stroke patients. After completion of a 2 week trial, the total FMA and MFT scores were significantly improved in both groups. However, the MFT subscores of hand motor function and grip power were significantly improved in the combination therapy group only. However, the post-therapy changes (Δ) did not differ significantly between the 2 groups.

Several studies have combined rTMS with other therapies to multiply the effects of the motor learning process. Finger motor tasks using numerical panels after rTMS and 10 minute ankle strengthening exercises before rTMS yielded significant improvements in motor performance (Kwon, Kim, Chang, Bang, & Shin, 2014; VanDerwerker et al., 2018). Conversely, task-specific occupational therapy, including stacking objects, opening jars, and eating finger foods immediately after rTMS or sham rTMS, showed no superiority to rTMS alone (Higgins, Koski, & Xie, 2013). More recently, virtual reality brain-computer interface training immediately after rTMS led to increased ipsilesional motor activity and improvements in behavioral function (Johnson et al., 2018). There have been several attempts to combine rTMS with other therapies. However, our intervention has an added advantage, because AO and rTMS can be carried out simultaneously. Previous studies have reported that both AO and rTMS have positive effects on motor recovery in stroke patients (Celnik et al., 2008; Cha & Kim, 2017; Lefaucheur, 2006). In particular, AO functions through the system of mirror neurons, a class of neural substrates that discharges during both AO and action execution (J. J. Q. Zhang, Fong, Welage, & Liu, 2018). Actions that are goal-oriented can activate mirror neuron systems and activate the motor learning process more effectively (Fadiga, Fogassi, Pavesi, & Rizzolatti, 1995). Furthermore, modulation of an observer’s motor system during observation may be supported by semantic information via a top-down mechanism (Senot et al., 2011).

Informed by previous studies, we tried to produce goal-oriented activities when creating the therapeutic AO video in the present study so that the patients could plan their behavior while watching. Considering that the effects of rTMS may diminish over time, this method is valuable. One TMS study found that MEP amplitude was depressed in the stimulated M1 by 20% immediately after rTMS, and that it returned to baseline 30 minutes later (Heide, Witte, & Ziemann, 2006). We expected that brain modulation would have a greater effect within the time window of the TMS when combined with AO. Although the changes in MFT score and grip power did not differ significantly between the groups, the results showed that distal upper extremity function improved significantly in the combination therapy group only, suggesting that the combination of AO and inhibitory rTMS facilitates recovery of hemiparetic hand function. Moreover, there were no reports of serious discomfort or other adverse events during the intervention, so this combined therapeutic intervention could be used to facilitate motor recovery in the upper extremities after stroke.

However, the results related to the Brunnstrom stage seemed to be inconsistent. A significant improvement was seen in the distal portions with regard to the Brunnstrom stage only in the control group. The return of hand function does not in every respect parallel the 6 recovery stages of the shoulder and elbow (Brunnstrom, 1966). Although the Brunnstrom stage is known to be correlated and well-responsive with respect to the evaluation of upper extremities in stroke patients (Safaz, Yilmaz, Yasar, & Alaca, 2009), it is a broad evaluation that is divided into only 6 categories and suitable for long-term follow-up. Thus, it may not have been sufficient to show changes in the patient group within 2 weeks, which might explain why the results were inconsistent. In this regard, we speculate that the longer the follow up, the better the results will be.

One unexpected finding of our study was the significant increase in contralesional rMT in the rTMS-only group. Shorter latency and higher amplitude of MEPs, shorter central motor conduction time, and diminished rMT are correlated with clinical measures evaluating motor functions in chronic stroke patients (Cakar et al., 2016). The exact time course of rMT after stroke is not well-known; however, it probably reduces over time after stroke but remains higher in the affected hemisphere with respect to that in the unaffected hemisphere at the chronic stage (Chipchase et al., 2012). A meta-analysis of inhibitory rTMS for stroke-induced upper limb motor deficit showed an enhancing effect on rMT in the unaffected hemisphere (L. Zhang, Xing, Shuai, et al., 2017). Nonetheless, in this study, contralesional rMT did not increase significantly in the trial group, and MEP latency and amplitude did not change significantly in either group. These results were probably due to a lack of homogeneity in the patient groups.

When cortical excitability changes in one hemisphere, it is modulated in homonymous regions of the contralesional hemisphere (Buetefisch, 2015). Intracortical disinhibition probably occurs due to impairment of the transcallosal fibers, and stroke patients exhibit unbalanced interhemispheric inhibition (Liepert, Hamzei, & Weiller, 2000; Sebastianelli et al., 2017). Inhibitory rTMS has been shown to restore the balance of interhemispheric inhibition after stroke (Heide et al., 2006). The optimal interval between stroke onset and rTMS is as yet unclear. However, several factors are alleged to influence the effect of rTMS. Stroke patients with younger age, exclusively subcortical lesion, mild motor impairment, and good functional status have shown superior upper limb recovery after rTMS (S. Y. Kim, Shin, Lee, Kim, & Hyun, 2016; Lee et al., 2015). Given that TMS has a greater effect in certain patient populations, a lack of homogeneity in the patient groups probably led to the inconsistent results in this study. Although we only recruited patients who had suffered unilateral stroke, the extent of descending motor pathway involvement would have been diverse. Therefore, further well-controlled studies are needed to investigate whether AO can reduce suppression of the contralesional hemisphere by inhibitory rTMS in a homogenous group of stroke patients.

This study had several limitations. Firstly, although we conducted a power calculation, the samples were diverse with regards to the extent and location of the lesions. These factors were not taken into account in the analysis. Secondly, we only observed the patients for a short period (2 weeks), so it will be necessary to compare the changes in latent effects in a long-term follow-up. Lastly, a control group of those who received conventional rehabilitation therapy for stroke without rTMS was not included in this study. Additionally, those who underwent rTMS but with a ‘sham’ type of stimulation and another control condition with ‘real’ stimulation on another scalp site (not on the motor cortex) would have generated more clear findings and demonstrated the site-specificity of the effects. Therefore, future studies involving more homogenous and larger cohorts with various methods of rTMS and longer duration will be needed to verify the efficacy of combined therapy.

5. Conclusions

In summary, our primary aim in this study was to elucidate the effect of combined rTMS and AO in patients following stroke. The intervention was conducted safely. The results showed that distal upper extremity function after therapy, as measured by MFT and grip power, was improved only in the trial group (rTMS with AO group) and not in the rTMS alone group. However, there was no significant difference in clinical outcomes between the 2 groups. The combination of rTMS with AO may be a safe intervention to improve upper extremity function after stroke. The long-term benefits of this combination therapy and deciding an appropriate target group should be investigated in future studies.

Footnotes

Acknowledgments

No potential conflict of interests relevant to this article were reported. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2019R1A2C2003020).

References

Askin, A., Tosun, A., & Demirdal, U.S. (2017). Effects of low-frequency repetitive transcranial magnetic stimulation on upper extremity motor recovery and functional outcomes in chronic stroke patients: A randomized controlled trial. Somatosensory & Motor Research, 34(2), 102–107. doi: 10.1080/08990220.2017.1316254

Bonita, R., & Beaglehole, R. (1988). Recovery of Motor Function after Stroke. Stroke, 19(12), 1497–1500. doi: 10.1161/01.Str.19.12.1497

Brich, L.F.M., Bachle, C., Hermsdorfer, J., & Stadler, W. (2018). Real-Time Prediction of Observed Action Requires Integrity of the Dorsal Premotor Cortex: Evidence From Repetitive Transcranial Magnetic Stimulation. Frontiers in Human Neuroscience, 12, 11. doi: 10.3389/fnhum.2018.00101

Brunnstrom, S. (1966). Motor testing procedures in hemiplegia: Based on sequential recovery stages. Physical therapy, 46(4), 357–375.

Buccino, G., Vogt, S., Ritzl, A., Fink, G.R., Zilles, K., Freund, H.J., & Rizzolatti, G. (2004). Neural circuits underlying imitation learning of hand actions: An event-related fMRI study. Neuron, 42(2), 323–334. doi: 10.1016/S0896-6273(04)00181-3

Buetefisch, C.M. (2015). Role of the Contralesional Hemisphere in Post-Stroke Recovery of Upper Extremity Motor Function. Frontiers in Neurology, 6, 214. doi: 10.3389/fneur.2015.00214

Cakar, E., Akyuz, G., Durmus, O., Bayman, L., Yagci, I., Karadag-Saygi, E., & Gunduz, O.H. (2016). The relationships of motor-evoked potentials to hand dexterity, motor function, and spasticity in chronic stroke patients: A transcranial magnetic stimulation study. Acta Neurologica Belgica, 116(4), 481–487. doi: 10.1007/s13760-016-0633-2

Carey, L.M., Abbott, D.F., Egan, G.F., Bernhardt, J., & Donnan, G.A. (2005). Motor impairment and recovery in the upper limb after stroke: Behavioral and neuroanatomical correlates. Stroke, 36(3), 625–629. doi: 10.1161/01.STR.0000155720.47711.83

Celnik, P., Webster, B., Glasser, D.M., & Cohen, L.G. (2008). Effects of action observation on physical training after stroke. Stroke, 39(6), 1814–1820. doi: 10.1161/Strokeaha.107.508184

10.

Cha, H.G., & Kim, M.K. (2017). Effects of strengthening exercise integrated repetitive transcranial magnetic stimulation on motor function recovery in subacute stroke patients: A randomized controlled trial. Technology and Health Care, 25(3), 521–529. doi: 10.3233/THC-171294

11.

Chipchase, L., Schabrun, S., Cohen, L., Hodges, P., Ridding, M., Rothwell, J.,... & Ziemann, U. (2012). A checklist for assessing the methodological quality of studies using transcranial magnetic stimulation to study the motor system: An international consensus study. Clinical Neurophysiology, 123(9), 1698–1704. doi: 10.1016/j.clinph.2012.05.003

12.

D’Innocenzo, G., Gonzalez, C.C., Nowicky, A.V., Williams, A.M., & Bishop, D.T. (2017). Motor resonance during action observation is gaze-contingent: A TMS study. Neuropsychologia, 103, 77–86. doi: https://doi.org/10.1016/j.neuropsychologia.2017.07.017

13.

Day, B.L., Rothwell, J.C., Thompson, P.D., Dick, J.P., Cowan, J.M., Berardelli, A., & Marsden, C.D. (1987). Motor cortex stimulation in intact man. 2. Multiple descending volleys. Brain, 110(Pt 5), 1191–1209.

14.

Dosenovic, S., Jelicic Kadic, A., Miljanovic, M., Biocic, M., Boric, K., Cavar, M.,... & Puljak, L. (2017). Interventions for Neuropathic Pain: An Overview of Systematic Reviews. Anesthesia & Analgesia, 125(2), 643–652. doi: 10.1213/ane.0000000000001998

15.

Du, J., Tian, L., Liu, W., Hu, J., Xu, G., Ma, M.,... & Liu, X. (2016). Effects of repetitive transcranial magnetic stimulation on motor recovery and motor cortex excitability in patients with stroke: A randomized controlled trial. European Journal of Neurology, 23(11), 1666–1672. doi: 10.1111/ene.13105

16.

Emara, T.H., Moustafa, R.R., Elnahas, N.M., Elganzoury, A.M., Abdo, T.A., Mohamed, S.A., & Eletribi, M.A. (2010). Repetitive transcranial magnetic stimulation at 1Hz and 5Hz produces sustained improvement in motor function and disability after ischaemic stroke. European Journal of Neurology, 17(9), 1203–1209. doi: 10.1111/j.1468-1331.2010.03000.x

17.

Fadiga, L., Fogassi, L., Pavesi, G., & Rizzolatti, G. (1995). Motor Facilitation during Action Observation - a Magnetic Stimulation Study. Journal of Neurophysiology, 73(6), 2608–2611.

18.

Gallese, V., Fadiga, L., Fogassi, L., & Rizzolatti, G. (1996). Action recognition in the premotor cortex. Brain, 119(Pt 2), 593–609.

19.

Heide, G., Witte, O.W., & Ziemann, U. (2006). Physiology of modulation of motor cortex excitability by low-frequency suprathreshold repetitive transcranial magnetic stimulation. Experimental Brain Research, 171(1), 26–34. doi: 10.1007/s00221-005-0262-0

20.

Higgins, J., Koski, L., & Xie, H. (2013). Combining rTMS and Task-Oriented Training in the Rehabilitation of the Arm after Stroke: A Pilot Randomized Controlled Trial. Stroke Research and Treatment, 2013, 539146. doi: 10.1155/2013/539146

21.

Ilkhani, M., Shojaie Baghini, H., Kiamarzi, G., Meysamie, A., & Ebrahimi, P. (2017). The effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on the treatment of aphasia caused by cerebrovascular accident (CVA). Medical journal of the Islamic Republic of Iran, 31, 137. doi: 10.14196/mjiri.31.137

22.

Jeannerod, M. (2001). Neural simulation of action: A unifying mechanism for motor cognition. Neuroimage, 14(1), S103–S109. doi: 10.1006/nimg.2001.0832

23.

Johnson, N.N., Carey, J., Edelman, B.J., Doud, A., Grande, A., Lakshminarayan, K., & He, B. (2018). Combined rTMS and virtual reality brain-computer interface training for motor recovery after stroke. Journal of Neural Engineering, 15(1), 016009. doi: 10.1088/1741-2552/aa8ce3

24.

Khedr, E.M., Ahmed, M.A., Fathy, N., & Rothwell, J.C. (2005). Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke. Neurology, 65(3), 466–468. doi: 10.1212/01.wnl.0000173067.84247.36

25.

Kim, H.J., Min, K., Lee, C.H., Cho, Y.K., Yoon, J.S., Cho, D.R.,... & Kim, M. (2017). Clinical Applicability and Psychometric Properties of Manual Function Test for Patients with Stroke. Tohoku journal of experimental medicine, 243(2), 85–93. doi: 10.1620/tjem.243.85

26.

Kim, S.Y., Shin, S.B., Lee, S.J., Kim, T.U., & Hyun, J.K. (2016). Factors Associated With Upper Extremity Functional Recovery Following Low-Frequency Repetitive Transcranial Magnetic Stimulation in Stroke Patients. Annals of rehabilitation medicine, 40(3), 373–382. doi: 10.5535/arm.2016.40.3.373

27.

Kraeutner, S.N., Keeler, L.T., & Boe, S.G. (2016). Motor imagery-based skill acquisition disrupted following rTMS of the inferior parietal lobule. Experimental Brain Research, 234(2), 397–407. doi: 10.1007/s00221-015-4472-9

28.

Kwon, T.G., Kim, Y.H., Chang, W.H., Bang, O.Y., & Shin, Y.I. (2014). Effective method of combining rTMS and motor training in stroke patients. Restorative Neurology and Neuroscience, 32(2), 223–232. doi: 10.3233/RNN-130313

29.

Lapenta, O.M., Ferrari, E., Boggio, P.S., Fadiga, L., & D’Ausilio, A. (2018). Motor system recruitment during action observation: No correlation between mu-rhythm desynchronization and corticospinal excitability. PLoS One, 13(11), e0207476. doi: 10.1371/journal.pone.0207476

30.

Le, Q., Qu, Y., Zhu, S., Tao, Y., & Li, Y. (2013). [Meta-analysis of the effect of low-frequency repetitive transcranial magnetic stimulation on paretic hand recovery after stroke]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi, 30(6), 1229–1234.

31.

Lee, J.H., Kim, S.B., Lee, K.W., Kim, M.A., Lee, S.J., & Choi, S.J. (2015). Factors associated with upper extremity motor recovery after repetitive transcranial magnetic stimulation in stroke patients. Annals of Rehabilitation Medicine, 39(2), 268–276. doi: 10.5535/arm.2015.39.2.268

32.

Lefaucheur, J.P. (2006). Stroke recovery can be enhanced by using repetitive transcranial magnetic stimulation (rTMS). Neurophysiologie Clinique/Clinical Neurophysiology, 36(3), 105–115. doi: 10.1016/j.neucli.2006.08.011

33.

Lefaucheur, J.P., Andre-Obadia, N., Antal, A., Ayache, S.S., Baeken, C., Benninger, D.H.,... & Garcia-Larrea, L. (2014). Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clinical Neurophysiology, 125(11), 2150–2206. doi: 10.1016/j.clinph.2014.05.021

34.

Liepert, J., Hamzei, F., & Weiller, C. (2000). Motor cortex disinhibition of the unaffected hemisphere after acute stroke. Muscle Nerve, 23(11), 1761–1763.

35.

Loo, C.K., & Mitchell, P.B. (2005). A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy. Journal of Affective Disorders, 88(3), 255–267. doi: 10.1016/j.jad.2005.08.001

36.

Miyamoto, S., Kondo, T., Suzukamo, Y., Michimata, A., & Izumi, S. (2009). Reliability and validity of the Manual Function Test in patients with stroke. American Journal of Physical Medicine & Rehabilitation, 88(3), 247–255. doi: 10.1097/PHM.0b013e3181951133

37.

Nardone, R., Holler, Y., Langthaler, P.B., Lochner, P., Golaszewski, S., Schwenker, K.,... & Trinka, E. (2017). rTMS of the prefrontal cortex has analgesic effects on neuropathic pain in subjects with spinal cord injury. Spinal Cord, 55(1), 20–25. doi: 10.1038/sc.2016.87

38.

Noohi, S., & Amirsalari, S. (2016). History, Studies and Specific Uses of Repetitive Transcranial Magnetic Stimulation (rTMS) in Treating Epilepsy. Iranian Journal of Child Neurology, 10(1), 1–8.

39.

Raghavan, P. (2015). Upper Limb Motor Impairment After Stroke. Physical Medicine and Rehabilitation Clinics, 26(4), 599–610. doi: 10.1016/j.pmr.2015.06.008

40.

Rizzolatti, G., Fadiga, L., Gallese, V., & Fogassi, L. (1996). Premotor cortex and the recognition of motor actions. Cognitive Brain Research, 3(2), 131–141.

41.

Rossi, S., Hallett, M., Rossini, P.M., & Pascual-Leone, A. (2009). Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clinical Neurophysiology, 120(12), 2008–2039. doi: https://doi.org/10.1016/j.clinph.2009.08.016

42.

Rossini, P.M., Barker, A.T., Berardelli, A., Caramia, M.D., Caruso, G., Cracco, R.Q.,... & Ziemann, U. (1994). Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: Basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalography and Clinical Neurophysiology, 91(2), 79–92.

43.

Rothwell, J.C., Day, B.L., Berardelli, A., & Marsden, C.D. (1984). Effects of motor cortex stimulation on spinal interneurones in intact man. Experimental Brain Research, 54(2), 382–384.

44.

Safaz, I., Yilmaz, B., Yasar, E., & Alaca, R. (2009). Brunnstrom recovery stage and motricity index for the evaluation of upper extremity in stroke: Analysis for correlation and responsiveness. International Journal of Rehabilitation Research, 32(3), 228–231. doi: 10.1097/MRR.0b013e32832a62ad

45.

Sebastianelli, L., Versace, V., Martignago, S., Brigo, F., Trinka, E., Saltuari, L., & Nardone, R. (2017). Low-frequency rTMS of the unaffected hemisphere in stroke patients: A systematic review. Acta Neurologica Scandinavica, 136(6), 585–605. doi: 10.1111/ane.12773

46.

Senot, P., D’Ausilio, A., Franca, M., Caselli, L., Craighero, L., & Fadiga, L. (2011). Effect of weight-related labels on corticospinal excitability during observation of grasping: A TMS study. Experimental Brain Research, 211(1), 161–167. doi: 10.1007/s00221-011-2635-x

47.

Sone, T., Nakaya, N., Iokawa, K., Hasegawa, K., Tsukada, T., Kaneda, M.,... & Suzuki, K. (2015). Prediction of upper limb recovery in the acute phase of cerebrovascular disease: Evaluation of “functional hand” using the manual function test. Journal of Stroke and Cerebrovascular Disease, 24(4), 815–822. doi: 10.1016/j.jstrokecerebrovasdis.2014.11.018

48.

Song, S., Zilverstand, A., Gui, W., Li, H.J., & Zhou, X. (2018). Effects of single-session versus multi-session non-invasive brain stimulation on craving and consumption in individuals with drug addiction, eating disorders or obesity: A meta-analysis. Brain Stimulation, doi: 10.1016/j.brs.2018.12.975

49.

Stilling, J.M., Monchi, O., Amoozegar, F., & Debert, C.T. (2019). Transcranial Magnetic and Direct Current Stimulation (TMS/tDCS) for the Treatment of Headache: A Systematic Review. Headache. doi: 10.1111/head.13479

50.

Takeuchi, N., Tada, T., Toshima, M., Chuma, T., Matsuo, Y., & Ikoma, K. (2008). Inhibition of the unaffected motor cortex by 1Hz repetitive transcranical magnetic stimulation enhances motor performance and training effect of the paretic hand in patients with chronic stroke. Journal of Rehabilitation Medicine, 40(4), 298–303. doi: 10.2340/16501977-0181

51.

Tarameshlu, M., Ansari, N.N., Ghelichi, L., & Jalaei, S. (2019). The effect of repetitive transcranial magnetic stimulation combined with traditional dysphagia therapy on poststroke dysphagia: A pilot double-blinded randomized-controlled trial. International Journal of Rehabilitation Research, doi: 10.1097/mrr.0000000000000336

52.

Tosun, A., Ture, S., Askin, A., Yardimci, E.U., Demirdal, S.U., Kurt Incesu, T.,... & 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(5), 361–367. doi: 10.1080/10749357.2017.1305644

53.

Tyson, S.F., Chillala, J., Hanley, M., Selley, A.B., & Tallis, R.C. (2006). Distribution of weakness in the upper and lower limbs post-stroke. Disability and Rehabilitation, 28(11), 715–719. doi: 10.1080/09638280500301584

54.

VanDerwerker, C.J., Ross, R.E., Stimpson, K.H., Embry, A.E., Aaron, S.E., Cence, B.,... & Gregory, C.M. (2018). Combining therapeutic approaches: rTMS and aerobic exercise in post-stroke depression: A case series. Topics in Stroke Rehabilitation, 25(1), 61–67. doi: 10.1080/10749357.2017.1374685

55.

Ward, N.S. (2005). Mechanisms underlying recovery of motor function after stroke. Postgraduate Medical Journal, 81(958), 510–514. doi: 10.1136/pgmj.2004.030809

56.

Yang, C., Guo, Z., Peng, H., Xing, G., Chen, H., McClure, M.A.,... & Mu, Q. (2018). Repetitive transcranial magnetic stimulation therapy for motor recovery in Parkinson’s disease: A Meta-analysis. Brain and Behavior, 8(11), e01132. doi: 10.1002/brb3.1132

57.

Zhang, J.J.Q., Fong, K.N.K., Welage, N., & Liu, K.P.Y. (2018). The Activation of the Mirror Neuron System during Action Observation and Action Execution with Mirror Visual Feedback in Stroke: A Systematic Review. Neural Plasticity, 2018, 2321045. doi: 10.1155/2018/2321045

58.

Zhang, L., Xing, G., Fan, Y., Guo, Z., Chen, H., & Mu, Q. (2017). Short-and Long-term Effects of Repetitive Transcranial Magnetic Stimulation on Upper Limb Motor Function after Stroke: A Systematic Review and Meta-Analysis. Clinical Rehabilitation, 31(9), 1137–1153. doi: 10.1177/0269215517692386

59.

Zhang, L., Xing, G., Shuai, S., Guo, Z., Chen, H., McClure, M.A.,... & Mu, Q. (2017). Low-Frequency Repetitive Transcranial Magnetic Stimulation for Stroke-Induced Upper Limb Motor Deficit: A Meta-Analysis. Neural Plasticity, 2017, 2758097. doi: 10.1155/2017/2758097