CHAPTER

Repetitive transcranial magnetic stimulation for motor recovery of the upper limb after stroke

14

Jitka L€ udemann-Podubecka´*,1, Kathrin B€osl*, Dennis Alexander Nowak*,† *HELIOS Klinik Kipfenberg, Kipfenberg, Germany Department of Neurology, University Hospital, Philips University, Marburg, Germany 1 Corresponding author: Tel.: +49-8465-175-66-131; Fax: +49-8465-175-184, e-mail address: [email protected]

†

Abstract Objective: Repetitive transcranial magnetic stimulation changes excitability of the motor cortex and it has hereby the potential to modulate changes in neural processing which impede motor recovery after stroke. Methods: This chapter presents an up-to-day systematic review of the treatment effects of repetitive transcranial magnetic stimulation (rTMS) in promoting motor recovery of the affected upper limb after stroke. Results: Thirty-seven trials were included in the analysis. The selected studies involved a total of 871 stroke subjects. All stimulation protocols pride on interhemispheric imbalance model. Interpretation: rTMS enhances motor recovery of the affected hand after stroke; however, the data available until today is too limited to support its routine use.

Keywords repetitive transcranial magnetic stimulation, stroke, motor recovery, upper limb

Abbreviations acute stroke chronic stroke cTBS dPMC fMRI iTBS

6 months after symptom onset continuous theta burst stimulation dorsal premotor cortex functional magnetic resonance imaging intermittent theta burst stimulation

Progress in Brain Research, Volume 218, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2014.12.001 © 2015 Elsevier B.V. All rights reserved.

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LTD LTP M1 M1/S1 PET rTMS S1 subacute stroke tDCS

long-term depression long-term potentiation primary motor cortex sensorimotor cortex positron emission tomography repetitive transcranial magnetic stimulation somatosensory cortex 1–6 months after symptom onset transcranial direct current stimulation

1 INTRODUCTION Stroke is the leading cause of death and principle cause of long-term disability worldwide (Kolominsky-Rabas et al., 2001; Lavados et al., 2007; Taylor et al., 1996), and optimizing the care management of stroke patients should be consequently a high priority. About two-thirds of stroke victims still suffer from profoundly impaired dexterity 6 months after the stroke (Kolominsky-Rabas et al., 2001). The past decade has seen a rapid increase of studies investigating potential approaches to use noninvasive stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), to enhance functional recovery of the affected upper limb after stroke. The present theoretical basis for the use of the neuromodulatory techniques in stroke patients is established especially by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies. They describe a relationship between the changes of task-induced neural activation after stroke and a disruption of the upper limb motor function and/or their functional recovery. There are also fMRI and TMS connectivity studies, which describe disturbed effective and functional connectivity especially between ipsilesional and contralesional M1 and its association with the amount of motor impairment. Given their long-lasting effect on cortical excitability changes, tDCS and rTMS have the potential to antagonize potential maladaptive changes within the cortical motor network and support upper limb motor recovery. The goals of this review are to summarize the current knowledge about (1) the relationship between the changes of the motor circuits in the cerebral cortex after stroke and its relationship to impaired functional recovery of the affected hand and (2) the potential of rTMS to enhance functional recovery of the affected hand. The primary goal of this review is to evaluate the effect of rTMS on upper limb motor function in patients with stroke by systematically reviewing the available data, as well as to discuss the factors, which could determine these effects.

2 NEURAL CORRELATES OF MOTOR RECOVERY AFTER STROKE Stroke frequently leads to impairment of upper limb motor function, after which a variable degree of motor recovery is seen. Numerous studies show that the recovery

2 Neural correlates of motor recovery after stroke

of the motor function is associated with extensive reorganization of the motor system at the cortical level (Grefkes and Ward, 2014; Rehme et al., 2012). Reorganization of motor circuits in the cerebral cortex is probably thought to contribute to recovery following stroke, but one important finding is the notion that plasticity does not need to be always adaptive, e.g., positive plasticity. The theory of “maladaptive plasticity” tainting motor recovery following stroke is based on numerous PET and fMRI studies, which describe a negative linear relationship between task-related brain activation and motor outcome of the affected upper limb (Chollet et al., 1991; Ward et al., 2003). Patients with poorer motor outcome recruited a number of motor-related brain regions of both hemispheres when moving the affected hand, whereas patients with good functional outcome exhibited a lateralized brain activation within one hemisphere, which is close to that to be found in healthy subjects moving one hand. These observations have helped to develop the idea that there is maladaptive interhemispheric competition after stroke, which may hamper the recovery of the affected hand. Therefore, blocking or reducing maladaptive plasticity with neuromodulation techniques may be a desirable therapy. However, the physiological meaning of widespread neural activation within the motor network of both hemispheres after stroke is still under debate. The key findings from some studies suggest, e.g., that the role of the contralesional motor areas for recovery of motor function may depend on several various factors such as time since stroke, lesion location, or intensity of motor deficit (Grefkes and Ward, 2014; Rehme et al., 2012). For example, an fMRI study investigated the pattern and time course of stroke-induced changes in the cortical motor system during the first 2 weeks after stroke (Rehme et al., 2011). This study describes a global reduction of neural activity followed by increases in ipsi- as well as contralesional motor areas in patients with a severe motor deficit, while patients with a mild deficit did not differ from healthy subjects. This indicates a dependence of the longitudinal change in neural activation within motor areas upon the degree of initial motor impairment. Additionally, this study demonstrates a positive correlation between the gradually increasing activity in contralesional primary motor cortex and premotor cortex and the functional recovery of the affected hand in severely affected patients and indicates thereby a supportive role of contralesional motor areas for motor recovery in severely affected patients at an early stage after stroke. Moreover, the simple localization of additional neural activity to a certain brain region by means of neuroimaging (PET, fMRI) is only one of the possibilities to describe neural changes following stroke. Recent fMRI and TMS studies describe stroke-induced changes of functional and effective connectivity between different brain regions (Grefkes and Ward, 2014) and indicate a relationship to the amount of motor impairment. Resting-state fMRI studies showed that a reduced functional connectivity between ipsi- and contralesional M1 is associated with the amount of motor impairment (Carter et al., 2012; Park et al., 2011; Wang et al., 2010), and that stronger functional connectivity between ipsilesional M1 and other brain areas is positively correlated with motor recovery (Park et al., 2011). These results demonstrate a key role of functional connectivity of ipsilesional M1 with other brain areas in the process of functional recovery after stroke. A recent fMRI study demonstrated

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that reduction of effective connectivity between ipsilesional premotor areas and ipsilesional M1 or alternatively a reduction of inhibitory influence from contralesional M1 to ipsilesional M1 correlates with the amount of motor impairment of the affected hand after stroke (Grefkes et al., 2008). These data confirm the key role of both M1 for motor recovery after stroke and give support to the hypothesis that overactivity of the contralesional hemisphere is maladaptive and negative for motor recovery. But then, we can find similar studies, which described a positive correlation between the “overactivity” of the contralesional motor areas and the motor improvement of the affected hand. For example, a TMS–fMRI study shows an inhibitory influence of the contralesional dorsal premotor cortex (dPMC) toward the ipsilesional M1 in well-recovered stroke patients and a facilitatory effect in those with greater clinical impairment (Bestmann et al., 2010). Collectively, the best part of studies, which investigated a relationship between reorganization of the motor system at the cortical level and the recovery of motor function following stroke, confirms the theory of “maladaptive overactivity” of the contralesional hemisphere. However, few task-related neural activity studies, as well as studies of functional and effective connectivity, controvert the general validity of this theory. This indicates that the plastic changes in neural processing and their impact on motor recovery after stroke are not completely understood.

3 MODULATION OF CORTICAL EXCITABILITY BY rTMS The combination of TMS with neuroimaging established several, now widely accepted insights into the basic mechanisms of action of rTMS and its distributed impact on brain networks (Bestmann et al., 2004). Several trials described their interregional interaction depending on anatomical connectivity. Often demonstrated was the capability of rTMS to target both local and remote brain regions tightly connected that constitute a cortical and subcortical network. For example, a study showed MRI-detectable changes of neural activity of primary and secondary cortical motor regions including sensorimotor cortex (M1/S1), supplementary motor area, dPMC, cingulate motor area, the putamen, and thalamus during high-frequency rTMS of the left M1/S1 (Bestmann et al., 2004). Moreover, it was often demonstrated that rTMS to M1 significantly influences the activity in the contralateral homologue (Ferbert et al., 1992; Meyer et al., 1995). Furthermore, concurrent TMS–fMRI studies showed a differential network effect after stimulation of different areas. For example, changes in subcortical activity during M1 stimulation can be distinguished from those evoked by stimulation of the dPMC despite overlap of their anatomical footprints, which indicates a diverse functional connectivity between different areas (Bestmann et al., 2003, 2005). Most authors agree that the post-effects of rTMS are due to changes in synaptic effectiveness, similar to long-term potentiation (LTP) and long-term depression (LTD), which are widely considered one of the major cellular mechanisms that underlie learning. LTP and LTD are described as long-lasting changes in signal transmission between two neurons, based on the ability of chemical synapses to change

4 rTMS for motor recovery after stroke

their strength (Thickbroom, 2007). This is one of the several phenomena underlying synaptic plasticity. A study, which investigated motor cortical physiology changes after behavioral motor training or rTMS, described significant increases of motor cortex excitability and expanding motor maps areas after each intervention, but the changes achieved with rTMS were greater than those achieved with motor training. A combination of both resulted in the largest changes (Lee et al., 2013). Such results indicate that the changes to neuroplasticity to be induced by motor learning are similar to those to be induced by rTMS. “The direction” of neural changes within the motor systems is determined by the specific pattern of the rTMS stimulation protocol. Numerous experiments tested diverse rTMS stimulation protocols and distinguished two principles depending on the rTMS effects on cortical excitability (Lang and Siebner, 2007). High-frequency rTMS (
5 Hz), intermittent theta burst stimulation (iTBS), and paired-pulse stimulation (interstimulus interval 1–5 ms) increase cortico-motor excitability representing LTP. Low-frequency rTMS (  1Hz), continuous theta burst stimulation (cTBS), and paired-pulse stimulation with interstimulus interval 3 ms result in reduction of cortico-motor excitability resembling LTD. More recent work has also started to use concurrent TMS–fMRI to investigate state-dependent effectiveness of rTMS within the cerebral motor network. A recent experiment demonstrated that TMS to left dPMC led to activity increases in contralateral right dPMC and M1 during active left-hand grip, whereas activity decreases were observed during the resting state (no-grip test) (Bestmann et al., 2008). Similarly, TMS to right parietal cortex increases the activity in left S1 during right-wrist somatosensory input, but decreases neural activity in left S1 in the absence of somatosensory input (Blankenburg et al., 2008). Such results indicate the possibility that the TMS effects are modulated in dependence of the behavioral context. A better understanding of the state-dependent effectiveness of rTMS may lead to a more appropriate application of this method as a tool to provide recovery of function in motor rehabilitation.

4 rTMS FOR MOTOR RECOVERY AFTER STROKE The present theoretical basis for the use of rTMS in rehabilitation of the affected hand after stroke is, despite its limitation, the interhemispheric imbalance model (Nowak et al., 2010). This model describes the neural activation changes after stroke to be a “disruption of the balance” between both hemispheres, with a “balance shift” toward the nonlesioned hemisphere. According to this theory, “overactive” motor areas of the nonlesioned hemisphere may inhibit physiological activity within motor areas of the lesioned hemisphere and hamper the recovery of the affected upper limb. The current application of rTMS in rehabilitation of upper limb dysfunction follows three potential ways of neuromodulation within this concept: (1) facilitatory rTMS over the ipsilesional M1, (2) inhibitory rTMS over the contralesional M1, and (3) bilateral rTMS consisting of facilitatory rTMS over ipsilesional M1 and inhibitory rTMS over contralesional M1.

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5 METHODS We reviewed the PubMed research database prior to May 31, 2014 to identify relevant trials. The search terms “repetitive transcranial magnetic stimulation” and “stroke” were used. The trials were included if they met the following criteria: (1) study on humans, (2) diagnosis of stroke, (3) rTMS used as an intervention, (4) motor assessment of the affected upper limb before and after the intervention, (5) placebocontrolled study design or study design with at least two experimental groups, and (6) three randomized patients at least.

6 RESULTS Thirty-seven trials were identified that corresponded with the inclusion criteria. These trials involved a total of 871 stroke subjects. Included trials showed a large variability regarding included subjects (number of included subjects, time from stroke, degree of upper limb impairment), rTMS stimulation protocol used (intensity, duration, number of rTMS sessions), type of hand motor assessment performed, and methodological quality. For sake of simplicity, the included trials were subcategorized according to the stimulated hemisphere: (1) rTMS over contralesional motor cortex (placebocontrolled trials), (2) rTMS over the ipsilesional motor cortex (placebo-controlled trials), (3) bilateral rTMS (placebo-controlled trials), and (4) rTMS in comparison (trials with and without placebo-control comparing different rTMS protocols). Tables 1–4 summarize studies subcategorized in each of the categories. The order of the studies in each table depends on (1) time since stroke and (2) applied rTMS protocol. The effectiveness of treatment was evaluated for each assessment after the rTMS intervention and each follow-up evaluation as the percentage difference to baseline. The difference between rTMS real–rTMS sham was defined to be the effectiveness of rTMS.

7 rTMS OVER THE CONTRALESIONAL HEMISPHERE IN PROMOTING MOTOR RECOVERY OF THE AFFECTED HAND AFTER STROKE Until today, 25 placebo-controlled human studies (n ¼ 472) investigated the effect of rTMS over the contralesional hemisphere on motor function of the affected hand after stroke (Ackerley et al., 2010; Avenanti et al., 2012; Barros Galva˜o et al., 2014; Conforto et al., 2012; Dafotakis et al., 2008; Di Lazzaro et al., 2013; Emara et al., 2010; Etoh et al., 2013; Fregni et al., 2006; Grefkes et al., 2010; Khedr et al., 2009; Kirton et al., 2008; Liepert et al., 2007; Mansur et al., 2005;

Table 1 rTMS over the contralesional motor cortex in promoting motor recovery of the affected hand after stroke (placebocontrolled studies)

Continued

Table 1 rTMS over the contralesional motor cortex in promoting motor recovery of the affected hand after stroke (placebocontrolled studies)—cont’d

Continued

Table 1 rTMS over the contralesional motor cortex in promoting motor recovery of the affected hand after stroke (placebocontrolled studies)—cont’d

Table 2 rTMS over the ipsilesional motor cortex in promoting motor recovery of the affected hand after stroke (placebocontrolled studies)

Continued

Table 2 rTMS over the ipsilesional motor cortex in promoting motor recovery of the affected hand after stroke (placebocontrolled studies)—cont’d

Continued

Table 2 rTMS over the ipsilesional motor cortex in promoting motor recovery of the affected hand after stroke (placebocontrolled studies)—cont’d

Table 3 rTMS bilateral in promoting motor recovery of the affected hand after stroke (placebo-controlled studies)

Table 4 Comparison of rTMS ipsilesional, rTMS contralesional, and rTMS bilateral in promoting motor recovery of the affected hand after stroke (studies without placebo-controlled) Age

30 (10 ipsiles, 59 ± 13 10 contrales, 10 bilater)

27 (9 ipsiles, 9 contrales, 9 bilater)

62 ± 8 years

Time after stroke

>6

67 ± 48 months

Stimulation parameters

Upper limb Stroke impairment aetiology

mild

mild moderate

isch.

isch. haem.

Stroke location

Intensity, duration

Adjunct therapies

Assessments

10-Hz rTMS + 1-Hz rTMS subc. 1 90% rMT 1000 pulses

1-mA tDCS + 1-Hz rTMS 1 subc. rTMS 90% rMT 1000 pulses; tDCS 20 min.

Negative correlation (−0,47) between pinch force changes and TCI ratio in all groups. Negative correlation (−0,5) between bimanual coordination changes and TCI unaff-aff

Outcome by first follow-up

Outcome by last follow-up

(% improvement to baseline)

Number sessions

(% improvement to baseline)

Bilateral

Ipsiles

Contrales

Bilateral

Ipsiles

Contrales

**38% **32% 35% −5% *12% *20%

**33% *16% 25% **−22% **18% 0%

6% 10% 8% 5% −4% 8%

**37% **30% 34% 8% 2% −2%

23% 13% 6%

22% 9% *24%

10% −1% 7%

27% *25% 9%

22% *20% 9%

12% 5% 6%

11% *−24% *24% 16% −14% *−24%

18% *−21% *22% 2% *−25% *−27%

6% −4% *20% −5% −9% −4%

20% 0% −2% −2% 1% 5%

17% 3% 1% −2% 1% 5%

8% −1% −2% −3% 1% 0%

Reference OGSC

Patients characteristics Number

Chronic stroke 7-days follow-up

MT Acceleration Pinch force Mean MEPipsiles MEPcontrales ICI

−

**30% *14% 22% −10% 2% 1%

7-days follow-up

Acceleration Pinch force Bimanual coordination Mean MEPcontrales MEPipsiles TCI aff-unaff TCI unaff-aff TCI ratio

2

Takeuchi et al. (2009)

1

Takeuchi et al. (2012)

11% 9% 10% 7% −2% 9%

aMT, active motor threshold; ARAT, Action Research Arm Test; BBT, Box and Block Test; cort., cortical; cTBS, continuous theta burst stimulation; contrales, contralesional; ipsiles, ipsilesional; FMUL, Fugl Meyer Upper Limb; FNS, functional neuromuscular stimulation; haem., hemorrhagic; isch., ischemic; JTHF, jebsen taylor hand function; ICI, Intracorticale inhibition; iSP, ipsilateral silent period; iTBS, intermittent theta burst stimulation; M1 MAUEF, Melbourne Assesment of Upper Extremity Function; M1, primary motor cortex; MAL, Motor Activity Log; MAS, Modified Ashworth Scale; MEP, motor evoked potential; MT, motor training; MRC, Medical Research Council Scale; NHPT, Nine-Hole-Peg-Test; PT, physiotherapy; PPT, Purdue Pegboard Test; PT, physiotherapy; rMT, resting motor treshold; rTMS, repetitive transcranial magnetic stimulation; S1, somatosensory cortex; subc., subcortical; STEF, Simple Test for Evaluating Hand Function; STT, Serial Targeting Task; TCI, Transcallosale inhibition; VMC, voluntary muscle contraction; WMFT, Wolf Motor Function Test; STT, serial targeting tast; SMLT, sequential motor learning task; *, **, ***, significant differences (p ≤ 0.05, p ≤ 0.01, p ≤ 0.001) in comparison to baseline

7 rTMS over the contralesional hemisphere

Meehan et al., 2011; Nowak et al., 2008; Sasaki et al., 2013; Senio´w et al., 2012; Sung et al., 2013; Takeuchi et al., 2005, 2008; Talelli et al., 2007, 2012; Theilig et al., 2011; Tretriluxana et al., 2013). Table 1 summarizes these studies.

7.1 PATIENTS CHARACTERISTICS Time after stroke: The majority of studies investigated the effectiveness of inhibitory rTMS on patients with chronic stroke. Thirteen studies (n ¼ 198) enrolled explicitly patients with chronic stroke (Ackerley et al., 2010; Avenanti et al., 2012; Barros Galva˜o et al., 2014; Di Lazzaro et al., 2013; Fregni et al., 2006; Kirton et al., 2008; Mansur et al., 2005; Meehan et al., 2011; Takeuchi et al., 2005, 2008; Talelli et al., 2007, 2012; Tretriluxana et al., 2013), and three studies (n ¼ 56) enrolled explicitly patients with acute stroke (Khedr et al., 2009; Liepert et al., 2007; Sasaki et al., 2013). The remaining studies enrolled mixed patientscollectives: four studies (n ¼ 96) acute and subacute stroke (Conforto et al., 2012; Grefkes et al., 2010; Nowak et al., 2008; Senio´w et al., 2012); two studies (n ¼ 36) acute, subacute, and chronic stroke (Dafotakis et al., 2008; Theilig et al., 2011); and three studies (n ¼ 86) subacute and chronic stroke (Emara et al., 2010; Etoh et al., 2013; Sung et al., 2013). Stroke etiology: Patients with ischemic stroke were investigated more often than patients with hemorrhagic stroke. Fourteen studies (n ¼ 251) enrolled explicitly patients with ischemic stroke (Conforto et al., 2012; Dafotakis et al., 2008; Di Lazzaro et al., 2013; Emara et al., 2010; Fregni et al., 2006; Grefkes et al., 2010; Khedr et al., 2009; Kirton et al., 2008; Meehan et al., 2011; Nowak et al., 2008; Takeuchi et al., 2005, 2008; Talelli et al., 2007, 2012). Nine studies (n ¼ 202) included also patients with hemorrhagic stroke (Ackerley et al., 2010; Avenanti et al., 2012; Barros Galva˜o et al., 2014; Etoh et al., 2013; Liepert et al., 2007; Sasaki et al., 2013; Senio´w et al., 2012; Sung et al., 2013; Theilig et al., 2011). Two articles (n ¼ 19) did not specify the etiology of stroke (Mansur et al., 2005; Tretriluxana et al., 2013). Lesion location: Patients with subcortical stroke were enrolled more often than patients with cortical stroke. Ten studies (n ¼ 138) investigated explicitly patients with subcortical stroke (Ackerley et al., 2010; Dafotakis et al., 2008; Etoh et al., 2013; Grefkes et al., 2010; Kirton et al., 2008; Liepert et al., 2007; Mansur et al., 2005; Nowak et al., 2008; Takeuchi et al., 2005, 2008), 13 studies (n ¼ 305) investigated mixed patients-collectives (Avenanti et al., 2012; Conforto et al., 2012; Di Lazzaro et al., 2013; Emara et al., 2010; Fregni et al., 2006; Khedr et al., 2009; Meehan et al., 2011; Sasaki et al., 2013; Senio´w et al., 2012; Sung et al., 2013; Talelli et al., 2007, 2012; Theilig et al., 2011). Two articles (n ¼ 29) did not specify the etiology of stroke (Barros Galva˜o et al., 2014; Tretriluxana et al., 2013). Severity of upper limb impairment: Subjects with moderate to mild sensorymotor impairment were investigated more often than those with a severe impairment. With the exception of three studies (n ¼ 64), which included also patients with severe impairment (Conforto et al., 2012; Kirton et al., 2008; Theilig et al., 2011), all studies (n ¼ 408) enrolled exclusively patients with moderate to mild sensory-motor

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impairment of the affected hand (Ackerley et al., 2010; Avenanti et al., 2012; Barros Galva˜o et al., 2014; Dafotakis et al., 2008; Di Lazzaro et al., 2013 Emara et al., 2010; Etoh et al., 2013; Fregni et al., 2006; Grefkes et al., 2010; Khedr et al., 2009; Liepert et al., 2007; Mansur et al., 2005; Meehan et al., 2011; Nowak et al., 2008; Sasaki et al., 2013; Senio´w et al., 2012; Sung et al., 2013; Takeuchi et al., 2005, 2008; Talelli et al., 2007, 2012; Tretriluxana et al., 2013).

7.2 STIMULATION PARAMETERS Stimulated area: All studies applied rTMS explicitly over the contralesional M1. Only one study investigated additional efficiency of inhibitory rTMS over the contralesional S1 (Meehan et al., 2011). Stimulation protocol: The most of studies investigated the efficiency of 1-Hz rTMS, with the stimulation intensity between 90% aMT and 120% rMT, and the stimulation duration 150–1800 pulses (Avenanti et al., 2012; Barros Galva˜o et al., 2014; Conforto et al., 2012; Dafotakis et al., 2008; Emara et al., 2010; Etoh et al., 2013; Fregni et al., 2006; Grefkes et al., 2010; Khedr et al., 2009; Kirton et al., 2008; Liepert et al., 2007; Mansur et al., 2005; Nowak et al., 2008; Sasaki et al., 2013; Senio´w et al., 2012; Sung et al., 2013; Takeuchi et al., 2005, 2008; Theilig et al., 2011; Tretriluxana et al., 2013). Only five studies investigated cTBS with a stimulation intensity of 80–90% aMT and stimulation duration 300–600 pulses (Ackerley et al., 2010; Di Lazzaro et al., 2013; Meehan et al., 2011; Talelli et al., 2007, 2012). Interesting is the fact that all studies which investigated cTBS explicitly enrolled chronic stroke subjects. Number of stimulation sessions: Ten Studies investigated the efficiency of a single rTMS session (Ackerley et al., 2010; Dafotakis et al., 2008; Grefkes et al., 2010; Liepert et al., 2007; Mansur et al., 2005; Nowak et al., 2008; Takeuchi et al., 2005, 2008; Talelli et al., 2007; Tretriluxana et al., 2013). Other studies realized repeated rTMS sessions over 3 (Meehan et al., 2011), 5 (Fregni et al., 2006; Khedr et al., 2009; Sasaki et al., 2013), 8 (Kirton et al., 2008), 10 (Avenanti et al., 2012; Barros Galva˜o et al., 2014; Conforto et al., 2012; Di Lazzaro et al., 2013; Emara et al., 2010; Etoh et al., 2013; Talelli et al., 2012; Theilig et al., 2011), 15 (Senio´w et al., 2012), and 20 (Sung et al., 2013) days. Adjunct therapies: Nine studies combined rTMS stimulation with a motor therapy or physiotherapy of the affected hand (Ackerley et al., 2010; Avenanti et al., 2012; Barros Galva˜o et al., 2014; Di Lazzaro et al., 2013; Emara et al., 2010; Etoh et al., 2013; Meehan et al., 2011; Senio´w et al., 2012; Talelli et al., 2012), one study with functional neuromuscular stimulation (Theilig et al., 2011).

7.3 FOLLOW-UP Thirteen studies realized a follow-up evaluation to examine a potential long-lasting effect of inhibitory rTMS (over 30 min to 90 days) for motor improvement of the affected hand (Avenanti et al., 2012; Barros Galva˜o et al., 2014; Conforto et al., 2012; Di Lazzaro et al., 2013; Emara et al., 2010; Fregni et al., 2006; Khedr

7 rTMS over the contralesional hemisphere

et al., 2009; Kirton et al., 2008; Senio´w et al., 2012; Takeuchi et al., 2005, 2008; Talelli et al., 2007, 2012).

7.4 EFFECTIVENESS Twenty studies reported a positive effect of inhibitory rTMS on motor recovery after stroke. Twelve of them (n ¼ 233) found a statistically significant effect (Avenanti et al., 2012; Barros Galva˜o et al., 2014; Dafotakis et al., 2008; Di Lazzaro et al., 2013; Emara et al., 2010; Liepert et al., 2007; Mansur et al., 2005; Sasaki et al., 2013; Sung et al., 2013; Takeuchi et al., 2005, 2008; Tretriluxana et al., 2013) and eight of them (n ¼ 141) did not (Conforto et al., 2012; Fregni et al., 2006; Grefkes et al., 2010; Khedr et al., 2009; Kirton et al., 2008; Meehan et al., 2011; Nowak et al., 2008; Theilig et al., 2011). The effect of rTMS (expressed as the difference between the improvement of hand function by rTMS real–rTMS sham) varied between 1% and 47%. Only five studies (n ¼ 98) showed a negative effect of rTMS over the unaffected hemisphere for recovery of the affected upper limb after stroke (Ackerley et al., 2010; Etoh et al., 2013; Senio´w et al., 2012; Talelli et al., 2007, 2012). The effectiveness of rTMS varied between –1% and –15%. Follow-up examinations showed a positive long-lasting effect in 11 trials (Avenanti et al., 2012; Barros Galva˜o et al., 2014; Conforto et al., 2012; Di Lazzaro et al., 2013; Emara et al., 2010; Fregni et al., 2006; Khedr et al., 2009; Kirton et al., 2008; Takeuchi et al., 2005, 2008; Talelli et al., 2007), but only four of them found a statistically significant effect (Avenanti et al., 2012; Emara et al., 2010; Khedr et al., 2009; Takeuchi et al., 2008). The effect of rTMS treatment for improvement of the affected upper limb varied between 4% and 33% at the time of follow-up. Only two trials showed a negative effect of inhibitory TMS for motor recovery of the affected hand (Senio´w et al., 2012; Talelli et al., 2012). The effect of rTMS varied between –4% and –7%.

7.4.1 Patient Characteristic-Dependent Efficiency The available data do not show no different efficiency of rTMS for motor recovery, depending on time after stroke, stroke etiology, lesion location, or severity of the upper limb impairment.

7.4.2 Stimulation Parameter-Dependent Efficiency Stimulation protocol-dependent efficiency: The available data show an inferior efficiency of cTBS compared to 1-Hz rTMS. Three (from five) studies, which applied the cTBS protocol, showed a negative effect for motor recovery after stroke (Ackerley et al., 2010; Talelli et al., 2007, 2012). Efficiency dependence on number of stimulation sessions: Single-session rTMS interventions generate effectiveness rates of 9–34%. The highest efficiency of rTMS on hand motor improvement shows trials, which applied three to five rTMS sessions (18–47%). In the trials that applied 10 rTMS session or more, the efficiency of rTMS varied between 15% and 29%. The available results of follow-up examinations confirm these results.

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7.5 SUMMARY The available data indicate a positive effect of inhibitory rTMS for motor recovery of the affected hand after stroke (especially 1-Hz rTMS), but simultaneously a limited potential for its repeated application over 10 days or more. Future studies should investigate if a longer time interval between the sessions increases effectiveness rates and long-term effectiveness.

8 rTMS OVER THE IPSILESIONAL HEMISPHERE IN PROMOTING MOTOR RECOVERY OF THE AFFECTED HAND AFTER STROKE Sixteen placebo-controlled trials (n ¼ 359) investigated the efficiency of rTMS over ipsilesional hemisphere for motor recovery of the affected upper limb after stroke (Ackerley et al., 2010; Ameli et al.,2009; Brodie et al., 2014; Chang et al., 2010, 2012; Emara et al., 2010; Hsu et al., 2013; Khedr et al., 2009, 2010; Kim et al., 2006; Malcolm et al., 2007; Pomeroy et al., 2007; Sasaki et al., 2013; Sung et al., 2013; Talelli et al., 2007, 2012). Table 2 summarizes these studies.

8.1 PATIENT CHARACTERISTICS Time after stroke: Five studies (n ¼ 130) included explicitly patients with acute stroke (Chang et al., 2010; Hsu et al., 2013; Khedr et al., 2009, 2010; Sasaki et al., 2013). Five trials (n ¼ 75) enrolled explicitly patients with chronic stroke (Ackerley et al., 2010; Brodie et al., 2014; Malcolm et al., 2007; Talelli et al., 2007, 2012). The remaining studies investigated mixed patients-collectives: one trial (n ¼ 27) acute and subacute stroke (Pomeroy et al., 2007), one trial (n ¼ 29) acute, subacute and chronic stroke (Ameli et al., 2009), and four trials (n ¼ 98) subacute and chronic stroke (Chang et al., 2012; Emara et al., 2010; Kim et al., 2006; Sung et al., 2013). Stroke etiology: Subjects with ischemic stroke were more frequently enrolled than those with hemorrhagic stroke. Eight trials (n ¼ 201) investigated explicitly subjects with ischemic stroke (Ameli et al.,2009; Chang et al., 2010; Emara et al., 2010; Hsu et al., 2013; Khedr et al., 2009, 2010; Talelli et al., 2007, 2012), and seven trials (n ¼ 143) also subjects with hemorrhagic stroke (Ackerley et al., 2010; Chang et al., 2012; Kim et al., 2006; Malcolm et al., 2007; Pomeroy et al., 2007; Sasaki et al., 2013; Sung et al., 2013). One trial (n ¼ 15) did not specify the etiology of stroke (Brodie et al., 2014). Lesion location: Only one study (n ¼ 10) explicitly enrolled subjects with subcortical stroke (Ackerley et al., 2010). The remaining studies investigated also subjects with cortical stroke. Severity of upper limb impairment: All studies investigated stroke subjects with a mild to moderate upper limb impairment. Only two studies (n ¼ 55) enrolled also patients with a severe upper limb impairment (Chang et al., 2010; Pomeroy et al., 2007).

8 rTMS over the ipsilesional hemisphere

8.2 STIMULATION PARAMETERS Stimulated area: All trials applied rTMS explicitly over the ipsilesional M1. Stimulation protocol: The trials investigated different stimulation protocols: 1 (Pomeroy et al., 2007), 3 (Khedr et al., 2009, 2010; Sasaki et al., 2013), 5 (Brodie et al., 2014; Emara et al., 2010), 10 (Ameli et al., 2009; Chang et al., 2010, 2012; Khedr et al., 2010; Kim et al., 2006), and 20 Hz (Malcolm et al., 2007) (with stimulation intensities between 80% and 130% rMT and stimulation durations between 200 and 1800 pulses), and iTBS (Ackerley et al., 2010; Hsu et al., 2013; Sung et al., 2013; Talelli et al., 2007, 2012) (with stimulation intensities between 80% aMT and 90% rMT, and stimulation durations between 600 and 1000 pulses). Interesting is the fact that the facilitatory TBS protocol was applied mainly on patients with chronic stroke, analogous to studies which investigated inhibitory TBS protocols. Number of stimulation sessions: Only three studies investigated the efficiency of a single rTMS session (Ameli et al., 2009; Kim et al., 2006; Talelli et al., 2007). Others studies applied repeated rTMS sessions over 5 (Brodie et al., 2014; Khedr et al., 2009, 2010; Sasaki et al., 2013), 8 (Kirton et al., 2008), 10 (Chang et al., 2010, 2012; Emara et al., 2010; Hsu et al., 2013; Malcolm et al., 2007; Talelli et al., 2012), and 20 (Wang et al., 2014) days. Adjunct therapies: Nine studies combined the facilitatory rTMS with a motor therapy of the affected upper limb (Ackerley et al., 2010; Brodie et al., 2014; Chang et al., 2010, 2012; Emara et al., 2010; Kim et al., 2006; Malcolm et al., 2007; Pomeroy et al., 2007; Talelli et al. 2012).

8.3 FOLLOW-UP Nine trials realized a follow-up evaluation ranging from 40 min to 12 months (Chang et al., 2010, 2012; Emara et al., 2010; Hsu et al., 2013; Khedr et al., 2009, 2010; Malcolm et al., 2007; Talelli et al., 2007, 2012).

8.4 EFFECTIVENESS Thirteen trials demonstrated a positive effect of facilitatory rTMS on functional recovery of the affected upper limb. Eight of them (n ¼ 194) found a statistically significant effect (Ameli et al., 2009; Emara et al., 2010; Hsu et al., 2013; Khedr et al., 2010; Kim et al., 2006; Sasaki et al., 2013; Sung et al., 2013; Talelli et al., 2007) and five of them (n ¼ 103) did not (Brodie et al., 2014; Chang et al., 2010, 2012; Khedr et al., 2009; Malcolm et al., 2007). The effectiveness of rTMS treatment varied between 12% and 56%. Only three trials (n ¼ 62) reported a negative effect of rTMS for functional recovery of the affected hand after stroke (Ackerley et al., 2010; Pomeroy et al., 2007; Talelli et al., 2007). The effectiveness of rTMS ranged between –3% and –36%.

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All trials which realized a follow-up evaluation showed a positive long-term effect of rTMS for motor recovery of the affected hand. This effect ranged between 10% and 146%.

8.4.1 Patient Characteristics-Dependent Efficiency

One trial (n ¼ 29) demonstrated a positive effect of 10-Hz rTMS on subjects with a subcortical, but not on those with a cortical lesion (Ameli et al., 2009). Other trials showed no evident patients characteristic-dependent efficiency.

8.4.2 Stimulation Parameter-Dependent Efficiency Stimulation protocol-dependent efficiency: One trial investigating the efficiency of 1 Hz (120% rMT, 5 blocks of 40 stimuli, with 3-min interblock intervals) over the affected hemisphere and demonstrated an evidently negative effect for motor recovery of the affected upper limb (Pomeroy et al., 2007). Two other trials applied iTBS and demonstrated a negative effect on motor function of the affected hand (Ackerley et al., 2010; Talelli et al., 2012). Efficiency dependence on number of stimulation sessions: Single rTMS session generate at average 14% hand function improvement. The best efficiency demonstrated studies which applied rTMS over 5 days (at average 23% improvement). By contrast, the application of rTMS over 10 days or more improves hand motor function by at average 18%. The available follow-up data show similar results.

8.5 SUMMARY Currently, there is reasonable evidence for stimulation protocol 10 Hz and for stimulation application over 10 sessions. However, the largest positive effects for hand function after stroke are achieved by 3-Hz rTMS applied over five sessions. Future studies are needed to make definitive conclusions regarding what rTMS protocols applied over how many sessions generates the best effect in promoting recovery of motor function of the affected hand after stroke.

9 BILATERAL STIMULATION IN PROMOTING MOTOR RECOVERY OF THE AFFECTED HAND AFTER STROKE Today only two placebo-controlled (n ¼ 74) trials tested the efficiency of bilateral stimulation for motor recovery of the affected hand after stroke (Sung et al., 2013; Wang et al., 2014). Table 3 summarizes these trials.

9.1 PATIENTS CHARACTERISTIC Time after stroke: One trial enrolled patients with subacute stroke (Wang et al., 2014), and the other patients with subacute and chronic stroke (Sung et al., 2013).

10 Comparing different rTMS protocols

Stroke etiology: One trial explicitly investigated subjects with ischemic stroke (Wang et al., 2014), and the other also subjects with hemorrhagic stroke (Sung et al., 2013). Lesion location: Both trials enrolled subcortical and cortical stroke subjects. Severity of upper limb impairment: Only subjects with moderate to mild motor impairment were investigated.

9.2 STIMULATION PARAMETERS Both studies investigated bilateral stimulation protocols with 1-Hz rTMS over contralesional M1 and iTBS over ipsilesional M1 (90% rMT, 1000 pulses) over 20 consecutive stimulation sessions without adjunct therapy.

9.3 FOLLOW-UP One trial examined follow-up after 3 months from the intervention (Wang et al., 2014).

9.4 EFFECTIVENESS Both studies reported a positive effect (of approximately 20% improvement) on hand function after stroke. A follow-up examination demonstrates a lasting effectiveness over 3 months (Wang et al., 2014).

10 COMPARING DIFFERENT rTMS PROTOCOLS Today nine studies (n ¼ 225) have compared the efficiency of different stimulation protocols on motor function of the affected hand (Ackerley et al., 2010; Emara et al., 2010; Khedr et al., 2009; Sasaki et al., 2013; Sung et al., 2013; Takeuchi et al., 2012, 2009; Talelli et al., 2007, 2012). Seven of them were placebo-controlled and they are summarized in Tables 1–3. Table 4 summarizes the studies that compared different rTMS protocols without placebo control. Six studies compared the efficiency of facilitatory rTMS over the affected hemisphere with inhibitory rTMS over the unaffected hemisphere (Ackerley et al., 2010; Emara et al., 2010; Khedr et al., 2009; Sasaki et al., 2013; Talelli et al., 2007, 2012). Three studies compared facilitatory rTMS, inhibitory rTMS, and bilateral stimulation (Sung et al., 2013; Takeuchi et al., 2012, 2009).

10.1 PATIENT CHARACTERISTICS Time after stroke: Patients with chronic stroke were more often investigated than patients with acute and subacute stroke. Five trials (n ¼ 98) exclusively enrolled subjects with a chronic stroke (Ackerley et al., 2010; Takeuchi et al., 2012, 2009; Talelli

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et al., 2007, 2012). Two trials (n ¼ 83) included subacute and chronic stroke subjects (Emara et al., 2010; Sung et al., 2013). Two trials (n ¼ 44) investigated only patients with acute stroke (Khedr et al., 2009; Sasaki et al., 2013). Stroke etiology: Patients with ischemic stroke were investigated more often than patients with hemorrhagic stroke. Five studies (n ¼ 125) explicitly enrolled patients with ischemic stroke (Emara et al., 2010; Khedr et al., 2009; Takeuchi et al., 2009; Talelli et al., 2007, 2012). Four studies (n ¼ 100) also enrolled patients with hemorrhagic stroke (Ackerley et al., 2010; Sasaki et al., 2013; Sung et al., 2013; Takeuchi et al., 2012). Lesion location: Subjects with subcortical stroke were enrolled more often than those with a cortical stroke. Three trials (n ¼ 67) explicitly investigated patients with a subcortical stroke (Ackerley et al., 2010; Takeuchi et al., 2012, 2009). Six studies (n ¼ 133) included both subcortical and cortical stroke patients (Emara et al., 2010; Khedr et al., 2009; Sasaki et al., 2013; Sung et al., 2013; Talelli et al., 2007, 2012). Severity of upper limb impairment: All trials investigated stroke subjects with mild to moderate upper limb impairment.

10.2 STIMULATION PARAMETERS Stimulated area: All studies applied the rTMS over M1. Stimulation protocol: Five studies compared 1-Hz rTMS contralesional with 3-Hz rTMS (Khedr et al., 2009; Sasaki et al., 2013), 5-Hz rTMS (Emara et al., 2010), 10-Hz rTMS (Takeuchi et al., 2012), and 1-mA tDCS (Takeuchi et al., 2009) ipsilesional. The stimulation intensity was between 80% and 130% rMT, and the stimulation duration ranged between 150 and 1800 pulses. Four studies compared cTBS contralesional with iTBS ipsilesional (Ackerley et al., 2010; Sung et al., 2013; Talelli et al., 2007, 2012). Stimulation intensity ranged between 80% aMT and 90% rMT and stimulation duration between 300 and 600 pulses. Number of stimulation sessions: Four studies realized a single rTMS session (Ackerley et al., 2010; Takeuchi et al., 2009, 2012; Talelli et al., 2007). Other studies applied repeated rTMS session over 5 (Khedr et al., 2009; Sasaki et al., 2013), 10 (Emara et al., 2010; Talelli et al., 2012), and 20 (Sung et al., 2013) days. Adjunct therapies: Four trials (Emara et al., 2010; Takeuchi et al., 2012, 2009; Talelli et al., 2012) combined the rTMS with a motor training of the affected upper limb.

10.3 FOLLOW-UP Six studies performed a follow-up test after 40 min to 3 months (Emara et al., 2010; Khedr et al., 2009; Takeuchi et al., 2012, 2009; Talelli et al., 2007, 2012).

10.4 EFFECTIVENESS Stimulated hemisphere-dependent efficiency: All studies, which compared bilateral rTMS with facilitatory and inhibitory TMS, demonstrated the greatest improvement of the affected hand with bilateral rTMS (Sung et al., 2013; Takeuchi et al.,

11 Discussion

2012, 2009). These results are relativized throughout the fact that all bilateral stimulation protocols applied double the number of pulses than a simple facilitatory or inhibitory stimulation protocol. Comparisons between inhibitory and facilitatory rTMS show a greater efficiency of inhibitory rTMS in five studies (Ackerley et al., 2010; Emara et al., 2010; Khedr et al., 2009; Sasaki et al., 2013; Sung et al., 2013; Talelli et al., 2012) and of facilitatory rTMS in three studies (Takeuchi et al., 2012, 2009; Talelli et al., 2007). One study showed a comparable efficiency of inhibitory or facilitatory rTMS for motor recovery of the affected hand. The between-groups differences do not show any statistical significance. The followup examinations showed similar results. Patient characteristics-dependent efficiency: The data demonstrated no evident subjects-dependent efficiency. Stimulation parameter-dependent efficiency: Compared to facilitatory protocols, inhibitory stimulation protocols showed better efficiencies after application of a single-session rTMS. Compared with inhibitory stimulation protocols, facilitatory stimulation protocols showed a better efficiency after application of repeated rTMS sessions.

11 DISCUSSION This review includes the results of 37 placebo-controlled trials, which investigated the efficiency of different rTMS protocols on motor recovery of the affected upper limb after stroke. These trials investigated a total of 871 subjects with stroke and showed huge heterogeneity regarding methodological quality, rTMS stimulation protocol used, stroke subjects included, and the hand motor assessment performed.

11.1 PATIENT CHARACTERISTIC-DEPENDENT EFFICIENCY Time since stroke: It is an interesting fact that the evidence supporting the positive effects of facilitatory rTMS is greater for the acute phase of stroke, and by contrast, the evidence for inhibitory rTMS is greater for the chronic phase of stroke. On the one hand, this fact can indicate a great number of “gray literature” by studies investigating the facilitatory rTMS in subacute and chronic stroke, or inhibitory rTMS in acute or subacute stroke, which may depose a worse efficiency of these stimulation protocols in these phases of stroke recovery. On the other hand, no study described a differential effectiveness of rTMS on motor recovery of the affected hand depending on the time since stroke. Comparing the effectiveness of rTMS in relation to the time from stroke over the study cohort included in this review, we did not detect hints that the effectiveness of rTMS varies between acute, subacute, or chronic stroke. Stroke etiology: The evidence for subject with an ischemic stroke is greater than the evidence for subject with a hemorrhagic stroke for facilitatory, inhibitory as well as bilateral stimulation protocols. These facts can indicate a better efficiency of rTMS in patients with an ischemic stroke. However, no study described a differential effect of rTMS depending on stroke etiology.

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Lesion location: The evidence of the effect of rTMS for motor recovery of the affected hand after stroke is greater by subject with a subcortical stroke, especially in studies that investigated inhibitory stimulation protocols. Additionally, one study demonstrated a positive effect of facilitatory rTMS in subject with a subcortical stroke, but not in those with a cortical stroke (Ameli et al., 2009). This result could indicate a better efficiency of rTMS in subjects with subcortical lesion. More data are needed before definitive conclusions can be drawn from this observation. Severity of upper limb impairment: The evidence of rTMS for the recovery of the affected upper limb is greater in subjects with a moderate to mild hand paresis, compared to subjects with a severe hand paresis. Despite of these facts, no study demonstrated a differential effect of a stimulation protocol for motor recovery, depending on severity of upper limb impairment, and the comparison of results of the available studies did not indicate any severity upper limb impairment-dependent efficiency.

12 STIMULATION PARAMETER-DEPENDENT EFFICIENCY Stimulated area: With the exception of one study, which applied rTMS over contralesional S1, all studies investigated the efficiency of rTMS over M1 for motor recovery of the affected hand after stroke. Futures studies should probe if rTMS applied over dPMC, an area relevant for complex motor performance and motor learning, is comparably effective. A current study on stroke subjects demonstrated, e.g., the association between motor task-related activation in contralesional dPMC and the dimension of motor impairment, as well as a relationship between the changes of functional connectivity of the contralesional dPMC with other brain regions and the level of clinical impairment (Bestmann et al., 2010). Stimulation protocol: The available data show a slightly better efficiency of facilitatory stimulation protocols in comparison to inhibitory stimulation protocols. Both rTMS protocols improve function of the affected hand in approximately 80% of patients. However, facilitatory stimulation protocols cause about 10% greater improvements than inhibitory protocols. Number of stimulation sessions: The best efficiency over one session demonstrated studies, which investigated the efficiency of a single rTMS session. However, the best absolute increase of hand motor function in relation to baseline was found in studies which applied rTMS over maximal five sessions. The application of rTMS over 10 sessions or more showed no additional effect. By contrast, the studies which applied rTMS over 10 sessions or more showed smaller absolute effect of rTMS for the affected hand than studies which applied rTMS over maximal five sessions. These results demonstrated trials which applied the inhibitory stimulation protocols, as well as trials which investigated the efficiency of facilitatory stimulation protocols.

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13 CONCLUSION The results of this review imply the supportive effect of rTMS for motor recovery of the affected hand after stroke, however, the data are to limited upon today to support its routine use. The best evidence for a positive effectiveness of inhibitory rTMS over the nonaffected hemisphere is available for subjects with chronic stroke, for facilitatory rTMS over the affected hemisphere, in contrast, on subjects with acute stroke. Future studies should gather more evidence for the effectiveness of bilateral stimulation protocols. In addition, the current literature has little data on stroke survivors with severe hand paresis. The application of rTMS for motor recovery following stroke is widely used within the context of the interhemispheric imbalance model. Recent studies question the general validity of this concept. Novel hypothetical concepts should be developed in the near future to develop novel individualized stimulation strategies and thereby increase the effectiveness of rTMS in a given stroke patient as rTMS effectiveness may vary depending on lesion location, time from stroke or severity of motor disability.

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References

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