Neuromuscular electrical stimulation of the median ...

Journal of Electromyography and Kinesiology xxx (2014) xxx–xxx

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Neuromuscular electrical stimulation of the median nerve facilitates low motor cortex excitability in patients with spinocerebellar ataxia Chih-Chung Chen a,1, Yu-Fen Chuang a,1, Hsiao-Chu Yang a, Miao-Ju Hsu b,c, Ying-Zu Huang d,e, Ya-Ju Chang a,⇑ a Department of Physical Therapy and Graduate Institute of Rehabilitation Science, College of Medicine and Healthy Aging Research Center, Chang Gung University, 259, Wen-Hwa 1st Rd, Kweishan, Taoyuan 333, Taiwan b Department of Physical Therapy, College of Health Science, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 807, Taiwan c Department of Physical Medicine and Rehabilitation, Kaohsiung Medical University Hospital, 100, Tzyou 1st Road, Kaohsiung 807, Taiwan d Department of Neurology, Chang Gung Memorial Hospital 5, Fusing St., Kweishan, Taoyuan 333, Taiwan e College of Medicine, Chang Gung University, 259, Wen-Hwa 1st Rd, Kweishan, Taoyuan 333, Taiwan

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Article history: Received 5 May 2014 Received in revised form 26 August 2014 Accepted 17 October 2014 Available online xxxx Keywords: Spinocerebellar ataxia (SCA) Motor evoked potential (MEP) Neuromuscular electrical stimulation (NMES) Silent period Cerebellum

a b s t r a c t The neuromodulation of motor excitability has been shown to improve functional movement in people with central nervous system damage. This study aimed to investigate the mechanism of peripheral neuromuscular electrical stimulation (NMES) in motor excitability and its effects in people with spinocerebellar ataxia (SCA). This single-blind case-control study was conducted on young control (n = 9), age-matched control (n = 9), and SCA participants (n = 9; 7 SCAIII and 2 sporadic). All participants received an accumulated 30 min of NMES (25 Hz, 800 ms on/800 ms off) of the median nerve. The central motor excitability, measured by motor evoked potential (MEP) and silent period, and the peripheral motor excitability, measured by the H-reflex and M-wave, were recorded in flexor carpi radialis (FCR) muscle before, during, and after the NMES was applied. The results showed that NMES significantly enhanced the MEP in all 3 groups. The silent period, H-reflex and maximum M-wave were not changed by NMES. We conclude that NMES enhances low motor excitability in patients with SCA and that the mechanism of the neuromodulation was supra-segmental. These findings are potentially relevant to the utilization of NMES for preparation of motor excitability. The protocol was registered at Clinicaltrials.gov (NCT02103075). Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction Spinocerebellar ataxia (SCA) is one of several hereditary neurodegenerative disorders characterized by progressive loss of coordination of gait and poor coordination of speech or eye movements (Ishida et al., 2011; Jayadev and Bird, 2013; Liepert et al., 2000a, 2004; Rossi et al., 2014). To date, no existing treatment can cure this disease. SCA is always observed in atrophy of the cerebellum, and the ataxia arises from damage to the different cerebellar regions (Chen et al., 2004; Ishida et al., 2011; Jayadev and Bird, 2013; Rossi et al., 2014; Soong, 2002, 2004). The primary neurophysiological function of the cerebellum is to maintain the excitability of the motor cortex and its subsequent descending tract for movement control (Di Lazzaro et al., 2002; Klein et al., ⇑ Corresponding author. 1

E-mail address: [email protected] (Y.-J. Chang). Both authors contributed equally to this work.

2012; Liepert et al., 1998; Meyer et al., 1994; Wessel et al., 1996). Current evidence shows that the cortical facilitation of motor excitability, measured by the size of the motor evoked potential (MEP) in a reaction-time task, is significantly less in SCA patients compared to healthy controls (Liepert et al., 2000b, 1998; Tamburin et al., 2004). An extension of the silent period (SP), thought to reflect the suppression of central excitability, was also demonstrated in some SCA patients (Ganos et al., 2014; Teo et al., 2008; Wessel et al., 1996). These findings suggest that either elevation of the low excitability baseline or restoration of the declined cortical facilitation could benefit the preparation of intentional movement in this disorder. Adequate central motor excitability is important for movement preparation. Studies showed that, during a reaction-time task in healthy humans, central motor excitability increased progressively as the onset of the movement approached (Klein et al., 2012; Power and Copithorne, 2013). For movement preparation, the low motor excitability in SCA was compensated via an early onset

http://dx.doi.org/10.1016/j.jelekin.2014.10.009 1050-6411/Ó 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Please cite this article in press as: Chen C-C et al. Neuromuscular electrical stimulation of the median nerve facilitates low motor cortex excitability in patients with spinocerebellar ataxia. J Electromyogr Kinesiol (2014), http://dx.doi.org/10.1016/j.jelekin.2014.10.009

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C.-C. Chen et al. / Journal of Electromyography and Kinesiology xxx (2014) xxx–xxx

with prolonged activation in the motor cortex. This indicates that, in SCA patients, a large proportion of intra-cortical neurons continually struggle to activate movement against the difficulties of initiation and control. Hence, the baseline elevation of central motor excitability, such as movement preparation via neuromodulation, was proposed to help SCA patients with low excitability (Liepert et al., 2000b). To date, there is no rehabilitation strategy that demonstrably improves central motor excitability in ataxia patients. Neuromuscular electrical stimulation (NMES), a type of non-invasive peripheral electrical stimulation, has been extensively used clinically for health promotion, including incremental gains in muscle strength (Sabut et al., 2010, 2011) and improvement of functional movements in central neurological disorders (Do et al., 2012; Makowski et al., 2012; Westerveld et al., 2012). NMES possesses the feature of easy control of the amplitude of evoked muscle contraction and the sequential induction of movement. Recent studies have reported that NMES could co-modulate the excitability of both primary motor and sensory cortexes in healthy humans (Schabrun et al., 2012). The temporary neuroplasticity induced by NMES for functional reorganization has been observed to occur via motor afferents (Chang et al., 2011). In patients with stroke, the elevation of motor excitability induced by NMES significantly benefit limb function during rehabilitative motor training (Takahashi et al., 2012). These evidences supported the use of NMES on SCA patients since that SCA patients with progressively impaired motor function but preserved sensory function potentially be able to experience improved cortical excitability using NMES before motor performance. The effects of NMES on central motor excitability are dependent on its electrical characteristics. In previous studies, an increase in MEP in healthy humans was produced by NMES with low pulse frequency (10–25 Hz) and high intensity (up to and above the motor threshold) (Chang et al., 2011; Chipchase et al., 2011; Khaslavskaia et al., 2002; Knash et al., 2003; Ridding et al., 2000). The largest increases in MEP were obtained by treatment durations of up to 30 min (Chang et al., 2011; Chipchase et al., 2011; Khaslavskaia et al., 2002; Knash et al., 2003; Ridding et al., 2000). In contrast, a decline in MEP for a short period in healthy humans was observed at low intensity (below the motor threshold) and high frequency (200 Hz) (Chipchase et al., 2011). Therefore, we proposed that delivery of NMES with low pulse frequency and above motor threshold intensity might promote the low cortical excitability in the patients with SCA. In summary, this is the first study to explore the central motor excitability modulated by peripheral NMES in patients with SCA. The purpose of this study was to investigate if patients with SCA can regain their central motor excitability by the neuromodulating effect of NMES to the similar extent of healthy non-SCA subjects, and to differentiate whether the motor excitability was coming from the central or peripheral portion of the descending motor pathway. Since SCA is a neurodegenerative disease and the motor symptoms progress with aging, the neuromodulating effect of NMES might be influenced by age. Therefore, the second purpose was to investigate the effects of age on NMES-induced central motor excitability. We hypothesized that a 30-min NMES program would elevate central motor excitability in SCA patients and that the elevation would be similar in younger and age-matched nonSCA subjects.

2. Methods 2.1. Study participants This study had a single-blind case-control design. Nine people with SCA (5 males and 4 females; mean ± SD age 43.7 ± 7.8 years;

7 SCAIII and 2 sporadic SCA), nine age-matched controls (3 males and 6 females; mean ± SD age 41.3 ± 4.2), and nine young controls (4 males and 5 females; mean ± SD age 24.3 ± 2.3) were recruited from the community. All participants with SCA had been diagnosed by neurologists and showed observable signs including dysmetria, intention tremor, and gait ataxia. All participants had: (a) no history of epilepsy; (b) no other neuromuscular disorder; (c) no fracture within the last 6 months; (d) restricted movement in the upper extremities; and (e) limited trembling of the hand, allowing for the recording of electromyography (EMG). The study protocol was approved by the Institutional Review Board in accordance with the Helsinki Declaration. The protocol was registered at Clinicaltrials.gov (NCT02103075). 2.2. Assessment of central motor excitability For the assessments, the qualified participants were seated comfortably on a chair with standard back support. No previous studies have reported an influence of hand dominance, so it was assumed that either arm would be acceptable for data collection. However, to avoid the potential influence, the tested upper limb was randomly selected. The upper limb was strapped to a custom-designed hand force plate transducer to determine the maximum voluntary contraction (MVC) of elbow flexion. Transcranial magnetic stimulation (TMS; Magstim 200, Magstim Company Ltd, UK) was then used to assess central motor excitability. The resting motor threshold (RMT) of the flexor carpi radialis (FCR) was quantified as the minimum intensity of TMS required to evoke the MEP above 50 lV in amplitude in 6 out of 10 stimulations (ICC = 0.97, intra-rater reliability in pilot study). Fifteen MEPs with 10-s intervals were evoked by TMS set to 120% of the RMT. For statistical analysis, the 10 middle MEPs were used after the other 5, the largest 2 and the smallest 3, were discarded. The SP was induced using TMS at 100% of the RMT while the participant held a constant FCR contraction at 10% of the MVC. The SP was defined by measuring the onset time, defined as the beginning of EMG suppression, to the offset time, defined as the earliest re-emergence of background EMG (Garvey et al., 2001; Vry et al., 2008). The onset/offset of the SP was defined as the mean plus 2 times the SD of the flat portion. The SP was measured 5 times, and all 5 recordings were used for statistical analysis. 2.3. Assessment of peripheral motor excitability Electrical stimulation (Stimulator model DS7A, Digitimer Ltd., England) was applied to the elbow portion of the median nerve for peripheral motor excitability assessment (Lin et al., 2012). For M-waves, the stimulation frequency was 1 Hz, and the intensity was considered supra-maximal at 120% of the intensity required for eliciting maximum M-waves. For H-reflex recording, the stimulating frequency was 0.1 Hz, and the intensity was adjusted to obtain the maximum H-reflex. The detailed protocol has been reported previously (Chang et al., 2011). The MEP, M-waves, and H-reflex were recorded by surface EMG electrodes. The surface electromyography (EMG) of the FCR was recorded by a bipolar surface electrode with a fixed interelectrode distance of 2 cm (B&L Engineering, Canada). The recording electrode was located on the muscle belly of FCR, with the direction parallel to the muscle fiber. A reference electrode was placed on the styloid process (Chang et al., 2011; Wassermann et al., 1992). The EMG activity was onsite pre-amplified by a factor of 350 and was further amplified at the mainframe amplifier (Gould, Inc., Valley View, OH, USA) with an input impedance greater than 10 MX, a CMRR equal to 100 dB at 60 Hz, and a gain range from 0.5 to 100,000 times. The signal



was digitized by a 12-bit resolution analog-to-digital converter (Metrabyte DAS 1600) at 4000 Hz. 2.4. Neuromuscular electrical stimulation After initial central and peripheral motor excitability assessments, all participants received the 30-min NMES (Stimulator model DS7A, Digitimer Ltd., England) on the median nerve of the selected side as an intervention. The stimulation frequency was 25 Hz with on/off times of 800/800 ms. The accumulated 30-min NMES was composed of 3 individual 10-min applications. The central and peripheral motor excitability assessments were taken every 10 min during NMES, and at 10 min and 20 min post-NMES. 2.5. Data analysis The motor excitability at the neuron pool of the spinal cord was calculated as the H-reflex amplitude divided by the maximal Mwave amplitude and expressed as H-reflex/Mmax. Central motor excitability was assessed by the MEP amplitude divided by the maximal M-wave amplitude and expressed as MEP/Mmax. These procedures were to eliminate the influence of neuromuscular transmission of a motor neurons. The H-reflex/Mmax and MEP/ Mmax amplitudes were normalized respectively to their pre-stimulus baseline values as relative H-reflex amplitude and relative MEP amplitude for statistical analysis. A two-way repeated-measures analysis of variance (ANOVA) and a post-hoc Tukey test were used to examine the effect of the NMES on the MEPs, H-reflex, maximal M-wave, and SP. The selected a value [probability of false-positive type I error] was set at 0.05.

Recruitment

Assessment for eligibility

Experiment

Procedure

Young participants (n=9).

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3. Results The flow of assigning the participants into groups through the stages of this study is charted in Fig. 1. None of the subjects discontinued the intervention. The participants’ demographic characteristics were summarized in Table 1. The statistical analysis of RMT at baseline showed that there was no significant difference among all groups (F2,24 = 1.358, p = 0.276) (Table 2). The MEPs facilitated by NMES in the SCA patients had similar trend to those of age-matched and young controls (Figs. 2 and 3). There was no significant interaction between group and time (F10,115 = 0.94, p = 0.4953), indicating that the MEPs increased over time in response to NMES in all groups. Post-hoc Tukey tests showed that the relative MEPs increased significantly (P < 0.05) from their individual baseline values in all 3 groups (mean ± standard deviation of young control: 129 ± 27% at the 20-min and 155 ± 29% at the 30-min measurement; age-matched control: 125 ± 58% at the 20-min and 126 ± 57% at the 30-min measurement; and SCA: 153 ± 85% at the 20-min and 170 ± 90% at the 30-min measurement; Table 2). The increase in the relative MEPs persisted up to 20 min after the stimulation ceased in all groups (F5,115 = 7.29, p < 0.05). This indicates that people with SCA can benefit from NMES to the same extent as healthy controls and the NMES did not produce abnormal facilitation or inhibition in people with SCA. For the SP, there was no significant interaction between group and time, (F10,112 = 1.11, p = 0.362). However, there was a significant group effect (F2,23 = 8.44, p < 0.05). Post-hoc Tukey tests showed that the pre-stimulation SP was significantly longer in the SCA group (74.63 ± 35.01 ms) than in the age-matched (46.19 ± 12.94 ms) and young control groups (37.38 ± 17.59 ms; p < 0.05; Table 2 and Fig. 4). The NMES had no effect on SP over time in any of the 3 groups (F5,112 = 1.08, p = 0.374).

Age-matched participants (n=9)

SCA participants (n=11)

Excluded (n=0)

Excluded (n=0)

Excluded due to personal reasons (n=2)

1. Received allocated intervention (n=9) 2. Did not receive allocated intervention (n=0)



Lost to follow-up Discontinued intervention (n=0)



Young healthy control group (n=9).

Age-matched control group (n=9)

SCA group (n=9)

Number for Analysis

Fig. 1. Flowchart of participants through the stages of the study.


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The maximum M-waves were not significantly different between the groups (F2,24 = 0.03, p = 0.97) before versus after the NMES (F5,119 = 1.70, p = 0.140). The relative H-reflexes were not significantly different among the groups over the duration of the

NMES (F10,113 = 1.29, p = 0.25) or between baseline and post-NMES measurements (F5,113 = 0.18, p = 0.97; Fig. 5). The above results suggested that the NMES did not change the peripheral motor excitabilities, including the neuromuscular transmission of a motor neuron and the a motor neuron pool excitability.

Table 1 Participant Information.

Number Sex Age (years) Body length (cm) Body weight (kg) Years after onset

4. Discussion

Young healthy control group

Age-matched control group

SCA group

9 4 Male 5 Female 24.3 ± 2.3 167.77 ± 4.52 67.88 ± 9.43

9 3 Male 6 Female 41.3 ± 4.1 163.22 ± 10.32 63.67 ± 10.39

9 5 Male 4 Female 43.7 ± 7.8 160.11 ± 10.33 55.89 ± 8.92 8.0 ± 3.1 7 SCAIII, 2 sporadic

Abbreviation: SCA: Spinocerebellar Ataxia.

This is the first study to explore modulation of central motor excitability by peripheral NMES in patients with SCA. The purpose of this study was to investigate the effect of a 30-min NMES program on TMS-induced motor excitability in patients with SCA, and to differentiate whether the motor excitability was coming from the central or peripheral portion of the descending motor pathway. The primary finding of this study is that TMS-induced excitability of the descending pathway from the motor cortex to

Table 2 Effect of ES intervention on central and peripheral motor excitabilities in all groups. Groups

Statistical analysis

Time

SCA (Mean ± SD)

Age-matched (Mean ± SD)

Young control (Mean ± SD)

F

P

RMT (% of maximum stimulator output)

Pre-ES

48.33 ± 6.78

52.56 ± 5.81

51.67 ± 4.33

F2,24 = 1.358,

p = 0.276

MEP (% of Pre-ES)

Pre-ES ES-10 ES-20 ES-30 Post-10 Post-20

100 139.10 ± 68.87 153.27 ± 85.18* 170.42 ± 90.71* 156.01 ± 75.56* 154.75 ± 75.08*

100 106.41 ± 35.91 125.11 ± 57.92* 125.64 ± 57.25* 123.42 ± 43.20* 165.40 ± 57.07*

100 116.69 ± 19.51 128.99 ± 26.68* 155.03 ± 28.95* 157.22 ± 29.77* 149.75 ± 29.69*

Group time interaction F10,115 = 0.94 P = 0.50 Time main effect F5,115 = 7.29 P < 0.0001* Group main effect F2,24 = 0.84 P = 0.45

SP (ms)


74.63 ± 35.01# 73.69 ± 18.80# 70.81 ± 29.28# 85.63 ± 24.50# 78.63 ± 29.80# 83.57 ± 29.60#

46.19 ± 12.94 54.91 ± 21.30 47.46 ± 15.79 44.87 ± 15.44 47.11 ± 12.88 55.93 ± 23.52

37.38 ± 17.59 39.38 ± 16.38 44.21 ± 19.18 42.38 ± 22.32 44.74 ± 22.86 45.37 ± 19.92

Group time interaction F10,112 = 1.11 P = 0.36 Time main effect F5,112 = 1.08 P = 0.37 Group main effect F2,23 = 8.44 P = 0.0018

M-wave (% of Pre-ES)


100 97.84 ± 16.65 93.38 ± 19.41 90.05 ± 15.48 92.54 ± 18.54 98.19 ± 24.13

100 98.35 ± 6.55 95.08 ± 12.03 97.83 ± 6.80 94.48 ± 3.78 92.37 ± 11.19

100 95.55 ± 8.56 99.10 ± 5.77 94.81 ± 11.41 92.26 ± 11.78 93.29 ± 11.97


H-reflex (% of Pre-ES)


100 86.18 ± 25.53 93.19 ± 40.30 87.21 ± 32.04 92.29 ± 20.61 86.90 ± 24.27

100 109.02 ± 25.11 103.13 ± 35.70 87.11 ± 35.47 99.52 ± 43.36 114.13 ± 40.07

100 114.96 ± 35.62 110.05 ± 43.90 123.68 ± 53.43 118.39 ± 37.67 111.23 ± 36.84


*

Abbreviation: ES: peripheral electrical stimulation, RMT: Resting Motor Threshold, SCA: Spinocerebellar Ataxia, SP: Silent Period. Values are presented as mean ± standard deviation. * Significantly different from Pre-ES. # Significantly different from age-matched control and young control.

Fig. 2. Representative raw MEPs elicited by TMS at the experimental time points. The traces were recorded before electrical stimulation (ES; Pre), 10 min after ES began (ES10), 20 min after ES began (ES-20), 30 min after ES began (ES-30), 10 min after ES ended (Post-10), and 20 min after ES ended (Post-20). Traces are from a representative SCA patient (upper traces), age-matched control (middle traces), and young control participant (lower traces). The first spike is the stimulus artifact and the subsequent wave is the MEP. The MEP started increasing at ES-20 in all groups. The MEPs were recorded while muscle was relaxed so that the SP is not shown in this figure.



Fig. 3. Group mean and standard errors of MEP amplitude at different time points on NMES. Time points were defined as in Fig. 2. Data were averaged across the participants in the SCA (black circles), age-matched control (white circles) and young healthy control (gray triangles) groups. Values are expressed as the mean percentage of the Pre-ES value; error bars are the standard error of the mean. ⁄: significantly different from Pre-ES in all groups (p < 0.05). There were no significant differences between any two of the groups at any individual time point.

the involved muscles is similarly increased by NMES in both SCA patients and healthy controls. Previous studies reported that electrical stimulation of the ulnar (Ridding et al., 2000), median (Chang et al., 2011), and common peroneal nerves in healthy participants (Khaslavskaia et al., 2002; Knash et al., 2003; Ridding et al., 2000) increased the TMS-induced MEP once its intensity was increased enough to produce visible muscle contractions. Consistent with the effect of the peripheral electrical stimulation, an accumulated 30 min of NMES (25 Hz) in our study was sufficient to increase this central excitability and could promote the motor cortex plasticity temporarily (Khaslavskaia et al., 2002; Knash et al., 2003). In contrast, the study by Ridding and coworkers reported that 1.5 h of stimulation (10 Hz) was required to induce an increase in MEP (Ridding et al., 2000). This difference might be attributable to different pulse frequencies (25 Hz vs. 10 Hz) and different durations of the NMES.

Fig. 4. Group mean and standard errors of SP at different time points on NMES. Time points were defined as in Fig. 2. Data were averaged across the participants in the SCA (black circles), age-matched control (white circles) and young healthy control (gray triangles) groups. Values are expressed as the mean percentage of the Pre-ES value; error bars are the standard error of the mean. ⁄: significantly different from age-matched and young control groups (p < 0.05).

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Fig. 5. Group mean and standard errors of H-reflex amplitude at different time points on NMES. Time points were defined as in Fig. 2. Data were averaged across the participants in the SCA (black circles), age-matched control (white circles), and young healthy control (gray triangles) groups. Values are expressed as the mean percentage of the Pre-ES value; error bars are the standard error of the mean. There were no significant changes from baseline in any of the groups.

The increase of the MEP on the cortico-spinal pathway in SCA has demonstrated an effect of NMES on the central motor nerve but not the peripheral one. The evidence for this is that the Hreflex, responsible for peripheral motor excitability, did not change significantly after NMES. Moreover, previous studies have reported that the H-reflex (Chang et al., 2011) and F-waves (Ridding et al., 2000) did not change after electrical stimulation. These findings excluded the possibility that the increase in motor excitability came from the peripheral nerve at the spinal cord level, including the a motor neurons, neuromuscular junction, and muscle fiber. Another study has also shown that the increase in the MEP in healthy humans was not the result of stimulus-induced increases in the excitability of spinal motor neurons (Ridding et al., 2000). Therefore, the increase in motor excitability in SCA patients occurs mainly in the upper motor neurons of the descending pathway. In our study the MEP increase after NMES produced a prolonged and augmented potentiation in the descending central motor pathway. It seems obviously helpful to apply NMES, an inexpensive intervention of physical modality. In this study, peripheral NMES facilitated the excitability of the descending pathway of the motor cortex up to 20 min after stimulation in either healthy controls or SCA patients. In contrast, non-invasive, repetitive TMS at a frequency greater than 5 Hz was found to facilitate cortical excitability for only 6 min in healthy humans (Gorsler et al., 2003). In another study, a burst of TMS also produced a facilitation of motor cortex excitability for up to 20 min in healthy humans (Di Lazzaro et al., 2002). Using TMS, the facilitation of MEP was relevant to synaptic plasticity via the NMDA receptor (Huang et al., 2007) and mainly in the modulation of I waves (Di Lazzaro et al., 2010). This suggests that the motor excitability in SCA patients might be increased via the NMDA receptor. However, this issue should be clarified by further investigation. There is little known about the underlying mechanism of the effect of NMES on central excitability in the motor cortex of SCA patients. It is anatomically possible that the afferents affected by NMES travel cranially to higher neurological levels via either the spino-thalamic tracts or spino-cerebellar tracts (Tortora, 2009). The sensory inputs created by cutaneous stimulation using NMES could be conducted via spino-thalamic tracts to the sensory cortex with relay through the thalamus. On the other hand, the muscular and joint afferents stimulated by NMES could be conducted via anterior or posterior spino-cerebellar tracts to the cerebellum for


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the afferent of sensory information. The cerebellum would then send out the feedback to upper motor neurons in the cerebral cortex via the cerebellothalamocortical tract, which responds to contralateral cortical inhibition (Argyelan et al., 2009; Molnar et al., 2004; Ni et al., 2010). A recent study found that peripheral electrical stimulation could co-modulate the excitability of primary sensory and motor cortexes in healthy humans (Schabrun et al., 2012). This study supports the claim that peripheral electrical stimulation is relayed to the primary sensory cortex via thalamo-cortical projections, activating or inducing a change in sensory processing, and this provides the signal for long term potentiation or depression-like changes in the primary motor cortex. In contrast, our study found that excitability in the descending neuro-pathway in both SCA patients and healthy controls is facilitated by NMES. Whether those tracts were activated or not, it is clear that the resting excitability of the central motor descending pathway was increased after NMES, and those tracts were certainly involved in the effect. The standard deviation of SCA group seemed to be larger than the other two groups although the statistical analysis did not show differences. After closely checked the individuals’ data, we found few subjects in SCA group have stronger MEP facilitation than others. Whether the variation of facilitation is from difference of genetic types of disease or other factors cannot be explained in the current study design. Future studies are suggested. In this study, the SCA group showed significantly longer SPs than the healthy controls. A prolonged SP has been observed previously in patients with degenerative cerebellar ataxia disease (Liepert et al., 1998; Nakashima et al., 1995; Oechsner and Zangemeister, 1999; Restivo et al., 2002; Schwenkreis et al., 2002; Wessel et al., 1996). The lengthening of the SP might not be a common phenomenon in all sub-types of SCA due to the genetic heterogeneity (Liepert et al., 1998; Nakashima et al., 1995; Oechsner and Zangemeister, 1999; Restivo et al., 2002; Schwenkreis et al., 2002; Wessel et al., 1996). The assessment method, such as the TMS intensity and definition of SP, could also affect the values of this parameter. A high amplitude of the MEP tended to increase the duration of the SP (Orth and Rothwell, 2004; Saisanen et al., 2008; Trompetto et al., 2001). This made the absolute duration of the SP incomparable to its value in the studies using a higher TMS intensity (Liepert et al., 1998; Nakashima et al., 1995; Wessel et al., 1996). Furthermore, the onset of the SP was defined inconsistently in these studies, sometimes as beginning at the stimulation artifact (Cantello et al., 2007), sometimes at the onset of the MEP (Restivo et al., 2002), and others at the onset of EMG suppression. Likely, the average duration of the SP in our healthy controls was comparable to the studies that used a relatively low TMS-induced intensity with the SP measured from the onset of EMG suppression (Garvey et al., 2001; Ridding et al., 1995; Vry et al., 2008). The effect of age on the potential evoked by peripheral NMES has not been investigated in previous studies. The current study found no age effect, indicating that the MEP evoked at 120% intensity of RMT recorded on flexor carpi radialis could be increased by NMES in participants of any age group. Previous studies reported no age effect on RMT for extensor and flexor carpi radialis (Kossev et al., 2002), first dorsal interosseous (Mills and Nithi, 1997), and thenar muscles (Rossini et al., 1992). A positive correlation between age and RMT has been reported, however, for the abductor pollicis brevis muscle (Matsunaga et al., 1998). Our study found that RMT recorded on the flexor carpi radialis was similar in either the age-matched or young healthy control groups. This suggested that there was no age effect on either the RMT or the MEP of the flexor carpi radialis. This study successfully demonstrate that peripheral NMES, a clinically available tool, has ability to facilitate the upper motor

neurons and the facilitation would not be diminished in people with degenerated cerebellar ataxia disease. It, thus, suggests that clinicians can potentially use NMES to prepare the motor cortex excitability for the subsequent motor rehabilitation. The dose and combining effect of NMES and motor rehabilitation are suggested to explore in future studies. 4.1. Study limitations This study may not be generalizable to all subtypes of SCA due to the small sample size and the predominant inclusion of patients with SCAIII. In addition, while the NMES parameters used here were effective, the dependence of the results on the dosage needed to be further verified. 5. Conclusion The low motor cortex excitability of individuals with SCAIII and sporadic SCA can be enhanced after a 30-min repetitive peripheral NMES to the same extent as in healthy controls. This indicates that people with SCA can benefit from NMES to the same extent as health controls. NMES, a clinically convenient and widely available intervention, is suggested to be a clinical option to modulate the cortical excitability in specific SCA patients. These findings are potentially relevant for the utilization of NMES in preparation of central motor excitability for motor rehabilitation in cerebellumrelated disorders. Conflict of interest The authors declare that they have no competing interests. Acknowledgements This work was supported by Chang Gung Medical Research Plan (Grant Number CMRP180101) and Healthy Aging Research Center (Grant Numbers EMRPD1D0291 and CMRPD1B0331), Chang Gung University, Taiwan. The manuscript was edited by Melissa Stauffer, PhD, of Scientific Editing Solutions. References Argyelan M, Carbon M, Niethammer M, Ulug AM, Voss HU, Bressman SB, et al. Cerebellothalamocortical connectivity regulates penetrance in dystonia. J Neurosci 2009;29(31):9740–7. Cantello R, Tarletti R, Varrasi C, Cecchin M, Monaco F. Cortical inhibition in Parkinson’s disease: new insights from early, untreated patients. Neuroscience 2007;150(1):64–71. Chang YJ, Hsieh TH, Huang YM, Hsu MJ, Wong AM-K. A lack of modulation of motor evoked potential in individuals with sensory impaired spinal cord injuries. JMBE 2011;31(1):37–43. Chen JT, Lin YY, Lee YC, Soong BW, Wu ZA, Liao KK. Prolonged central motor conduction time of lower limb muscle in spinocerebellar ataxia 6. J Clin Neurosci 2004;11(4):381–3. Chipchase LS, Schabrun SM, Hodges PW. Corticospinal excitability is dependent on the parameters of peripheral electric stimulation: a preliminary study. Arch Phys Med Rehabil 2011;92(9):1423–30. Di Lazzaro V, Oliviero A, Mazzone P, Pilato F, Saturno E, Dileone M, et al. Short-term reduction of intracortical inhibition in the human motor cortex induced by repetitive transcranial magnetic stimulation. Exp Brain Res 2002;147(1):108–13. Di Lazzaro V, Profice P, Pilato F, Dileone M, Oliviero A, Ziemann U. The effects of motor cortex rTMS on corticospinal descending activity. Clin Neurophysiol 2010;121(4):464–73. Do AH, Wang PT, King CE, Schombs A, Cramer SC, Nenadic Z. Brain–computer interface controlled functional electrical stimulation device for foot drop due to stroke. Conf Proc IEEE Eng Med Biol Soc 2012;2012:6414–7. Ganos C, Zittel S, Minnerop M, Schunke O, Heinbokel C, Gerloff C, et al. Clinical and neurophysiological profile of four German families with spinocerebellar ataxia type 14. Cerebellum 2014;13(1):89–96. Garvey MA, Ziemann U, Becker DA, Barker CA, Bartko JJ. New graphical method to measure silent periods evoked by transcranial magnetic stimulation. Clin Neurophysiol 2001;112(8):1451–60.


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Chih-Chung Chen received the Master of Science degree in School of Physical Therapy from National Taiwan University, Taiwan, in 2000, the Master of Philosophy degree in Rehabilitation Sciences from University of Ulster, in 2003, and the Ph.D. degree in Health and Life Sciences from Leeds Metropolitan University, United Kingdom, in 2008. He served as the Assistant Professor in Department of Physical Therapy in Hung Kuang University in 2009, and was in Department of Physical Therapy in Chang Gung University, Taiwan, after 2010. He was qualified as Physical Therapist in United Kingdom and Taiwan.

Yu-Fen Chuang received the Master of Science degree in physical therapy management of developmental disabilities from New York University in 1994. In 2008, she received her Ph.D. degree in department of special education from National Changhua University of Education. In 1992, she was a physical therapist at Taichung Rehabilitation Hospital. From 1993 to 1995, she was a physical therapist at Manhattan Developmental Disabilities Center. Since 1996 she was a lecturer at department of physical therapy in Fooyin University for one year, and in Chang Gung University after 1997. She has been the assistant professor at department of physical therapy in Chang Gung University from 2008 until now.


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C.-C. Chen et al. / Journal of Electromyography and Kinesiology xxx (2014) xxx–xxx Hsiao-Chu Yang received the Master of Science degree in rehabilitation science from Chang-Gung University, Taiwan, in 2005. She is a medical consultant of Taiwan Spinocerebellar Ataxia Association from 2010 until now. She is also a physical therapist at neihu branch of Cathay General Hospital.

Miaoju Hsu received the B.S. in Rehabilitation Medicine in National Taiwan University. After graduation, she worked as a clinical physical therapist for two years in Mackay Memorial Hospital, Taipei, Taiwan. She pursued for her Master degree and Ph.D in Physical Therapy and Rehabilitation Science, University of Iowa, Iowa, USA. Since 2006, she has been a faculty member of Department of Physical Therapy, Kaohsiung Medical University, Kaohsiung City, Taiwan and is appointed as an adjunct senior physical therapist in Koahsiung Medical University Chung-Ho Memorial Hospital.

Ying-Zu Huang received the Doctor of Medicine degree from Taipei Medical University, Taiwan, in 1991, and the Master of Science degree in biomedical engineering from National Cheng Kung University, Taiwan, in 1996. After working as a physician in Neurology for years, he was a research fellow, National Hospital for Neurology and Neurosurgery, UK from 2001 to 2004, and received the PhD degree in neurological studies from Institute of Neurology, University College London, UK, in 2005. Dr Huang is currently an Associate Professor of Chang Gung University, Taiwan, and Physician Scientist of Chang Gung Memorial Hospital, Taiwan. Since 2013, he has been the president of Taiwan Society of Clinical Neurophysiology. He is also a member of the editorial board of Clinical Neurophysiology and an active reviewer for more than 30 international journals.

Ya-Ju Chang received the Ph.D. degree from Physical Therapy and Rehabilitation Science Graduate Program, University of Iowa, Iowa City. She is currently a Professor in the Department of Physical Therapy and Graduate Program of Rehabilitation Science, Chang Gung University, Tao-yuan, Taiwan. Her research interest focuses primarily on neuromuscular adaptations after central nervous system lesions, including spinal circuitry adaptation, fatigue adaptations, and therapeutic intervention by electrical stimulation. She currently is the primary investigator of research projects of ‘‘The reversal of neuromuscular adaptation in human with spinal cord injury II’’ and ‘‘Establishing the central and peripheral fatigue indexes and VR based anti-fatigue training paradigm for individuals with Parkinson Disease.’’ She is a member of Healthy Aging Research Center of Chang Gung University and is in charge of integrating motor performance analysis laboratory.
