Disability and Rehabilitation
ISSN: 0963-8288 (Print) 1464-5165 (Online) Journal homepage: http://www.tandfonline.com/loi/idre20
Effects of repetitive transcranial magnetic stimulation on lower extremity spasticity and motor function in stroke patients Maryam Rastgoo, Sofia Naghdi, Noureddin Nakhostin Ansari, Gholamreza Olyaei, Shohreh Jalaei, Bijan Forogh & Hamidreza Najari To cite this article: Maryam Rastgoo, Sofia Naghdi, Noureddin Nakhostin Ansari, Gholamreza Olyaei, Shohreh Jalaei, Bijan Forogh & Hamidreza Najari (2016): Effects of repetitive transcranial magnetic stimulation on lower extremity spasticity and motor function in stroke patients, Disability and Rehabilitation To link to this article: http://dx.doi.org/10.3109/09638288.2015.1107780
Published online: 15 Feb 2016.
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Date: 16 February 2016, At: 07:39
DISABILITY AND REHABILITATION, 2016 http://dx.doi.org/10.3109/09638288.2015.1107780
RESEARCH PAPER
Effects of repetitive transcranial magnetic stimulation on lower extremity spasticity and motor function in stroke patients Maryam Rastgooa, Sofia Naghdib, Noureddin Nakhostin Ansarib, Gholamreza Olyaeib, Shohreh Jalaeib, Bijan Foroghc and Hamidreza Najarid a
Department of Physiotherapy, School of Rehabilitation Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Physiotherapy, Faculty of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran; cDepartment of Physical Medicine and Rehabilitation, Firozgar University Hospital, Iran University of Medical Sciences, Tehran, Iran; dDepartment of Internal Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
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b
ABSTRACT
ARTICLE HISTORY
Purpose: To investigate the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on lower extremity (LE) spasticity, motor function and motor neurone excitability in chronic stroke patients. Method: This study was a randomised sham-controlled cross-over trial with 1-week follow-up. A total of 20 post-stroke patients were randomised to receive active (n ¼ 10) or sham (n ¼ 10) rTMS. Fourteen of them (7 in each group) crossed over to the sham or active rTMS after a washout period of 1 month. Interventions consist of five consecutive daily sessions of active or sham rTMS to the unaffected lower extremity motor area (1000 pulses; 1 Hz; 90% of the tibialis anterior motor threshold). Outcome measures were modified modified ashworth scale (MMAS), the H-reflex, lower extremity section of Fugl–Mayer assessment (LE-FMA) and timed UP and GO (TUG) test. All outcomes were measured at three levels in each intervention period: pre- and postintervention and 1-week follow-up. Results: Friedman’s test revealed significant improvement in MMAS score only after active rTMS. This improvement lasted for one week after the active rTMS. Repeated measure analysis of variance (ANOVA) showed significant time*intervention interaction for LE-FMA. There are no differences between groups for the MMAS and LE-FMA. No significant change in Hmax/Mmax ratio and TUG test was noted. Conclusion: Low-frequency rTMS over the LE motor area can improve clinical measures of muscle spasticity and motor function. More studies are needed to clarify the changes underlying this improvement in spasticity.
Received 5 August 2014 Revised 25 August 2015 Accepted 10 October 2015 Published online 10 February 2016 KEYWORDS
H-reflex; motor function; repetitive transcranial magnetic stimulation; spasticity; stroke
ä IMPLICATIONS FOR REHABILITATION
Spasticity is a common disorder and one of the causes of long-term disability after stroke. Physical therapy modalities, oral medications, focal intervention and surgical procedures have been used for spasticity reduction. Beneficial effect of the repetitive transcranial magnetic stimulation (rTMS) for post-stroke upper extremity spasticity reduction and motor function improvement was demonstrated in previous studies. This study shows amelioration of lower extremity spasticity and motor function improvement after five daily sessions of inhibitory rTMS to the unaffected brain hemisphere which lasted for at least 1 week following the intervention.
Introduction Stroke is the major cause of adult disability around the word.[1] Spasticity is a common disorder and one of the causes of long-term disability after stroke. The prevalence of spasticity in chronic phase after stroke is reported about 20%.[2] Spasticity is defined by Lance (1980) as a velocity-dependant increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerk, CONTACT Maryam Rastgoo ß 2016 Taylor & Francis
resulting from hyper excitability of the stretch reflex.[3] Untreated spasticity of the lower extremity may cause gait disorders, muscle-tendinous unit stiffness and dependent mobility post-stroke.[4] In addition to physical therapy, numerous oral medications, focal intervention, and surgical procedures have been used for spasticity reduction. However, for treating spasticity,
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physiotherapy modalities have shown unsatisfactory results and pharmacologic and surgical medications are associated with several disadvantages. Therefore, there is a pressing need for the development of a new intervention. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique that induces changes in cortical excitability at the stimulation site and transsynaptically at distant areas. Depending on the frequency of the pulses, two modes of rTMS are commonly used after stroke: (1) high-frequency (41 Hz) fascilatory mode which is applied to the affected hemisphere to increase its excitability and (2) low-frequency (1 Hz) inhibitory mode which is applied to the unaffected hemisphere to reduce its excitability and therefore decrease inhibition from the unaffected to the affected hemisphere (interhemispheric competition).[5,6] These effects may outlast the duration of stimulation, minutes or even hours after it.[6] The interhemispheric competition hypothesis suggests that balancing excitability between the two hemispheres may improve functional behaviour in people after stroke.[5] Previous studies on normal subjects showed that modulation of cortical excitability by rTMS, affect spinal segmental (alpha motor neurone) excitability by changing descending cortico-spinal projections in both the upper and lower limb.[7,8] In the last decade, rTMS has been used in various neurological conditions of multiple sclerosis,[9,10] spinal cord injuries,[11,12] and cerebral palsy [13] to control muscle spasticity. There are also studies which investigated the effect of rTMS on upper extremity spasticity in patients with chronic stroke.[14–16] Motor function improvement following the use of the low-frequency rTMS in stroke patients has also been shown in previous studies.[17,18] Our prior pilot case series study work showed the beneficial effect of the rTMS in lower extremity spasticity.[19] To our knowledge, there are no controlled study investigating the effect of low-frequency rTMS on LE spasticity and motor neurone excitability post-stroke. Therefore, the purpose of this study is to assess the effect of five consecutive sessions of 1-Hz rTMS on LE spasticity, alpha motor neurone excitability and motor function in post-stroke patients. We hypothesised that by inhibiting the unaffected hemisphere, and reducing the interhemispheric competition, symmetric activity of the two brain hemispheres may be returned. Increasing the activity of the affected corticospinal pathway can modulate the alpha motor neurones excitability through the direct and indirect connexions. Therefore, decrease in spinal circuits’ excitability and improvement of spasticity may happen.[20] Improvement of motor function is expected after the decrease in spasticity.
Methods Study design This study is a randomised, sham-controlled, cross-over trial with 1-week follow-up which was conducted under one way blind condition.
Participants Inclusion criteria for participants were as follows: (1) adult age 18 years (2) first ever stroke which resulted in unilateral hemiparesis (3) time past since onset of stroke to be 6 months (4) at least one spastic muscle group in the affected side of the patient (5) ability to walk independently (with or without walking aids). Exclusion criteria were as follows: (1) the presence of contraindications for the use of rTMS such as cardiac pacemaker or intracranial implants (2) grade 4 of the MMAS score (3) use of antispastic drugs (4) local injection of botulinum toxin type A in past 3 months. Subjects who met the inclusion criteria and did not have exclusion criteria were assigned to the study. Patients with post-stroke were recruited from rehabilitation centre of Firozgar hospital, Iran University of Medical Science and from stroke rehabilitation clinic in rehabilitation faculty of Tehran University of Medical Science. The demographic information of the patients was obtained through interview. Localisation of the cerebral lesion was determined by image studying of the brain. As shown in Figure 1, from 26 patients who were identified as potential participants for this study, 20 of them enrolled to the study. Patients were randomised into two groups: AS group are the patients who had the active rTMS as the first and sham rTMS as the second intervention period and, SA group are the patients who had sham rTMS as the first and active rTMS as the second intervention period. Randomisation was done through random assignment by individuals. Six patients (3 in each group) refused to do second intervention and 14 patients were crossed over to second intervention period, 4 weeks after the end of the first one.
Procedures The study protocol was approved by the ethics committees of Tehran University of Medical Science, Iran. The informed consent was obtained from all the patients. All outcomes were measured at three levels: (1) preintervention, (2) post-intervention, (3) 1-week follow-up in each intervention period. Assessments and interventions for all patients were done by a well-trained
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Figure 1. Diagram of the study design, Abbreviation: rTMS, repetitive transcranial magnetic stimulation; As group, group of patients who did active rTMS in the first intervention period and sham rTMS in the second intervention period; SA group of patients to whom sham rTMS was the first and active rTMS was the second intervention.
physiotherapist and patients were blinded to the intervention.
Outcome measures Primary outcome measures were as follows: (1) modified modified ashworth scale (MMAS) to assess muscle spasticity and (2) Hmax/Mmax ratio as the electrophysiologic index of motor neurone excitability. Secondary outcome measures were as follows: (1) Timed Up and Go (TUG) test for gait evaluation; (2) Fugl– Mayer assessment (FMA) for assessing the lower extremity motor function.
Spasticity evaluation Modified Modified Ashworth Scale (MMAS) was used for the assessment of the ankle plantar flexors and knee extensors spasticity. The MMAS is an ordinal level measure of spasticity, which grades the intensity of spasticity from 0 to 4 according to the resistance to a quick, passive movement. In MMAS score, 0 mean no increase in muscle tone and 4 mean the affected part rigid in flexion or extension. It has been proved that the MMAS is a reliable tool for measuring knee extensors post–stroke spasticity [21] and ankle plantar flexors spasticity.[22] For evaluating the knee extensor spasticity, the patient was in side-lying position, hip and knee in
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extension, head in midline. The physiotherapist was behind the patient, place one hand above the knee to stabilise the femur and moved the knee from maximal extension to maximum flexion with the other hand. For evaluating the ankle plantar flexor spasticity, the patient was in supine position, with his lower limbs in extension. The physiotherapist stabilises the ankle with one hand and moved the ankle from maximal plantarflexion to dorsiflexion with the other hand.
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Electrophysiological evaluation For the electrophysiological measurement of motor neurone excitability, the affected side Soleus compound motor action potential (CMAP or M) and H-reflex were evoked. H-reflex is considered as a reliable electrophysiologic equivalent of stretch reflex and motor neurone excitability.[23] In this study, an electromyography machine (Myo Quick, Micromed Company, Italy) was used. The patient was asked to lie in the prone position while his feet was suspended over the end of the bed, his head was in midline and turned to one side and his arms were placed on his body sides. Tibial nerve was electrically stimulated with bipolar silver-silver chloride stimulator electrode in the popliteal fossa. The stimulus was a single 1-ms rectangular pulse delivered every 5 sec. The recording surface electrode was placed 2 cm under the junction of lateral and medial head of the gastrocnemius muscle. The reference electrode was placed to the skin 3 cm distal to the recording electrodes on the soleus muscle and the ground electrode was attached to the skin approximately between the recording and reference electrodes. The EMG signal was amplified (1 mV/Division) and bandpass filtered (2 Hz to 10 KHz). The intensity of the stimulation was progressively increased from below the M-wave threshold to maximum M wave. The ratio of the Hmax/Mmax was calculated by dividing the maximum peak-to-peak amplitude of H-reflex by that of the M-wave.[24]
Gait evaluation We used Timed Up and Go test (TUG) for gait evaluation. TUG is a simple and quick functional mobility test. It includes a series of motor tasks that require balance control in addition to muscle strength and coordination.[25] Excellent reliability for this test was reported in chronic post-stroke patients.[26] For performing the test, patient was instructed to stand up from a chair with an armchair, walk 3 m, turn, walk back and sit down to the
same chair. The time taken to complete the test was recorded. In this study, three consecutive measurements were done and the average value was calculated in each assessment level.
Motor function evaluation Motor function of the lower extremity was assessed by Fugl–Mayer assessment (FMA). FMA is considered the gold standard for evaluating the motor function recovery after stroke.[27,28] FMA for the motor function of the lower extremity, with a maximum 34 point, consist of items in reflexes, synergic patterns and coordination. Each item is rated on a 3-point ordinal scale, 2-point for complete performance, 1-point for partial performance and 0-point for no performance.[29]
Interventions Patients received five consecutive daily sessions of active or sham rTMS in the morning between 8:00 a.m. and 12:00 a.m. In this study, rTMS was performed with a figure of eight coil (diameter of each wing, 90 mm) connected to the Magstim stimulator (Magstim Co, Ltd, UK). Patients seated in a comfortable reclining armchair during the intervention. In active rTMS, a train of 1000 pulses of 1-Hz rTMS with an intensity of 90% of the tibialis anterior MT over about 20 min was delivered to the LE motor cortex of the unaffected brain hemisphere. This frequency and intensity was chosen because its beneficial effect for upper extremity spasticity [15,16] and lower extremity motor function [18] in post-stroke patients was proven in previous studies. Motor threshold (MT) was defined as the lowest stimulus intensity required to evoke motor evoked potentials (MEPs) of 50 mV in peak-to-peak amplitude in at least three of five consecutive trials in the TA muscle.[30] The site, where was used for MT determination, was considered as the stimulation site. This site was typically, from 0 to 2 cm lateral to the vertex and 1 to 2 cm posterior to the vertex.[18] The stimulation site was marked on the scalp and the centre of the coil was maintained in that position for the entire duration of stimulation. If no MEP was recorded from the unaffected LE, the coil was held tangentially to the scalp with its centre placed 1 cm lateral and 1 cm posterior from the vertex.[35] In these cases, the stimulus intensity was set at 100% of the MT intensity for induction MEPs in the unaffected biceps brachii muscle. For delivering the rTMS, the coil was placed tangentially to the subjects head, and the handle pointing
MAGNETIC STIMULATION IN STROKE SPASTICITY
posteriorly and positioned at 60 with respect to mid sagittal axis of the head.[9,10] For the sham stimulation, the coil held over the unaffected LE motor area as for active stimulation but with application of an audio coil, no magnetic stimulation was delivered to the brain.
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Statistical analysis All statistical analysis was done using the SPSS package 18.0. The significant level was defined as p50/05. The data of the two groups was pooled together and the statistics were done for the total number of the patients who received active and sham rTMS as either the first or the second intervention period. Subanalysis was done when it was necessary. Because all data met the criterion of normality (Kolmogorov–Smirnov test), repeated measure analysis of variance (ANOVA) was performed to evaluate the effects of interventions (active rTMS vs. sham rTMS) in time (pre- and post-intervention and 1-week follow-up) on TUG, FMA and Hmax/Mmax ratio. Effect sizes for F ratios were reported as eta-squared (Z2). A post hoc analysis was performed with Bonferroni correction. For MMAS, median and quartiles range (Table 2) is calculated, and as it is an ordinal level measurement, nonparametric tests were used. The effect over time was evaluated using Friedman test. Post hoc analysis with Wilcoxon signed-rank test was conducted. Mann– Whitney U-test was used to compare the MMAS scores of the patients between the two interventions. Spearman’ rho correlation test was applied to detect the relationship between the spasticity reduction (LE MMAS) and the motor function improvement (LE FMA).
Results Participant characteristics The demographic and baseline clinical characteristic of the patients in both AS and SA group are demonstrated in Table 1. No significant difference was found between the two groups regarding the demographic and baseline clinical characteristics (Table 2). No adverse events were reported by any of the patients throughout the study.
Modified modified ashworth scale The median and quartiles range of the LE-MMAS at three levels of assessments are provided in Table 2. In this study, LE-MMAS score is improved significantly only after the active rTMS and this improvement is sustained 1-week after the intervention.
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Table 1. Characteristics of participants. Parameters Age (years) Gender Male Female Time since the stroke (months) Type of stroke Ischaemic Haemorrhagic Paretic side Right Left localisation of the cerebral lesion Cortex Subcortex Both cortex and subcortex TUG test LE-FMA Hmax/Mmax ratio
AS group (n ¼ 10)
SA group (n ¼ 10)
p value*
54.6 SD 11.75
49.7 SD 11
0.33
8 2 30.2 SD 18.3
8 2 27.4 SD 20.1
1
8 2
7 3
3 7
4 6
3 7 – 24.8 SD 21.3 26.2 SD 5.1 0.48 SD 0.2
– 8 2 28.9 SD 15.7 25.1 SD 3.3 0.58 SD 0.2
0.75 0.6 0.64 0.08
0.63 0.58 0.32
*As determined with the chi-square for proportions and MMAS scale and with the t-test for independent groups for continuous variables. AS group, group of patients to whom active rTMS was the first and sham rTMS was the second intervention; SA group, group of patients to whom sham rTMS was the first and active rTMS was the second intervention; SD, standard deviation; LE-FMA, lower extremity Fugl–Mayer assessment; TUG, Timed Up and GO.
The Mann–Whitney U-test on LE-MMAS scores did not identify a statistical significant difference between groups (pre–Z ¼ 1.43, p ¼ 0.17; post–Z ¼ 0.09, p ¼ 0.94; follow-up Z ¼ 0.55, p ¼ 0.61). Within-group analysis by using Friedman test revealed significant change in patients who received active rTMS ( 2 (2) ¼ 17.07, p50.01). Post hoc analysis with the Willcoxon signed-rank test showed a significant decrease in MMAS score between the pre- and the post-intervention (p ¼ 0.02) and between the pre and the 1-week follow-up (p ¼ 0.02) for active rTMS intervention. Friedman test revealed no significant difference in time in patients who received sham rTMS ( 2 (2) ¼ 6, p ¼ 0.1). Post hoc analysis with the Wilcoxon signed-rank test showed no significant improvement in MMAS score in the post-intervention (p ¼ 0.09) or 1-week follow-up (p ¼ 0.3) in comparison to pre-intervention.
Fugl–Mayer assessment Descriptive data of the LE-FMA is provided in Figure 2. It shows that LE-FMA improves only after active rTMS and these improvements are sustained 1-week after the intervention. Repeated measure ANOVA, revealed that the main effect for time was statistically significant [F(2,64) ¼ 9.95, p50.01, 2 ¼ 0.24]. Post hoc analysis indicated a significant difference between pre- and post-intervention (LE-FMA mean difference ¼ 0.67, p50.01) and a trend towards significance between pre-intervention and 1-week follow-up (LE-FMA mean difference ¼ 0.41, p ¼ 0.06). Significant interaction of
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Table 2. Median (quartiles range) of the LE-MMAS in active and sham rTMS stimulation in time (at different level of assessment). Active rTMS (n ¼ 17)
LE MMAS
Pre
post
2 (1–3)
1 (0–2)
1-week follow-up 1 (0–2)
Sham rTMS (n ¼ 17) Pre
post
1 (1–2.5)
1 (0.5–2.5)
1-week follow-up 1 (1–2.5)
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LE-MMAS, lower extremity modified modified ashworth scale.
Figure 2. The change in the mean ± standard division of the lower extremity Fugl–Mayer assessment (LE–FMA), the Timed Up and Go (TUG) test, and the mean of Hmax/Mmax ratio in time (different level of assessments) after the active and sham rTMS. LE–FMA improved significantly after the active rTMS (p50.01) and 1-week follow – up (p ¼ 0.06) comparison to before it.*p 0.06 pair post hoc analysis by the Bonferroni correction.
intervention time is also shown [F(2,64) ¼ 20.17, p50.01, 2 ¼ 0.39]. However, the main effect of intervention is not significant [F(1, 32) ¼ 0.88, p ¼ 0.35, 2 ¼ 0.02].
TUG test As it is shown in Figure 2, TUG test changes show similar manner of improvement in both active and sham intervention over time. Repeated measure ANOVA reveals significant main effect of time [F(2,64) ¼ 5.58, p50.01, 2 ¼ 0.15]. Post hoc analyses shows a significant difference between pre-intervention and 1-week followup (TUG test mean differences ¼ 2.05, p5 0.01). No significant interaction of intervention time is shown. [F(2,64) ¼ 1.34, p ¼ 0.27, 2 ¼ 0.04] regarding the TUG test. The main effect of intervention is not significant [F(1,32) ¼ 0, p ¼ 0.9, 2 ¼ 0].
The Hmax/Mmax ratio Because of poor H-reflex recordings, electrophysiologic data of two patients (1 in each group) did not entered to the final analysis. As it is shown in Figure 2, the mean of pre intervention Hmax/Mmax ratio in active rTMS is
decreased after the intervention but this decrease is not sustained in the 1-week follow-up. The change in the Hmax/Mmax ratio after sham intervention shows minor changes (Figure 2). The repeated measure ANOVA did not identify a statistically significant effect of time [F(2,56) ¼ 1.58, p ¼ 0.21, 2 ¼ 0.05]. The main effect of intervention [F(1,28) ¼ 0.58, p ¼ 0.48, 2 ¼ 0.02] was also insignificant. There was also insignificant interaction of time and intervention for the Hmax/Mmax ratio [F(2,56) ¼ 1.78, p ¼ 0.18, 2 ¼ 0.06].
Correlation Spearman’s rho test showed no significant correlation between the spasticity reduction (LE-MMAS) and the motor function improvement (LE-FMA) either in active rTMS (r ¼ 0.3, p ¼ 0.26) or sham rTMS (r ¼ 0.2, p ¼ 0.44) group.
Discussion Effect on lower extremity spasticity The results of this study suggest that five consecutive daily sessions of low-frequency (1 Hz) rTMS over the
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unaffected LE motor cortex can reduce LE spasticity and improve motor function in patients after stroke and the effect is maintained for at least 1-week after the stimulations. This result is consistent with other studies detecting the effect of rTMS on upper extremity post-stroke spasticity,[14–16] lower extremity spasticity in multiple sclerosis patients,[9,10] lower extremity spasticity in incomplete spinal cord injury patients,[11,12] and poststroke motor function.[17,18] To the author’s knowledge, the present study is the first controlled study detecting the effect of low-frequency rTMS on LE post-stroke spasticity. In this study, LE spasticity was evaluated both clinically by means of the MMAS score and electrophysiologically by means of H-reflex measurements. However, the clinical improvements in spasticity (MMAS score) was not accompanied by electrophysiologic changes (Hmax/Mmax). Studies on normal subjects showed motor neurone excitability change after rTMS.[7,8] It is thought that rTMS can modulate spinal excitability by changing cortical excitability and corticospinal cells activity.[20] In this study, the motor neurone excitability (Hmax/Mmax ratio) was decreased after active stimulation (about 18%) and returned to the baseline value in 1-week follow-up. This decrease was not reaching the statistical significant level. This result is in contrast with previous studies on multiple sclerosis LE spasticity [9,10] which showed both the clinical and electrophysiological improvement in spasticity after rTMS. In the previous studies about the anti spastic effect of rTMS in the spinal cord injury patients, like ours, clinical reduction of spasticity did not accompanied by the electrophysiologic changes.[11] Different results of these studies may be due to the different source of spasticity. Different pathophysiology is involved in different type of upper motor neurone disease spasticity.[31] Another reason for the nonsignificant change in the neurophysiologic measure of spasticity in our study and the study of Kumru et al.[11] might be the lesser sessions (5 sessions) in comparison to the previous studies which used rTMS for 2 weeks (10 sessions) [9,10] on multiple sclerosis LE spasticity. Further study with more treatment session is recommended. Furthermore, subanalysis in each group shows more decrease in Hmax/Mmax ratio after active rTMS in SA group which the baseline value of the Hmax/Mmax ratio was higher. However, the change in Hmax/Mmax for both groups was not statistically significant. This may suggest that low-frequency (1 Hz) rTMS to the unaffected LE motor area is more effective with respect to the spinal hyperexcitability reduction in patients with higher alpha motor neurone excitability.
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The use of Hmax/Mmax for detecting the change in stretch reflex hyperexcitability has been criticised by the authors who proposed HSLP/MSLP as a better and more sensitive measure for the motor neurone pool excitability.[32,33] Significant and consistent improvement of the clinical aspect of muscle spasticity (MMAS) after active rTMS in the present study may suggest that the MMAS score as a clinical measure of the spasticity is sensitive to changes compared to Hmax/Mmax ratio.
Effect on lower extremity motor function In this study, LE motor function was evaluated by means of the FMA and the TUG test. Statistical analysis shows that the LE-FMA was improved only after the active rTMS (not after the sham rTMS) (Figure 2). Although ANOVA showed significant effect of time intervention interactions, the effect of rTMS on LE-FMA improvement was modest because no difference between the groups was found. Improved LE motor performance in this study is consistent with the previous works which show the beneficial effect of rTMS in motor improvement after stroke.[16–18] Following stroke, the two brain hemispheres balance of activity is disrupted. Interhemispheric competition hypothesis state that the motor cortex of the unaffected hemisphere becomes disinhibited and exerts exaggerated inhibition onto the motor cortex of the affected hemisphere. Reduced interhemispheric competition was posed as a potential mechanism underlining the functional improvements after stroke. [5] It has been proved from the previous studies that 1 Hz rTMS over the LE motor cortex can decrease the unaffected and increased the affected hemisphere excitability in post-stroke patients.[18] The rTMS is also able to affect other brain areas through the stimulated neurones connexions with other structures.[6] Without additional neurophysiologic studies to investigate the cortical excitability in this study, we can speculate on these mechanisms underlies spasticity and motor improvement. The observed motor improvement represented by change in LE-FMA score is at least in part due to the decrease in the LE spasticity. Lower synergistic activity and more isolated controlled movement with better speed can be done after the decrease in spasticity. In the present study, no significant correlation was observed between the spasticity reduction and the motor function improvement. This finding could be due to the small sample of patient recruited for this study. A previous study, however, demonstrated that the reduction of spasticity improved the motor function.[34] Further study is required to evaluate the relationship between the spasticity and motor
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function to demonstrate whether improvement in the severity of spasticity influence the motor function. Motor function improvement and amelioration of spasticity with active rTMS was maintained during the 1week follow-up. Previous studies have also shown that cumulative plastic changes can be produced by rTMS in healthy subjects [35] as well as in those with multiple sclerosis,[9] spinal cord injury [11] and storke.[18] Plastic change in the central nervous system (CNS) following the rTMS is considered as the potential mechanism for rTMS after effects.[36] The TUG test, no mater of active or sham rTMS intervention, showed similar changes (Figure 2). Like our study, in a study about the effect of rTMS on LE spasticity and gait in spinal cord injury patients, in spite of the improvement in the LE spasticity only after active stimulation, TUG test was improved after both the active and sham stimulation.[12] This nonspecific improvement in the TUG test may imply that patients became familiar with the test through the different level of assessments. No significant improvement in the TUG test in spite of the spasticity and LE-FMA improvement in the present study may be due to the minority of walking problems in the studied patients. All of the patients in this study had minor problems in walking and most of them could walk independently without walking aids (3 of them did the test with a walking aid). If the participants had more problems in gait, the result of the rTMS on walking might be more significant. This study had number of limitations. First, due to the long period of this cross over study, we lose some of the patients in the second period of the study; secondly, the duration of the intervention (5 days) was quit short to see changes in gait; thirdly, the assessments and treatment were done by a same physiotherapist; fourthly, the localisation of the cerebral lesion was not same and this may affect the patients’ response to the intervention; fifthly, the absence of a taping sensation on the scalp by the patients in sham stimulation may compromise the blindness of patients. However, because participants were naive to rTMS, they could not distinguish between active and sham stimulation.
Conclusion Low-frequency rTMS over the unaffected hemisphere reduces the spasticity and improve motor function in the LE post stroke patients. These improvements were not accompanied with gait improvement.
Acknowledgements Special thanks to the Department of Physical Medicine and Rehabilitation of Firozgar University Hospital for their kind cooperation.
Declaration of interest The authors report no conflict of interest. This study was done by the financial support from the Research Deputy, Tehran University of Medical Sciences.
References 1. Lavados PM, Hennis AJM, Fernandes JG, et al. Stroke epidemiology, prevention and management strategies at a regional level: Latin America and Caribbean. Lancet Neurol. 2007;6:362–372. 2. Lundstrom E, Ternet A, Borg G. Prevalence of disabling spasticity 1 year after first-ever stroke. Eur. J. Neurol. 2008;15:533–539. 3. Lance JW. The control of muscle tone, reflexes, and movement: Robert Wartenberg Lecture. Neurology. 1980;30:1303–1313. 4. Singer R, Dunne J, Allison G. Reflex non-reflex and nonreflex elements of hypertonia in triceps surae muscles following acquired brain injury: implications for rehabilitation. Disabil Rehabil. 2001;23:749–757. 5. Nowak DA, Grefks C, Ameli M, et al. Interhemispheric competition after stroke: brain stimulation to enhance recovery of function of the affected hand. Neurorehabil Neural Repair. 2009;23:641–656. 6. Corti M, Patten C, Triggs W. Repetitive transcranial magnetic stimulation of motor cortex after stroke. Am J Phys Med Rehabil. 2012;91:254–269. 7. Valero-Cabre A, Oliveri M, Gangitano M, Pascual-Leone A. Modulation of spinal cord excitability by subthreshold repetitive transcranial magnetic stimulation of the primary motor cortex in humans. Neuro Rep. 2001;12:3845–3848. 8. Perez MA, Lungholt BKS, Nielsen JB. Short-term adaptation in spinal cord circuits evoked by repetitive transcranial magnetic stimulation: possible underlying mechanisms. Exp Brain Res. 2005;162:202–212. 9. Centonze D, Koch G, Versace V, et al. Repetitive transcranial magnetic stimulation of the motor cortex ameliorates spasticity in multiple sclerosis. Neurology. 2007;68:1045–1050. 10. Mori F, Codeca C, Kusayanagi H, et al. Effects of intermittent theta burst stimulation on spasticity in patients with multiple sclerosis. Eur J Neurol. 2010;17:295–300. 11. Kumru H, Murillo N, Samso JV, et al. Reduction of spasticity with repetitive transcranial magnetic stimulation in patients with spinal cord injury. Neurorehabil Neural Repair. 2010;24:435–441. 12. Kumru H, Benito J, Murillo N, et al. Effects of highfrequency repetitive transcranial magnetic stimulation on motor and gait improvement in incomplete spinal cord injury patients. Neurorehabil Neural Repair. 2013;27: 421–429. 13. Valle AC, Dionisio K, Pitskel NB, et al. Low and highfrequency repetitive transcranial magnetic stimulation for
MAGNETIC STIMULATION IN STROKE SPASTICITY
14.
15.
16.
Downloaded by [Orta Dogu Teknik Universitesi] at 07:39 16 February 2016
17.
18.
19.
20.
21.
22.
23.
the treatment of spasticity. Dev Med Child Neurol. 2007;49:534–538. Mally J, Dinya E. Recovery of motor disability and spasticity in post-stroke after repetitive transcranial magnetic stimulation (rTMS). Brain Res Bull. 2008;76:388–395. Kakuda W, Abo M, Kobayashi k, et al. Anti-spastic effect of low-frequency rTMS applied with occupational therapy in post-stroke patients with upper limb hemiparesis. Brain Injury. 2011;25:496–502. Barros Galvao SC, Costa dos Santos RB, Borba dos Santos P, et al. Efficacy of coupling repetitive transcranial magnetic stimulation and physical therapy to reduce upper limb spasticity in stroke patients: A randomized control trial. Arch Phys Med Rehabil. 2014;95:222–229. Fregni F, Boggio PS, Valle AC, et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke. 2006;37:2115–2122. Wang RY, Tseng HY, Liao KK, et al. rTMS combined with task-oriented training to improve symmetry of interhemispheric corticomotor excitability and gait performance after stroke: a randomized trial. Neurorehabil Neural Repair. 2012;26:222–230. Naghdi S, Ansari NN, Rastgoo M, et al. A pilot study on the effects of low frequency repetitive transcranial magnetic stimulation on lower extremity spasticity and motor neuron excitability in patients after stroke. J BodyW Mov Ther. 2015;19:616-623. Mori F, Koch G, Foti C, et al. The use of repetitive transcranial magnetic stimulation (rTMS) for the treatment of spasticity. Prog Brain Res. 2009;175:429–439. Ansari NN, Naghdi S, Younesian P, et al. Inter- and intrarater reliability of the modified modified ashworth scale in patients with knee extensor poststroke spasticity. Physiother Theory Pract. 2008;24:205–213. Ghotbi N, Ansari NN, Naghdi S, et al. Inter-rater reliability of the modified modified ashworth scale in assessing lower limb muscle spasticity. Brain Injury. 2009;23: 815–819. Misazek JE. The H reflex as a tool in neurophysiology: its limitations and uses in understanding nervous system function. Muscle and Nerves. 2003;28:144–160.
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24. Ansari NN, Naghdi S, Hasson S, et al. Efficacy of therapeutic ultrasound and infrared in the management of muscle spasticity. Brain Injury. 2009;23:632–638. 25. Podsiadle D, Richardson S. The timed ‘‘Up & Go’’: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39:142–148. 26. Ng SS, Hui-Chan CW. The timed up & go test: its reliability and association with lower-limb impairments and locomotor capacities in people with chronic stroke. Arch Phys Med Rehabil. 2005;86:1641–1647. 27. Sanford J, Moreland J, Swanson LR, et al. Reliability of the Fugl-Meyer assessment for testing motor performance in patients following stroke. Physical Therapy. 1993;73: 447–454. 28. Barak S, Duncan PW. Issues in selecting outcome measures to assess functional recovery after stroke. NeuroRX. 2006;3:505–524. 29. Fugl-Meyer AR, Ja¨a¨sko¨l L, Leyman I, et al. The post–stroke hemiplegic patient: 1. A method for evaluation of physical performance. Scand J Rehabil Med. 1975;7:13–31. 30. Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol. 2003;2:145–156. 31. Nielsen JB, Corne C, Hultborn H. The spinal pathophysiology of spasticity-from a basic science point of view. Acta Physiol (Oxf). 2007;189:171–180. 32. Funase K, Imanaka K, Nishihira Y. Excitability of the soleus motoneuron pool revealed by the developmental slope of the H-reflex as reflex gain. Electromyogr Clin Neurophysiol; 1994;34:477–489. 33. Higashi T, Funase K, Kusano K, et al. Motoneuron pool excitability of hemiplegic patients: assessing recovery stages by using H-reflex and M response. Arch Phys Med Rehabil. 2001;82:1604–1610. 34. Johnson CA, Burridge JH, Strike PW, et al. The effect of combined use of botulinum toxin type A and functional electric stimulation in the treatment of spastic drop foot after stroke: a preliminary investigation. Ach Phys Med Rehabil. 2004;85:902–909. 35. Baumer T, Lange R, Liepert J, et al. Repeated premotor rTMS leads to cumulative plastic changes of motor cortex excitability in humans. Neuroimage. 2003;20:550–560. 36. Cooke SF, Bliss TVP. Plasticity in the human central nervous system. Brain. 2006;129:1659–1673.
ISSN: 0963-8288 (Print) 1464-5165 (Online) Journal homepage: http://www.tandfonline.com/loi/idre20
Effects of repetitive transcranial magnetic stimulation on lower extremity spasticity and motor function in stroke patients Maryam Rastgoo, Sofia Naghdi, Noureddin Nakhostin Ansari, Gholamreza Olyaei, Shohreh Jalaei, Bijan Forogh & Hamidreza Najari To cite this article: Maryam Rastgoo, Sofia Naghdi, Noureddin Nakhostin Ansari, Gholamreza Olyaei, Shohreh Jalaei, Bijan Forogh & Hamidreza Najari (2016): Effects of repetitive transcranial magnetic stimulation on lower extremity spasticity and motor function in stroke patients, Disability and Rehabilitation To link to this article: http://dx.doi.org/10.3109/09638288.2015.1107780
Published online: 15 Feb 2016.
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Date: 16 February 2016, At: 07:39
DISABILITY AND REHABILITATION, 2016 http://dx.doi.org/10.3109/09638288.2015.1107780
RESEARCH PAPER
Effects of repetitive transcranial magnetic stimulation on lower extremity spasticity and motor function in stroke patients Maryam Rastgooa, Sofia Naghdib, Noureddin Nakhostin Ansarib, Gholamreza Olyaeib, Shohreh Jalaeib, Bijan Foroghc and Hamidreza Najarid a
Department of Physiotherapy, School of Rehabilitation Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Physiotherapy, Faculty of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran; cDepartment of Physical Medicine and Rehabilitation, Firozgar University Hospital, Iran University of Medical Sciences, Tehran, Iran; dDepartment of Internal Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
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b
ABSTRACT
ARTICLE HISTORY
Purpose: To investigate the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on lower extremity (LE) spasticity, motor function and motor neurone excitability in chronic stroke patients. Method: This study was a randomised sham-controlled cross-over trial with 1-week follow-up. A total of 20 post-stroke patients were randomised to receive active (n ¼ 10) or sham (n ¼ 10) rTMS. Fourteen of them (7 in each group) crossed over to the sham or active rTMS after a washout period of 1 month. Interventions consist of five consecutive daily sessions of active or sham rTMS to the unaffected lower extremity motor area (1000 pulses; 1 Hz; 90% of the tibialis anterior motor threshold). Outcome measures were modified modified ashworth scale (MMAS), the H-reflex, lower extremity section of Fugl–Mayer assessment (LE-FMA) and timed UP and GO (TUG) test. All outcomes were measured at three levels in each intervention period: pre- and postintervention and 1-week follow-up. Results: Friedman’s test revealed significant improvement in MMAS score only after active rTMS. This improvement lasted for one week after the active rTMS. Repeated measure analysis of variance (ANOVA) showed significant time*intervention interaction for LE-FMA. There are no differences between groups for the MMAS and LE-FMA. No significant change in Hmax/Mmax ratio and TUG test was noted. Conclusion: Low-frequency rTMS over the LE motor area can improve clinical measures of muscle spasticity and motor function. More studies are needed to clarify the changes underlying this improvement in spasticity.
Received 5 August 2014 Revised 25 August 2015 Accepted 10 October 2015 Published online 10 February 2016 KEYWORDS
H-reflex; motor function; repetitive transcranial magnetic stimulation; spasticity; stroke
ä IMPLICATIONS FOR REHABILITATION
Spasticity is a common disorder and one of the causes of long-term disability after stroke. Physical therapy modalities, oral medications, focal intervention and surgical procedures have been used for spasticity reduction. Beneficial effect of the repetitive transcranial magnetic stimulation (rTMS) for post-stroke upper extremity spasticity reduction and motor function improvement was demonstrated in previous studies. This study shows amelioration of lower extremity spasticity and motor function improvement after five daily sessions of inhibitory rTMS to the unaffected brain hemisphere which lasted for at least 1 week following the intervention.
Introduction Stroke is the major cause of adult disability around the word.[1] Spasticity is a common disorder and one of the causes of long-term disability after stroke. The prevalence of spasticity in chronic phase after stroke is reported about 20%.[2] Spasticity is defined by Lance (1980) as a velocity-dependant increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerk, CONTACT Maryam Rastgoo ß 2016 Taylor & Francis
resulting from hyper excitability of the stretch reflex.[3] Untreated spasticity of the lower extremity may cause gait disorders, muscle-tendinous unit stiffness and dependent mobility post-stroke.[4] In addition to physical therapy, numerous oral medications, focal intervention, and surgical procedures have been used for spasticity reduction. However, for treating spasticity,
[email protected] Damavand Ave. Imam Hussein SQ. Tehran, Post Code: 1616913111, Iran
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physiotherapy modalities have shown unsatisfactory results and pharmacologic and surgical medications are associated with several disadvantages. Therefore, there is a pressing need for the development of a new intervention. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique that induces changes in cortical excitability at the stimulation site and transsynaptically at distant areas. Depending on the frequency of the pulses, two modes of rTMS are commonly used after stroke: (1) high-frequency (41 Hz) fascilatory mode which is applied to the affected hemisphere to increase its excitability and (2) low-frequency (1 Hz) inhibitory mode which is applied to the unaffected hemisphere to reduce its excitability and therefore decrease inhibition from the unaffected to the affected hemisphere (interhemispheric competition).[5,6] These effects may outlast the duration of stimulation, minutes or even hours after it.[6] The interhemispheric competition hypothesis suggests that balancing excitability between the two hemispheres may improve functional behaviour in people after stroke.[5] Previous studies on normal subjects showed that modulation of cortical excitability by rTMS, affect spinal segmental (alpha motor neurone) excitability by changing descending cortico-spinal projections in both the upper and lower limb.[7,8] In the last decade, rTMS has been used in various neurological conditions of multiple sclerosis,[9,10] spinal cord injuries,[11,12] and cerebral palsy [13] to control muscle spasticity. There are also studies which investigated the effect of rTMS on upper extremity spasticity in patients with chronic stroke.[14–16] Motor function improvement following the use of the low-frequency rTMS in stroke patients has also been shown in previous studies.[17,18] Our prior pilot case series study work showed the beneficial effect of the rTMS in lower extremity spasticity.[19] To our knowledge, there are no controlled study investigating the effect of low-frequency rTMS on LE spasticity and motor neurone excitability post-stroke. Therefore, the purpose of this study is to assess the effect of five consecutive sessions of 1-Hz rTMS on LE spasticity, alpha motor neurone excitability and motor function in post-stroke patients. We hypothesised that by inhibiting the unaffected hemisphere, and reducing the interhemispheric competition, symmetric activity of the two brain hemispheres may be returned. Increasing the activity of the affected corticospinal pathway can modulate the alpha motor neurones excitability through the direct and indirect connexions. Therefore, decrease in spinal circuits’ excitability and improvement of spasticity may happen.[20] Improvement of motor function is expected after the decrease in spasticity.
Methods Study design This study is a randomised, sham-controlled, cross-over trial with 1-week follow-up which was conducted under one way blind condition.
Participants Inclusion criteria for participants were as follows: (1) adult age 18 years (2) first ever stroke which resulted in unilateral hemiparesis (3) time past since onset of stroke to be 6 months (4) at least one spastic muscle group in the affected side of the patient (5) ability to walk independently (with or without walking aids). Exclusion criteria were as follows: (1) the presence of contraindications for the use of rTMS such as cardiac pacemaker or intracranial implants (2) grade 4 of the MMAS score (3) use of antispastic drugs (4) local injection of botulinum toxin type A in past 3 months. Subjects who met the inclusion criteria and did not have exclusion criteria were assigned to the study. Patients with post-stroke were recruited from rehabilitation centre of Firozgar hospital, Iran University of Medical Science and from stroke rehabilitation clinic in rehabilitation faculty of Tehran University of Medical Science. The demographic information of the patients was obtained through interview. Localisation of the cerebral lesion was determined by image studying of the brain. As shown in Figure 1, from 26 patients who were identified as potential participants for this study, 20 of them enrolled to the study. Patients were randomised into two groups: AS group are the patients who had the active rTMS as the first and sham rTMS as the second intervention period and, SA group are the patients who had sham rTMS as the first and active rTMS as the second intervention period. Randomisation was done through random assignment by individuals. Six patients (3 in each group) refused to do second intervention and 14 patients were crossed over to second intervention period, 4 weeks after the end of the first one.
Procedures The study protocol was approved by the ethics committees of Tehran University of Medical Science, Iran. The informed consent was obtained from all the patients. All outcomes were measured at three levels: (1) preintervention, (2) post-intervention, (3) 1-week follow-up in each intervention period. Assessments and interventions for all patients were done by a well-trained
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Figure 1. Diagram of the study design, Abbreviation: rTMS, repetitive transcranial magnetic stimulation; As group, group of patients who did active rTMS in the first intervention period and sham rTMS in the second intervention period; SA group of patients to whom sham rTMS was the first and active rTMS was the second intervention.
physiotherapist and patients were blinded to the intervention.
Outcome measures Primary outcome measures were as follows: (1) modified modified ashworth scale (MMAS) to assess muscle spasticity and (2) Hmax/Mmax ratio as the electrophysiologic index of motor neurone excitability. Secondary outcome measures were as follows: (1) Timed Up and Go (TUG) test for gait evaluation; (2) Fugl– Mayer assessment (FMA) for assessing the lower extremity motor function.
Spasticity evaluation Modified Modified Ashworth Scale (MMAS) was used for the assessment of the ankle plantar flexors and knee extensors spasticity. The MMAS is an ordinal level measure of spasticity, which grades the intensity of spasticity from 0 to 4 according to the resistance to a quick, passive movement. In MMAS score, 0 mean no increase in muscle tone and 4 mean the affected part rigid in flexion or extension. It has been proved that the MMAS is a reliable tool for measuring knee extensors post–stroke spasticity [21] and ankle plantar flexors spasticity.[22] For evaluating the knee extensor spasticity, the patient was in side-lying position, hip and knee in
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extension, head in midline. The physiotherapist was behind the patient, place one hand above the knee to stabilise the femur and moved the knee from maximal extension to maximum flexion with the other hand. For evaluating the ankle plantar flexor spasticity, the patient was in supine position, with his lower limbs in extension. The physiotherapist stabilises the ankle with one hand and moved the ankle from maximal plantarflexion to dorsiflexion with the other hand.
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Electrophysiological evaluation For the electrophysiological measurement of motor neurone excitability, the affected side Soleus compound motor action potential (CMAP or M) and H-reflex were evoked. H-reflex is considered as a reliable electrophysiologic equivalent of stretch reflex and motor neurone excitability.[23] In this study, an electromyography machine (Myo Quick, Micromed Company, Italy) was used. The patient was asked to lie in the prone position while his feet was suspended over the end of the bed, his head was in midline and turned to one side and his arms were placed on his body sides. Tibial nerve was electrically stimulated with bipolar silver-silver chloride stimulator electrode in the popliteal fossa. The stimulus was a single 1-ms rectangular pulse delivered every 5 sec. The recording surface electrode was placed 2 cm under the junction of lateral and medial head of the gastrocnemius muscle. The reference electrode was placed to the skin 3 cm distal to the recording electrodes on the soleus muscle and the ground electrode was attached to the skin approximately between the recording and reference electrodes. The EMG signal was amplified (1 mV/Division) and bandpass filtered (2 Hz to 10 KHz). The intensity of the stimulation was progressively increased from below the M-wave threshold to maximum M wave. The ratio of the Hmax/Mmax was calculated by dividing the maximum peak-to-peak amplitude of H-reflex by that of the M-wave.[24]
Gait evaluation We used Timed Up and Go test (TUG) for gait evaluation. TUG is a simple and quick functional mobility test. It includes a series of motor tasks that require balance control in addition to muscle strength and coordination.[25] Excellent reliability for this test was reported in chronic post-stroke patients.[26] For performing the test, patient was instructed to stand up from a chair with an armchair, walk 3 m, turn, walk back and sit down to the
same chair. The time taken to complete the test was recorded. In this study, three consecutive measurements were done and the average value was calculated in each assessment level.
Motor function evaluation Motor function of the lower extremity was assessed by Fugl–Mayer assessment (FMA). FMA is considered the gold standard for evaluating the motor function recovery after stroke.[27,28] FMA for the motor function of the lower extremity, with a maximum 34 point, consist of items in reflexes, synergic patterns and coordination. Each item is rated on a 3-point ordinal scale, 2-point for complete performance, 1-point for partial performance and 0-point for no performance.[29]
Interventions Patients received five consecutive daily sessions of active or sham rTMS in the morning between 8:00 a.m. and 12:00 a.m. In this study, rTMS was performed with a figure of eight coil (diameter of each wing, 90 mm) connected to the Magstim stimulator (Magstim Co, Ltd, UK). Patients seated in a comfortable reclining armchair during the intervention. In active rTMS, a train of 1000 pulses of 1-Hz rTMS with an intensity of 90% of the tibialis anterior MT over about 20 min was delivered to the LE motor cortex of the unaffected brain hemisphere. This frequency and intensity was chosen because its beneficial effect for upper extremity spasticity [15,16] and lower extremity motor function [18] in post-stroke patients was proven in previous studies. Motor threshold (MT) was defined as the lowest stimulus intensity required to evoke motor evoked potentials (MEPs) of 50 mV in peak-to-peak amplitude in at least three of five consecutive trials in the TA muscle.[30] The site, where was used for MT determination, was considered as the stimulation site. This site was typically, from 0 to 2 cm lateral to the vertex and 1 to 2 cm posterior to the vertex.[18] The stimulation site was marked on the scalp and the centre of the coil was maintained in that position for the entire duration of stimulation. If no MEP was recorded from the unaffected LE, the coil was held tangentially to the scalp with its centre placed 1 cm lateral and 1 cm posterior from the vertex.[35] In these cases, the stimulus intensity was set at 100% of the MT intensity for induction MEPs in the unaffected biceps brachii muscle. For delivering the rTMS, the coil was placed tangentially to the subjects head, and the handle pointing
MAGNETIC STIMULATION IN STROKE SPASTICITY
posteriorly and positioned at 60 with respect to mid sagittal axis of the head.[9,10] For the sham stimulation, the coil held over the unaffected LE motor area as for active stimulation but with application of an audio coil, no magnetic stimulation was delivered to the brain.
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Statistical analysis All statistical analysis was done using the SPSS package 18.0. The significant level was defined as p50/05. The data of the two groups was pooled together and the statistics were done for the total number of the patients who received active and sham rTMS as either the first or the second intervention period. Subanalysis was done when it was necessary. Because all data met the criterion of normality (Kolmogorov–Smirnov test), repeated measure analysis of variance (ANOVA) was performed to evaluate the effects of interventions (active rTMS vs. sham rTMS) in time (pre- and post-intervention and 1-week follow-up) on TUG, FMA and Hmax/Mmax ratio. Effect sizes for F ratios were reported as eta-squared (Z2). A post hoc analysis was performed with Bonferroni correction. For MMAS, median and quartiles range (Table 2) is calculated, and as it is an ordinal level measurement, nonparametric tests were used. The effect over time was evaluated using Friedman test. Post hoc analysis with Wilcoxon signed-rank test was conducted. Mann– Whitney U-test was used to compare the MMAS scores of the patients between the two interventions. Spearman’ rho correlation test was applied to detect the relationship between the spasticity reduction (LE MMAS) and the motor function improvement (LE FMA).
Results Participant characteristics The demographic and baseline clinical characteristic of the patients in both AS and SA group are demonstrated in Table 1. No significant difference was found between the two groups regarding the demographic and baseline clinical characteristics (Table 2). No adverse events were reported by any of the patients throughout the study.
Modified modified ashworth scale The median and quartiles range of the LE-MMAS at three levels of assessments are provided in Table 2. In this study, LE-MMAS score is improved significantly only after the active rTMS and this improvement is sustained 1-week after the intervention.
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Table 1. Characteristics of participants. Parameters Age (years) Gender Male Female Time since the stroke (months) Type of stroke Ischaemic Haemorrhagic Paretic side Right Left localisation of the cerebral lesion Cortex Subcortex Both cortex and subcortex TUG test LE-FMA Hmax/Mmax ratio
AS group (n ¼ 10)
SA group (n ¼ 10)
p value*
54.6 SD 11.75
49.7 SD 11
0.33
8 2 30.2 SD 18.3
8 2 27.4 SD 20.1
1
8 2
7 3
3 7
4 6
3 7 – 24.8 SD 21.3 26.2 SD 5.1 0.48 SD 0.2
– 8 2 28.9 SD 15.7 25.1 SD 3.3 0.58 SD 0.2
0.75 0.6 0.64 0.08
0.63 0.58 0.32
*As determined with the chi-square for proportions and MMAS scale and with the t-test for independent groups for continuous variables. AS group, group of patients to whom active rTMS was the first and sham rTMS was the second intervention; SA group, group of patients to whom sham rTMS was the first and active rTMS was the second intervention; SD, standard deviation; LE-FMA, lower extremity Fugl–Mayer assessment; TUG, Timed Up and GO.
The Mann–Whitney U-test on LE-MMAS scores did not identify a statistical significant difference between groups (pre–Z ¼ 1.43, p ¼ 0.17; post–Z ¼ 0.09, p ¼ 0.94; follow-up Z ¼ 0.55, p ¼ 0.61). Within-group analysis by using Friedman test revealed significant change in patients who received active rTMS ( 2 (2) ¼ 17.07, p50.01). Post hoc analysis with the Willcoxon signed-rank test showed a significant decrease in MMAS score between the pre- and the post-intervention (p ¼ 0.02) and between the pre and the 1-week follow-up (p ¼ 0.02) for active rTMS intervention. Friedman test revealed no significant difference in time in patients who received sham rTMS ( 2 (2) ¼ 6, p ¼ 0.1). Post hoc analysis with the Wilcoxon signed-rank test showed no significant improvement in MMAS score in the post-intervention (p ¼ 0.09) or 1-week follow-up (p ¼ 0.3) in comparison to pre-intervention.
Fugl–Mayer assessment Descriptive data of the LE-FMA is provided in Figure 2. It shows that LE-FMA improves only after active rTMS and these improvements are sustained 1-week after the intervention. Repeated measure ANOVA, revealed that the main effect for time was statistically significant [F(2,64) ¼ 9.95, p50.01, 2 ¼ 0.24]. Post hoc analysis indicated a significant difference between pre- and post-intervention (LE-FMA mean difference ¼ 0.67, p50.01) and a trend towards significance between pre-intervention and 1-week follow-up (LE-FMA mean difference ¼ 0.41, p ¼ 0.06). Significant interaction of
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Table 2. Median (quartiles range) of the LE-MMAS in active and sham rTMS stimulation in time (at different level of assessment). Active rTMS (n ¼ 17)
LE MMAS
Pre
post
2 (1–3)
1 (0–2)
1-week follow-up 1 (0–2)
Sham rTMS (n ¼ 17) Pre
post
1 (1–2.5)
1 (0.5–2.5)
1-week follow-up 1 (1–2.5)
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LE-MMAS, lower extremity modified modified ashworth scale.
Figure 2. The change in the mean ± standard division of the lower extremity Fugl–Mayer assessment (LE–FMA), the Timed Up and Go (TUG) test, and the mean of Hmax/Mmax ratio in time (different level of assessments) after the active and sham rTMS. LE–FMA improved significantly after the active rTMS (p50.01) and 1-week follow – up (p ¼ 0.06) comparison to before it.*p 0.06 pair post hoc analysis by the Bonferroni correction.
intervention time is also shown [F(2,64) ¼ 20.17, p50.01, 2 ¼ 0.39]. However, the main effect of intervention is not significant [F(1, 32) ¼ 0.88, p ¼ 0.35, 2 ¼ 0.02].
TUG test As it is shown in Figure 2, TUG test changes show similar manner of improvement in both active and sham intervention over time. Repeated measure ANOVA reveals significant main effect of time [F(2,64) ¼ 5.58, p50.01, 2 ¼ 0.15]. Post hoc analyses shows a significant difference between pre-intervention and 1-week followup (TUG test mean differences ¼ 2.05, p5 0.01). No significant interaction of intervention time is shown. [F(2,64) ¼ 1.34, p ¼ 0.27, 2 ¼ 0.04] regarding the TUG test. The main effect of intervention is not significant [F(1,32) ¼ 0, p ¼ 0.9, 2 ¼ 0].
The Hmax/Mmax ratio Because of poor H-reflex recordings, electrophysiologic data of two patients (1 in each group) did not entered to the final analysis. As it is shown in Figure 2, the mean of pre intervention Hmax/Mmax ratio in active rTMS is
decreased after the intervention but this decrease is not sustained in the 1-week follow-up. The change in the Hmax/Mmax ratio after sham intervention shows minor changes (Figure 2). The repeated measure ANOVA did not identify a statistically significant effect of time [F(2,56) ¼ 1.58, p ¼ 0.21, 2 ¼ 0.05]. The main effect of intervention [F(1,28) ¼ 0.58, p ¼ 0.48, 2 ¼ 0.02] was also insignificant. There was also insignificant interaction of time and intervention for the Hmax/Mmax ratio [F(2,56) ¼ 1.78, p ¼ 0.18, 2 ¼ 0.06].
Correlation Spearman’s rho test showed no significant correlation between the spasticity reduction (LE-MMAS) and the motor function improvement (LE-FMA) either in active rTMS (r ¼ 0.3, p ¼ 0.26) or sham rTMS (r ¼ 0.2, p ¼ 0.44) group.
Discussion Effect on lower extremity spasticity The results of this study suggest that five consecutive daily sessions of low-frequency (1 Hz) rTMS over the
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unaffected LE motor cortex can reduce LE spasticity and improve motor function in patients after stroke and the effect is maintained for at least 1-week after the stimulations. This result is consistent with other studies detecting the effect of rTMS on upper extremity post-stroke spasticity,[14–16] lower extremity spasticity in multiple sclerosis patients,[9,10] lower extremity spasticity in incomplete spinal cord injury patients,[11,12] and poststroke motor function.[17,18] To the author’s knowledge, the present study is the first controlled study detecting the effect of low-frequency rTMS on LE post-stroke spasticity. In this study, LE spasticity was evaluated both clinically by means of the MMAS score and electrophysiologically by means of H-reflex measurements. However, the clinical improvements in spasticity (MMAS score) was not accompanied by electrophysiologic changes (Hmax/Mmax). Studies on normal subjects showed motor neurone excitability change after rTMS.[7,8] It is thought that rTMS can modulate spinal excitability by changing cortical excitability and corticospinal cells activity.[20] In this study, the motor neurone excitability (Hmax/Mmax ratio) was decreased after active stimulation (about 18%) and returned to the baseline value in 1-week follow-up. This decrease was not reaching the statistical significant level. This result is in contrast with previous studies on multiple sclerosis LE spasticity [9,10] which showed both the clinical and electrophysiological improvement in spasticity after rTMS. In the previous studies about the anti spastic effect of rTMS in the spinal cord injury patients, like ours, clinical reduction of spasticity did not accompanied by the electrophysiologic changes.[11] Different results of these studies may be due to the different source of spasticity. Different pathophysiology is involved in different type of upper motor neurone disease spasticity.[31] Another reason for the nonsignificant change in the neurophysiologic measure of spasticity in our study and the study of Kumru et al.[11] might be the lesser sessions (5 sessions) in comparison to the previous studies which used rTMS for 2 weeks (10 sessions) [9,10] on multiple sclerosis LE spasticity. Further study with more treatment session is recommended. Furthermore, subanalysis in each group shows more decrease in Hmax/Mmax ratio after active rTMS in SA group which the baseline value of the Hmax/Mmax ratio was higher. However, the change in Hmax/Mmax for both groups was not statistically significant. This may suggest that low-frequency (1 Hz) rTMS to the unaffected LE motor area is more effective with respect to the spinal hyperexcitability reduction in patients with higher alpha motor neurone excitability.
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The use of Hmax/Mmax for detecting the change in stretch reflex hyperexcitability has been criticised by the authors who proposed HSLP/MSLP as a better and more sensitive measure for the motor neurone pool excitability.[32,33] Significant and consistent improvement of the clinical aspect of muscle spasticity (MMAS) after active rTMS in the present study may suggest that the MMAS score as a clinical measure of the spasticity is sensitive to changes compared to Hmax/Mmax ratio.
Effect on lower extremity motor function In this study, LE motor function was evaluated by means of the FMA and the TUG test. Statistical analysis shows that the LE-FMA was improved only after the active rTMS (not after the sham rTMS) (Figure 2). Although ANOVA showed significant effect of time intervention interactions, the effect of rTMS on LE-FMA improvement was modest because no difference between the groups was found. Improved LE motor performance in this study is consistent with the previous works which show the beneficial effect of rTMS in motor improvement after stroke.[16–18] Following stroke, the two brain hemispheres balance of activity is disrupted. Interhemispheric competition hypothesis state that the motor cortex of the unaffected hemisphere becomes disinhibited and exerts exaggerated inhibition onto the motor cortex of the affected hemisphere. Reduced interhemispheric competition was posed as a potential mechanism underlining the functional improvements after stroke. [5] It has been proved from the previous studies that 1 Hz rTMS over the LE motor cortex can decrease the unaffected and increased the affected hemisphere excitability in post-stroke patients.[18] The rTMS is also able to affect other brain areas through the stimulated neurones connexions with other structures.[6] Without additional neurophysiologic studies to investigate the cortical excitability in this study, we can speculate on these mechanisms underlies spasticity and motor improvement. The observed motor improvement represented by change in LE-FMA score is at least in part due to the decrease in the LE spasticity. Lower synergistic activity and more isolated controlled movement with better speed can be done after the decrease in spasticity. In the present study, no significant correlation was observed between the spasticity reduction and the motor function improvement. This finding could be due to the small sample of patient recruited for this study. A previous study, however, demonstrated that the reduction of spasticity improved the motor function.[34] Further study is required to evaluate the relationship between the spasticity and motor
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function to demonstrate whether improvement in the severity of spasticity influence the motor function. Motor function improvement and amelioration of spasticity with active rTMS was maintained during the 1week follow-up. Previous studies have also shown that cumulative plastic changes can be produced by rTMS in healthy subjects [35] as well as in those with multiple sclerosis,[9] spinal cord injury [11] and storke.[18] Plastic change in the central nervous system (CNS) following the rTMS is considered as the potential mechanism for rTMS after effects.[36] The TUG test, no mater of active or sham rTMS intervention, showed similar changes (Figure 2). Like our study, in a study about the effect of rTMS on LE spasticity and gait in spinal cord injury patients, in spite of the improvement in the LE spasticity only after active stimulation, TUG test was improved after both the active and sham stimulation.[12] This nonspecific improvement in the TUG test may imply that patients became familiar with the test through the different level of assessments. No significant improvement in the TUG test in spite of the spasticity and LE-FMA improvement in the present study may be due to the minority of walking problems in the studied patients. All of the patients in this study had minor problems in walking and most of them could walk independently without walking aids (3 of them did the test with a walking aid). If the participants had more problems in gait, the result of the rTMS on walking might be more significant. This study had number of limitations. First, due to the long period of this cross over study, we lose some of the patients in the second period of the study; secondly, the duration of the intervention (5 days) was quit short to see changes in gait; thirdly, the assessments and treatment were done by a same physiotherapist; fourthly, the localisation of the cerebral lesion was not same and this may affect the patients’ response to the intervention; fifthly, the absence of a taping sensation on the scalp by the patients in sham stimulation may compromise the blindness of patients. However, because participants were naive to rTMS, they could not distinguish between active and sham stimulation.
Conclusion Low-frequency rTMS over the unaffected hemisphere reduces the spasticity and improve motor function in the LE post stroke patients. These improvements were not accompanied with gait improvement.
Acknowledgements Special thanks to the Department of Physical Medicine and Rehabilitation of Firozgar University Hospital for their kind cooperation.
Declaration of interest The authors report no conflict of interest. This study was done by the financial support from the Research Deputy, Tehran University of Medical Sciences.
References 1. Lavados PM, Hennis AJM, Fernandes JG, et al. Stroke epidemiology, prevention and management strategies at a regional level: Latin America and Caribbean. Lancet Neurol. 2007;6:362–372. 2. Lundstrom E, Ternet A, Borg G. Prevalence of disabling spasticity 1 year after first-ever stroke. Eur. J. Neurol. 2008;15:533–539. 3. Lance JW. The control of muscle tone, reflexes, and movement: Robert Wartenberg Lecture. Neurology. 1980;30:1303–1313. 4. Singer R, Dunne J, Allison G. Reflex non-reflex and nonreflex elements of hypertonia in triceps surae muscles following acquired brain injury: implications for rehabilitation. Disabil Rehabil. 2001;23:749–757. 5. Nowak DA, Grefks C, Ameli M, et al. Interhemispheric competition after stroke: brain stimulation to enhance recovery of function of the affected hand. Neurorehabil Neural Repair. 2009;23:641–656. 6. Corti M, Patten C, Triggs W. Repetitive transcranial magnetic stimulation of motor cortex after stroke. Am J Phys Med Rehabil. 2012;91:254–269. 7. Valero-Cabre A, Oliveri M, Gangitano M, Pascual-Leone A. Modulation of spinal cord excitability by subthreshold repetitive transcranial magnetic stimulation of the primary motor cortex in humans. Neuro Rep. 2001;12:3845–3848. 8. Perez MA, Lungholt BKS, Nielsen JB. Short-term adaptation in spinal cord circuits evoked by repetitive transcranial magnetic stimulation: possible underlying mechanisms. Exp Brain Res. 2005;162:202–212. 9. Centonze D, Koch G, Versace V, et al. Repetitive transcranial magnetic stimulation of the motor cortex ameliorates spasticity in multiple sclerosis. Neurology. 2007;68:1045–1050. 10. Mori F, Codeca C, Kusayanagi H, et al. Effects of intermittent theta burst stimulation on spasticity in patients with multiple sclerosis. Eur J Neurol. 2010;17:295–300. 11. Kumru H, Murillo N, Samso JV, et al. Reduction of spasticity with repetitive transcranial magnetic stimulation in patients with spinal cord injury. Neurorehabil Neural Repair. 2010;24:435–441. 12. Kumru H, Benito J, Murillo N, et al. Effects of highfrequency repetitive transcranial magnetic stimulation on motor and gait improvement in incomplete spinal cord injury patients. Neurorehabil Neural Repair. 2013;27: 421–429. 13. Valle AC, Dionisio K, Pitskel NB, et al. Low and highfrequency repetitive transcranial magnetic stimulation for
MAGNETIC STIMULATION IN STROKE SPASTICITY
14.
15.
16.
Downloaded by [Orta Dogu Teknik Universitesi] at 07:39 16 February 2016
17.
18.
19.
20.
21.
22.
23.
the treatment of spasticity. Dev Med Child Neurol. 2007;49:534–538. Mally J, Dinya E. Recovery of motor disability and spasticity in post-stroke after repetitive transcranial magnetic stimulation (rTMS). Brain Res Bull. 2008;76:388–395. Kakuda W, Abo M, Kobayashi k, et al. Anti-spastic effect of low-frequency rTMS applied with occupational therapy in post-stroke patients with upper limb hemiparesis. Brain Injury. 2011;25:496–502. Barros Galvao SC, Costa dos Santos RB, Borba dos Santos P, et al. Efficacy of coupling repetitive transcranial magnetic stimulation and physical therapy to reduce upper limb spasticity in stroke patients: A randomized control trial. Arch Phys Med Rehabil. 2014;95:222–229. Fregni F, Boggio PS, Valle AC, et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke. 2006;37:2115–2122. Wang RY, Tseng HY, Liao KK, et al. rTMS combined with task-oriented training to improve symmetry of interhemispheric corticomotor excitability and gait performance after stroke: a randomized trial. Neurorehabil Neural Repair. 2012;26:222–230. Naghdi S, Ansari NN, Rastgoo M, et al. A pilot study on the effects of low frequency repetitive transcranial magnetic stimulation on lower extremity spasticity and motor neuron excitability in patients after stroke. J BodyW Mov Ther. 2015;19:616-623. Mori F, Koch G, Foti C, et al. The use of repetitive transcranial magnetic stimulation (rTMS) for the treatment of spasticity. Prog Brain Res. 2009;175:429–439. Ansari NN, Naghdi S, Younesian P, et al. Inter- and intrarater reliability of the modified modified ashworth scale in patients with knee extensor poststroke spasticity. Physiother Theory Pract. 2008;24:205–213. Ghotbi N, Ansari NN, Naghdi S, et al. Inter-rater reliability of the modified modified ashworth scale in assessing lower limb muscle spasticity. Brain Injury. 2009;23: 815–819. Misazek JE. The H reflex as a tool in neurophysiology: its limitations and uses in understanding nervous system function. Muscle and Nerves. 2003;28:144–160.
9
24. Ansari NN, Naghdi S, Hasson S, et al. Efficacy of therapeutic ultrasound and infrared in the management of muscle spasticity. Brain Injury. 2009;23:632–638. 25. Podsiadle D, Richardson S. The timed ‘‘Up & Go’’: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39:142–148. 26. Ng SS, Hui-Chan CW. The timed up & go test: its reliability and association with lower-limb impairments and locomotor capacities in people with chronic stroke. Arch Phys Med Rehabil. 2005;86:1641–1647. 27. Sanford J, Moreland J, Swanson LR, et al. Reliability of the Fugl-Meyer assessment for testing motor performance in patients following stroke. Physical Therapy. 1993;73: 447–454. 28. Barak S, Duncan PW. Issues in selecting outcome measures to assess functional recovery after stroke. NeuroRX. 2006;3:505–524. 29. Fugl-Meyer AR, Ja¨a¨sko¨l L, Leyman I, et al. The post–stroke hemiplegic patient: 1. A method for evaluation of physical performance. Scand J Rehabil Med. 1975;7:13–31. 30. Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol. 2003;2:145–156. 31. Nielsen JB, Corne C, Hultborn H. The spinal pathophysiology of spasticity-from a basic science point of view. Acta Physiol (Oxf). 2007;189:171–180. 32. Funase K, Imanaka K, Nishihira Y. Excitability of the soleus motoneuron pool revealed by the developmental slope of the H-reflex as reflex gain. Electromyogr Clin Neurophysiol; 1994;34:477–489. 33. Higashi T, Funase K, Kusano K, et al. Motoneuron pool excitability of hemiplegic patients: assessing recovery stages by using H-reflex and M response. Arch Phys Med Rehabil. 2001;82:1604–1610. 34. Johnson CA, Burridge JH, Strike PW, et al. The effect of combined use of botulinum toxin type A and functional electric stimulation in the treatment of spastic drop foot after stroke: a preliminary investigation. Ach Phys Med Rehabil. 2004;85:902–909. 35. Baumer T, Lange R, Liepert J, et al. Repeated premotor rTMS leads to cumulative plastic changes of motor cortex excitability in humans. Neuroimage. 2003;20:550–560. 36. Cooke SF, Bliss TVP. Plasticity in the human central nervous system. Brain. 2006;129:1659–1673.
