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Repetitive Transcranial Magnetic Stimulation

After a lesion, functional reorganization of the remaining circuits at the cortical and subcortical levels can contribute to the recovery of function. Repetitive transcranial magnetic stimulation (rTMS) s a non-invasive technique that has been shown to modulate cortical excitability and induce changes over the descending corticospinal output (Kumru et al. 2010). This cortical modulation may be useful in promoting active recovery of motor function to obtain functional benefit from gait rehabilitation. Previous studies have shown rTMS to be beneficial in reduced spasticity among patient with multiple sclerosis, cerebral palsy, and spastic quadriplegia (Wassermann & Lisanby 2001).

Table 7 Studies of rTMS for Reducing Spasticity

Author Year

Country
Research Design

Score
Total Sample Size

MethodsOutcome
Nardone et al. 2014

Austria

RCT Crossover

PEDro=7

N=9

Population: Individuals (n=9): Mean Age: 45.7 yr; Gender: males=8, females=1; Injury etiology: fracture=7, disc prolapse=2; Level of injury: cervical=5, thoracic=4; Level of severity: AIS C=4, AIS D=5. Controls (n=8): Mean Age: 44.4 yr; Gender: males=7, females=1.

Intervention: Individuals were randomly allocated to receive either real rTMS (n=4) or a sham rTMS (n=5). Intervention was conducted daily over 5 days with real rTMS individuals receiving 2 sec-long bursts at 20 Hz with interstimulus interval of 28 sec, for a total of 1600 pulses over 20 min at an intensity of 90% of the resting motor threshold. After a 4 wk washout period, individuals were crossed over, although only four of the five sham rTMS individuals received real rTMS. Assessments were conducted at baseline, after first session, after final session and at 1 wk follow-up.

Outcome Measures: Modified

Ashworth Scale (MAS), Spinal Cord Injury Assessment Tool for Spasticity (SCAT), Monosynaptic test reflex responses (H-reflex), Maximal H-reflex response (H-max), Maximum soleus motor action potential (M-max).

1.     Spasticity was significantly reduced after real rTMS intervention, as measured by both MAS (p=0.0013) and SCAT (p=0.0008).

2.     MAS and SCAT values significantly decreased after the first intervention session (MAS: p=0.0001; SCAT: p=0.0001).

3.     MAS and SCAT scores at 1 wk follow-up were still significantly lower than baseline scores (MAS: p=0.0006; SCAT: p=0.0002).

4.     H-max/M-max ratio did not change significantly over the four assessments (p=0.17) amongst individuals (controls not assessed for H-max/M-max).

5.     Reciprocal inhibition according to H-reflex responses was significantly modified in individuals during real rTMS intervention (p=0.00004) compared to healthy controls.

6.     The conditioned H-reflex response significantly decreased after first intervention session and from first to last intervention session (both p<0.0001).

7.     Conditioned H-reflex responses at 1 wk follow-up were still significantly lower than baselines scores (p<0.0001).

Effect Sizes: Forest plot of standardized mean differences (SMD±95%C.I.) as calculated from pre- and post-intervention data.

Benito et al. 2012

Spain

RCT

PEDro=7

N=17

Population: Mean age: 37.3 yr; Gender: males=13, females=4; Injury etiology: traumatic=9, non-traumatic=8; Level of injury: cervical=7, thoracic=10; Level of severity: AIS D=17.

Intervention: Individuals were randomly allocated to receive either real rTMS (n=7) or a sham rTMS (n=10). Three individuals who received sham rTMS were crossed-over to receive real rTMS 3 wk after completing the sham protocol. Real rTMS individuals received 2 sec bursts at 20 Hz (40 pulses/burst) with intervals of 28 sec, for a total of 1800 pulses over 20 min. The intensity of stimulation was set at 90% of the resting motor threshold. Assessments were conducted at baseline, after the last intervention session, and at 2 wk follow-up.

Outcome Measures: Modified

Ashworth Scale (MAS), Lower Extremities Motor Score (LEMS), Walking Index for SCI II Scale (WISCI II), Gait velocity, Step length and cadence assessment during the Ten-meter Walking Test, Timed Up and Go test (TUG).

1.     Real rTMS individuals experienced significantly less spasticity according to MAS scores at the end of the last intervention session compared to baseline (p=0.027) but sham rTMS group did not (p=0.066).

2.     Real rTMS individuals demonstrated significant improvements in LEMS scores at the end of the last intervention session compared to baseline (p=0.005) but sham rTMS group did not (p=0.258).

3.     No significant changes were observed within each group for WISCI II scores (p=0.68 and p=0.109 for real and sham rTMS respectively).

4.     Gait velocity, cadence, step length, and TUG significantly improved amongst real rTMS individuals at the end of the last intervention session in comparison to baseline (p=0.005, p=0.009, p=0.013, and p=0.017 respectively).

5.     Sham rTMS individuals only improved in step length and TUG after the last intervention session compared to baseline (p=0.018 and p=0.043 respectively).

Kumru et al. 2010

Spain

Case Control

N=21

Population: Mean age: 36.2 yr; Injury etiology: traumatic and non-traumatic SCI; Level of injury: C4-T2, AIS C/D; Mean time since injury: 7.3 mo.

Intervention: Cases (n=14)–5 days of excitability of the primary motor cortex with high frequency repetitive transcranial magnetic stimulation (rTMS) to the leg motor area (20 trains of 40 pulses at 20 Hz; intensity of 90% of resting motor threshold for the biceps brachii muscle); Controls (n=7)–Sham procedure.

Outcome Measures: Modified Ashworth Scale (MAS), Visual Analog Scale (VAS), Spinal Cord Injury Spasticity Evaluation Tool (SCI-SET).

1.    8/14 individuals receiving the intervention spontaneously reported improved sleep quality and longer uninterrupted sleep.

2.    Mean stimulation intensity used was 41.9±6.0% of maximal stimulator output.

3.    Spasticity was significantly reduced at the end of the first and the last intervention sessions from both lower extremities when compared with the baseline condition as measured by the MAS (p<0.006) and Visual Analog Scale (p<0.002); these effects were maintained 1 wk post intervention.

4.    According to SCI-SET, spasticity was reduced significantly after 5 days of intervention (p=0.003), and this improvement remained 1 wk post intervention.

Table 8 Systematic Reviews of Repetitive Transcranial Magnetic Stimulation for Reducing Spasticity

Author Year

Country
Research Design

Score
Total Sample Size

MethodsOutcome
Nardone et al. 2015

Austria

Review of published articles between 1966-2014

AMSTAR=4

N=49

 

Method: Comprehensive literature search with no language restrictions. Missing or incomplete data was obtained after direct contact with the authors of selected articles.

Databases: MEDLINE, EMBASE.

Level of evidence: No restrictions on research design were implemented. Only articles reporting data on studies using Transcranial Magnetic Stimulation (TMS) and Repetitive TMS (rTMS) on individuals with SCI were included.

Questions/measures/hypothesis:

1.     Examine the effectiveness of TMS/rTMS as a clinical tool after SCI.

2.     Examine the use of TMS/rTMS techniques to observe and map neural mechanisms and cortical exctiability post-SCI.

1.     Two studies revealed significant improvements in spasticity, focusing the intervention on leg motor areas of the brain was found to improve walking speed and spasticity of lower limbs.

2.     Pain relief and significant analgesic effects were found to be obtained after rTMS intervention.

3.     The use of sub-threshold TMS can also be used to study the mechanisms of reorganisation processes by inhibiting outgoing electromyography readings.

4.     TMS can enable mapping of motor cortical output by accurately assessing the number of cortical sites eliciting evoked potentials for a target muscle.

5.     Further studies are required to assess the safety and efficacy of TMS/rTMS with one study suggesting that high levels are required to obtain motor cortical excitability which can induce discomfort and pain in the patient.

Discussion

Nardone et al. (2014) completed a double blinded, sham controlled crossover RCT to evaluate the disynaptic reciprocal primary inhibition (i.e., mediated via pathway of muscle spindle 1a afferent to motoneurones of the antagonist muscle) of the soleus motoneurons in SCI study subjects. Study subjects were randomly allocated to receive either real rTMS (n=4) or a sham rTMS (n=5). Treatment was conducted daily over five days with real rTMS patients receiving two second duration bursts at 20 Hz with an interstimulus interval of 28 seconds for a total of 1600 pulses over 20 minuntes at an intensity of 90% of the resting motor threshold. After a four-week washout period, study subjects were crossed over, although only four of the five sham rTMS patients received real rTMS. Assessments were conducted at baseline and at initial, final, and one-week follow-up visits using the MAS, Spinal Cord Injury Assessment Tool for Spasticity (SCATS), monosynaptic test reflex responses (H-reflex), maximal H-reflex response (H-max), and maximal soleus motor action. Study results showed that spasticity was significantly reduced after real rTMS intervention, as measured by both MAS (p=0.0013) and SCATS (p=0.0008). MAS and SCATS values significantly decreased after the first treatment session (MAS: p<0.0001; SCAT: p<0.0001). MAS and SCAT scores at one-week follow-up were still significantly lower than baseline scores (MAS: p=0.0006; SCAT: p=0.0002). H-max/M-max ratio did not change significantly over the four assessments (p=0.17) among study subjects (controls not assessed for H-max/M-max). Reciprocal inhibition, according to H-reflex responses, was significantly modified in study subjects during real rTMS intervention (p=0.00004) compared to healthy controls. The conditioned H-reflex response significantly decreased after the first treatment session and from first to last treatment sessions (both p<0.0001). Conditioned H-reflex responses at one-week follow-up were still significantly lower than baselines scores (p<0.0001). The results of this study support and extend previous findings demonstrating the effects of rTMS on spasticity in SCI individuals.

Similarly, Benito et al. (2012) completed a double-blind sham controlled RCT (rTMS n=7, sham n=10) to study the effects of rTMS on spasticity in SCI. Three patients who received sham rTMS were crossed-over to receive real rTMS three weeks after completing the sham protocol. Real rTMS patients received two second bursts at 20 Hz (40 pulses/burst) with intervals of 28 seconds, for a total of 1800 pulses over 20 minuntes. The intensity of stimulation was set at 90% of the resting motor threshold. The study demonstrated that real rTMS resulted in significantly less spasticity according to MAS scores at the end of the last treatment session compared to baseline (p=0.027), but sham rTMS did not (p=0.066).

Kumru et al. (2010) examined the efficacy of rTMS on 15 individuals with incomplete SCI. rTMS was applied in two-second bursts at 20 Hz (40 pulses/burst) to the primary motor cortex over five days. Spasticity was significantly reduced at the end of the first and the last treatment sessions from both lower extremities when compared with the baseline condition as measured by the MAS (p<0.006). Additionally, unsolicited disclosures of improved sleep quality were reported by patients. These results remained one week post-treatment.

Nardone et al. (2015) completed a systematic review of published articles between 1966 and 2014 (n=49) using the MEDLINE, EMBASE Databases with no language and research design restrictions. Only articles reporting data on studies using Transcranial Magnetic Stimulation (TMS) and repetitive TMS (rTMS) on individuals with SCI were included. Nardone et al. (2015) sought to examine the effectiveness of TMS/rTMS as a clinical tool after SCI and examine the use of TMS/rTMS techniques to observe and map neural mechanisms and cortical excitability post-SCI. Two studies revealed significant improvements in spasticity; in particular, focusing treatment on leg motor areas of the brain was found to improve walking speed and spasticity of lower limbs. Additionally, pain relief was also reported post rTMS treatment.

Sub-threshold TMS can also be used to study the mechanisms of reorganisation processes by inhibiting outgoing electromyography readings. As well, TMS can enable mapping of motor cortical output by accurately assessing the number of cortical sites eliciting evoked potentials for a target muscle. Nardone et al. (2015) recommended that further studies are required to assess the safety and efficacy of TMS/rTMS as one study suggested that high levels of stimulation are required to obtain motor cortical excitability which can then induce discomfort and pain in the patient.

Conclusions

There is level 1a evidence (from two RCTs and one case control; Nardone et al. 2014; Benito et al. 2012; Kumru et al. 2010) that rTMS decreases spasticity and improves walking speed.

Repetitive transcranial magnetic stimulation may provide spasticity relief and improve walking speed over the short-term but long-term effectiveness is unknown