Transcutaneous spinal cord stimulation effects on spasticity in patients with spinal cord injury: A systematic review

Abstract

Context

Spasticity is one of the most prevalent impairments following spinal cord injury (SCI). It can lead to a decrease in the patient's functional level. Transcutaneous spinal cord stimulation (tSCS) has demonstrated motor function improvements following SCI. No systematic reviews were published examining the influences of tSCS on spasticity post-SCI.

Objectives

This review aimed to investigate the effects of tSCS on spasticity in patients with SCI.

Methods

PubMed, SCOPUS, PEDro, CINAHL, MEDLINE, REHABDATA, AMED, and Web of Science databases were searched until June 2021. The Physiotherapy Evidence Database (PEDro) scale was used to assess the methodological quality of the selected studies.

Results

Six studies met the inclusion criteria. Five studies were pilot studies, and one was a case series. The scores on the PEDro scale ranged from two to four, with a median score of four. The results showed heterogenous evidence for the effects of tSCS on spasticity reduction post-SCI.

Conclusions

TSCS appears safe and well-tolerated intervention in patients with SCI. The evidence for the effectiveness of tSCS on spasticity in chronic SCI patients is limited. Further randomized controlled studies are strongly needed to study the effects of tSCS on patients with SCI.

Introduction

Spinal cord injury (SCI) is a leading cause of disability and morbidity worldwide.¹ Spasticity occurs in the upper motor neuron injury (above T12/L1).² Approximately 70% of patients with SCI exhibit spasticity.³ Spasticity is characterized by increases in muscle tone, hyperreflexia, clonus sign, and muscle spasms, which can reduce a patient's functional level.^4–6

Spasticity is caused by lesions of descending pathways.⁷ It results from the loss of monoaminergic modulation of spinal interneurons and motoneurons. Also, it can result from plastic changes at the cellular level to compensate for the loss of these neuromodulators below the lesion level.^8,9 Consequences of spasticity are: Firstly, reduced depression of neurotransmitter release from Ia muscle spindle afferents upon their repeated activation.¹⁰ Secondly, hyper-excitability of interneurons that mediate polysynaptic excitation [9]. Thirdly, a decrease in the inhibitory capacity of postsynaptic inhibitory circuits.¹¹ And fourthly, an increase in motoneuronal excitability.¹² Morphological changes in muscles and connective tissue secondary to spastic conditions may further accentuate resistance to passive stretch.¹³

Medications such as Botulinum toxin and Baclofen are commonly used for reducing spasticity post-SCI.^14,15 However, common adverse effects for these agents include muscle weakness, malaise, and pain at the injection site.^14,15 Despite their widespread use, there is inadequate evidence to guarantee pharmacological agents for spasticity reduction.¹⁶ In the last decade, many physical therapy modalities were prescribed for reducing spasticity and improving functional ability in patients with SCI and other neurological disorders.^17–22 However, they have disadvantages such as time-consuming and high cost.

Transcutaneous spinal cord stimulation (tSCS) reported unprecedented motor function improvements following severe SCI.²³ The computational modeling,²⁴ human physiological studies,^25–27 and microdialysis techniques in animal experiments suggest that spinal cord stimulation can recruit local inhibitory spinal circuits through stimulation of afferent fibers and promote the release of inhibitory neurotransmitters.^28,29 TSCS increases spinal reflex activity through evoked Hoffmann-like reflex (H-reflex) activity that may result from activation of proprioceptive afferents within the dorsal roots.^30–32 The non-invasive spinal stimulation may also evoke motor outcomes by facilitating spinal and residual supraspinal motor pathways.^31,32 To date, there are no systematic reviews published examining the impacts of tSCS on spasticity post-SCI. Therefore, this systematic review aimed to investigate the effects of tSCS on spasticity in patients with SCI.

Methods

Search strategy

PubMed, SCOPUS, PEDro, CINAHL, MEDLINE, REHABDATA, AMED, and Web of Science databases were searched from inception to June 2021. The key search terms were: (“transcutaneous spinal cord stimulation” OR “tSCS” OR “spinal cord stimulation)” AND (“Spinal cord injuries [Mesh]” OR “SCI)” AND (“muscle spasticity [Mesh]” OR “muscle stiffness” OR “muscle hypertonia [Mesh]” OR “tone)” AND (Appendix A). Two authors independently identified the related studies according to the inclusion and exclusion criteria. The current study followed all guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) approach.³³ The process of study selection was presented in Figure 1.

Figure 1.

Summary of literature review process.

Selection criteria

Patients, Intervention, Control, Outcomes, and Study design (PICOS) approach was followed.³⁴ Studies were included in the systematic review if they (a) P: assessed patients with SCI; I: tSCS; C: compared with active, passive, or no control groups; O: examined spasticity; and S: any study design published in English. Studies were excluded if they (a) assessed patients with other neurological (i.e. traumatic brain injury, multiple sclerosis) or musculoskeletal (i.e. fractures) disorders, (b) used animal models, and (c) combined tSCS with other stimulation forms (i.e. tDCS, rTMS). Two authors independently screened the included studies by reading titles and abstracts of the extracted research papers. If the abstracts were ambiguous and had no sufficient details, the authors would read the full text to make the final decision. Disagreements between the authors were resolved by discussion with the third author.

Data extraction

Upon selection process, the following data and descriptive information were extracted: (a) study design, (b) characteristics of the study, (c) parameters of tSCS and treatment protocols, (d) outcomes for pre and post-treatment in experimental and control groups, and (e) harm or adverse effects. The data were not pooled for meta-analysis because of the heterogeneity and the inability to contact the authors of the included studies.

Quality assessment

Two authors evaluated the methodological quality of the included studies using the Physiotherapy Evidence Database scale (PEDro). It provides a summary of the internal and external validity of the studies.³⁵ Four items of the PEDro scale have been validated, while the other points have face validity.³⁶ As well, acceptable inter-rater reliability has been verified.^35,37 Table 1 displays the methodological quality scores for the included studies.

Table 1.

Study characteristics.

Study	Participants characteristics and study design	Protocol	Intervention	Adverse effects
Hofstoetter et al. 201438	Study design: Case series Sample size: 3 Sex (M/F): 2/1 Age (Mean): 32.7 ASIA: D Neurological level: C5, T9 Time since injury (months): >12	Device: Schwamedico GmbH, Ehringshausen, Germany Size (cm2): 25 Frequency (Hz): 50 Pulse width (ms): 2 biphasic rectangular pulses Duration (min): 30 Sessions (n): 1	Single session of tSCS Two interconnected stimulating skin electrodes were placed paraspinally at the T11/T12 vertebral levels, and two rectangular electrodes (8 × 13 cm) on the abdomen for the reference	No
Freyvert et al. 201839	Study design: Pilot Sample size: 6 Sex (M/F): 4/2 Age (Mean): 19.1 ASIA: B Neurological level: C2-C6 Time since injury (months): >12	Device: NA Intensity (mA): 20–100 Frequency (Hz): 5–30 Duration: 60–120 Sessions (n): NS/6 weeks	tSCS + Drug (buspirone) + Grip strength exercises Cathode was placed over C5 and reference electrode was placed over the anterior superior iliac spine	No
Sayenko et al. 201840	Study design: Pilot Sample size: 15 Sex (M/F): 12/3 Age (Mean): 31.2 ASIA: A,B,C Neurological level: C4-T2 Time since injury (months): >12	Device: A custom-built constant current stimulator Intensity (mA): 150 Current density (mA/cm2): 15 Size (cm2): 10 Pulse width (ms):1 monophasic pulses Frequency (Hz): 0.2–30 Duration (min): 120 Sessions (n): 12 3/wk for 4 wks	tSCS + Postural control exercises Cathode: between the spinous processes of the T11-T12 or L1-L2 vertebrae Anode: over the iliac crests	No
Hofstoetter et al. 202041	Study design: Pilot Sample size: 12 Sex (M/F): 9/3 Age (Mean): 41.3 ASIA: A, C, D Neurological level: C4-T7 Time since injury (months): >12	Device: Schwamedico GmbH, Ehringshausen, Germany Pulse width (ms): 1 biphasic rectangular pulses Size (cm2): 25 Frequency (Hz): 50 Duration: 30 Sessions (n): 1	Single session of tSCS Two interconnected stimulating skin electrodes were placed paraspinally at the T11/T12 vertebral levels, and two rectangular electrodes (8 × 13 cm) on the abdomen for the reference	No
Inanici et al. 202142	Study design: Pilot Sample size: 6 Sex (M/F): 4/2 Age (Mean): 42 ASIA: C3-C5 Neurological level: B,C,D Time since injury (months): >12	Device: now ONWARD Medical BV, Eindhoven, Netherlands Intensity (mA): 0–120 Size (cm2): 6 Frequency (Hz): 30 Duration (min): 120 Sessions (n): 8	tSCS + 24-session Upper extremity motor training Cathodes: were placed midline on the skin of the neck, one above and one below the injury level Anodes: were placed symmetrically over the anterior iliac crests of pelvis.	No

NS: Not Specified, M/F: Male/Female, tSCS: transcutaneous spinal cord stimulation.

Results

Search strategy

An electronic search of PubMed (yielding 23 articles), SCOPUS (41), PEDro (2), REHABDATA (17), MEDLINE (12), CINAHL (18), AMED (8), and Web of Science (60) produced a total of 181 citations. After removing duplicates, 139 citations were reviewed. Of those, 122 publications were excluded because their abstracts showed that they did not match the inclusion criteria. After that, seventeen publications were subjected to more detailed analysis because the abstracts did not reveal the inclusion criteria. Subsequently, twelve articles were eliminated because they are not experimental studies and assessed other motor impairments. A total of five studies were identified for the inclusion criteria in this systematic review. The process of article selection for systematic review was displayed in Figure 1.

Study characteristics

Participants

A total of forty-two patients were included in this analysis, 26.20% of whom were females. The mean age for all patients was 34.01 years old. In terms of the injury severity, two studies included patients with incomplete SCI with grade B³⁸ and grade D on the Americans Spinal Cord Injury Association (ASIA) scale,³⁹ and three studies included patients with mixed SCI (i.e. complete and incomplete) with various grades (i.e. A, B, C, D).^40–42 Concerning the injury level, the selected studies included SCI patients with an injury level (C3-T9).^38–42 All the selected studies included patients with chronic SCI (>12 months). The study characteristics were presented in Table 1.

Intervention

Five studies were met the inclusion criteria. Four studies were pilot studies [39–42], and one was a case series.³⁸ Two studies administrated a single session of tSCS on patients with SCI using (SchwamedicoGmbH, Ehringshausen, Germany) stimulator for 30 minutes.^38,41 Two interconnected stimulating skin electrodes were placed paraspinally at the T11/T12 vertebral levels and two rectangular electrodes (8 × 13 cm) on the abdomen for reference. Both studies used active electrode sizes of 25 cm², frequencies of 50 Hz, and 1–2 ms biphasic rectangular pulses.

In the study of Freyvert et al. (2018), the participants received combined tSCS, drug (buspirone), and grip strength exercises intervention for 60–120 minutes over six weeks, with no specific session number. The type of tSCS device was not reported in the study. The cathodes were placed over the C5 of a spine, while the anodes were placed over the anterior superior iliac spine as a reference. The intensity was set at 20–100 mA and frequency at 5–30 Hz.³⁹

Moreover, the participants in the study by Sayenko et al. (2018) received tSCS plus postural control exercises intervention using a custom-built constant current stimulator for 30 minutes, three times per week, for four weeks. The cathodes were placed between the spinous processes of the T11-T12 or L1-L2 vertebrae, while the anodes were placed over the iliac crests as a reference. The size of the active electrodes that were used is 10 cm², the pulse width was 1 monophasic pulse, the current density was 15 mA/cm², the intensity was 150 mA, and the frequency was 0.2–30 Hz.⁴⁰

Finally, in the study of Inanici et al. (2021), the participants received eight sessions of tSCS using (now ONWARD Medical BV, Eindhoven, Netherlands) device plus twenty-four sessions of upper extremity motor training. The session duration was 120 minutes each. The tSCS was administrated a single time per week over two months. The upper extremity motor training was applied three times weekly over two months. In the tSCS treatment session, the cathode electrodes were placed midline on the skin of the neck, one above and one below the injury level, while the anodes were placed symmetrically over the anterior iliac crests of the pelvis as a reference. The size of active electrodes was 6 cm², the intensity was set at 0–120 mA, and frequency at 30 Hz.⁴²

Outcome measures

Except for the study of Hofstoetter et al. (2014),³⁸ the selected studies used the Modified Ashworth Scale (MAS) to assess spasticity in patients with SCI [39–42]. Hofstoetter et al. (2014) used the index of spasticity derived from the pendulum test³⁸ (Table 2).

Table 2.

Outcome measures.

Study	Outcome measure	Time of assessment	Intervention outcomes	Results
Hofstoetter et al. 201438	Index of spasticity-pendulum test	At baseline and post intervention	Pre: 0.8 ± 0.4 Post: 0.9 ± 0.3	Spasticity of both quadriceps was reduced after tSCS
Freyvert et al. 201839	MAS	At baseline and post intervention	Pre: 2 Post: 1+	Spasticity of both upper extremities was reduced after tSCS
Sayenko et al. 201840	MAS	At baseline and post intervention	Pre: 0 Post: 1+	Lower extremities muscle tone increased in severe paralyzed patients
Hofstoetter et al. 202041	*MAS	T0: baseline, T1: post intervention, and T2: 2 hours post intervention	T0: 31.75 (8.63–37.38) T1: 23.50 (14.63–32.25) T2: 24.75 (13.25–30.88)	Spasticity in lower extremities was reduced after tSCS
Inanici et al. 202142	**MAS	At baseline, post intervention, and follow-up	3.5 ± 3.0	Reduction in upper extremity spasticity was progressive throughout stimulation sessions and maintained up to 10–15 days after stimulation treatment ended

MAS: Modified Ashworth Scale, tSCS: transcutaneous spinal cord stimulation.

*Median (interquartile range (IQR)).

**The average decrease in MAS score.

Effects of tSCS on spasticity after SCI

In two studies, both quadriceps³⁸ and lower extremities muscle spasticity⁴¹ were reduced after the tSCS intervention. Moreover, in the other two studies, the participants showed a reduction in the upper extremities’ spasticity following combined tSCS interventions.^39,42 The spasticity reduction was maintained up to 10–15 days after the intervention.⁴² Finally, in the study by Sayenko et al. (2018), the lower extremities muscle tone wan increased in severe paralyzed SCI patients after tSCS plus postural control exercises intervention.⁴⁰

Adverse effects

The included studies did not show any adverse effects or harmful complications in patients with SCI after the tSCS interventions.^38–42

Quality assessment

The score on the PEDro scale ranged from two to four, with a median of four. Overall, three studies met two criteria,^38,41,42 and two met four criteria^39,40 for low risk of bias. Table 3 displays the methodological quality scores for the included studies.

Table 3.

Methodological quality scores.

Study	Randome allocation	Concealed allocation	Groups similar at baseline	Participant blinding	Therapist blinding	Assessor blinding	<15% dropouts	Intention to treat analysis	Between-group differences reported	Point estimate and variability reported	Total (0–10)
Hofstoetter et al. 201438							*	*			2
Freyvert et al. 201839				*		*	*	*			4
Sayenko et al. 201840				*		*	*	*			4
Hofstoetter et al. 202041							*	*			2
Inanici et al. 202142							*	*			2
Median = 4

*Low risk of bias.

Discussion

To our knowledge, this is the first systematic review examining the impacts of tSCS on spasticity post-SCI. The main findings based on six studies showed heterogenous evidence for the positive effects of tSCS on spasticity in patients with SCI. Similarly, Hofstoetter et al. (2021) demonstrated a significant reduction in spasticity in a patient with multiple sclerosis after receiving tSCS.⁴³ Megía García et al. (2020) showed improvements in motor functions, including voluntary movement, muscle strength, and function, in patients with chronic SCI after the tSCS intervention.⁴⁴

Presynaptic inhibition from homonymous and heteronymous nerves is reduced after SCI,⁴⁵ thus the post-activation depression of repetitively activated Ia afferents.^9,10,46 Dysfunction in these presynaptic regulatory mechanisms after SCI results in an increased excitatory neurotransmitter release from Ia afferents. It contributes to the exaggerated stretch reflexes and hypertonia associated with spasticity.^9,14 The continuous generation of Ia activity in multiple roots by tSCS, especially in those containing afferents from flexor nerves, would increase the level of presynaptic inhibition distributed to Ia terminals connected with ipsilateral limb muscles.^26,47,48 Further, tSCS increases spinal reflex activity through evoked Hoffmann-like reflex activity resulting from activation of proprioceptive afferents.^30–32

The MAS⁴⁹ and the pendulum tests were used in the selected studies to assess spasticity in patients with SCI. The pendulum test correlates with the MAS in patients with SCI.⁵⁰ These measures were complemented by the assessments of other presentations of spasticity, such as clonus and muscle spasms.⁹ The latter being pathophysiologically distinct from exaggerated stretch reflexes.⁹ Except for the study of Sayenko et al. (2018),⁴⁰ the selected studies showed positive effects of the tSCS intervention on spasticity in patients with chronic SCI.^38,39,41,42 The patients in the selected studies were chronic (>6 months) with various ASIA scale grades and injury levels. The session duration and frequency for the selected studies were 30–120 minutes per session, with sessions range 1–12 sessions. The treatment dosage, including the electrode site, intensity, frequency, pulse width, and electrode size was varied between the selected studies. It makes determining the population who most likely would benefit from the intervention, long-term effects, and the optimal treatment dosage is difficult.

The current review included four pilot studies and one case series with a methodological quality ranged from two to four, with a median of four. The methodological quality for the included studies was poor on the PEDro scale (range 2–4); hence, the clinical effects cannot be confirmed. Besides, the sample size for the selected studies was small (>20). As a small sample size, the calculation of the significant difference was difficult.⁵¹ Thus, we cannot generalize and confirm the effects of the tSCS treatment in patients with SCI. Due to the insufficiency of randomized controlled trials, small sample sizes, poor methodological quality, and various tSCS treatment protocols used in the treatment of patients with SCI, it makes us unable to recognize the actual impacts of the tSCS treatment on spasticity in patients with SCI as it has a negative impact on patient's quality of life. Finally, as the studies included only chronic SCI, so we are unable to clarify the effects of tSCS on spasticity in those with acute and subacute SCI. Further high-quality studies with a large sample size and long-term follow-up are strongly warranted.

The present study has some limitations. First, the selected studies were published in English. Thus, studies published in alternate languages were not included in the analysis. Second, it included only pilot studies and case series due to the lack of randomized clinical trials on the present subject. Finally, the meta-analysis was not performed due to the heterogeneity between the included studies.

Conclusion

The tSCS intervention is safe and feasible in patients with SCI. The evidence for the effects of tSCS on spasticity in patients with SCI is limited. Further high-quality studies are strongly needed to study the impact of tSCS on patients with SCI.

Disclaimer statements

Funding The authors have no source of funding.

Acknowledgements None

Conflict of interest The authors have no potential conflicts of interest to disclose.

Appendix A: Search strategy in MEDLINE

1. Spinal cord injuries (MeSH).

2. SCI

3. 1 or 2

4. transcutaneous spinal cord stimulation

5. tSC

6. 4 or 5

7. Muscle spasticity (MeSH)

8. Muscle stiffness

9. Muscle hypertonia (MeSH)

10. Tone

11. 7 or 8 or 9

12. 3 and 6 and 11