Sage Journals: Discover world-class research

Abstract

Introduction

Repetitive peripheral sensory stimulation (RPSS) followed by 4-hour task-specific training (TST) improves upper limb motor function in subjects with stroke who experience moderate to severe motor upper limb impairments. Here, we compared effects of RPSS vs sham followed by a shorter duration of training in subjects with moderate to severe motor impairments in the chronic phase after stroke.

Methods

This single-center, randomized, placebo-controlled, parallel-group clinical trial compared effects of 18 sessions of either 1.5 h of active RPSS or sham followed by a supervised session that included 45 min of TST of the paretic upper limb. In both groups, subjects were instructed to perform functional tasks at home, without supervision. The primary outcome measure was the Wolf Motor Function Test (WMFT) after 6 weeks of treatment. Grasp and pinch strength were secondary outcomes.

Results

In intention-to-treat analysis, WMFT improved significantly in both active and sham groups at 3 and 6 weeks of treatment. Grasp strength improved significantly in the active, but not in the sham group, at 3 and 6 weeks. Pinch strength improved significantly in both groups at 3 weeks, and only in the active group at 6 weeks.

Conclusions

The between-group difference in changes in WMFT was not statistically significant. Despite the short duration of supervised treatment, WMFT improved significantly in subjects treated with RPSS or sham. These findings are relevant to settings that impose constraints in duration of direct contact between therapists and patients. In addition, RPSS led to significant gains in hand strength.

Trial Registry Name: Peripheral Nerve Stimulation and Motor Training in Stroke Clinical Trials.gov identifier: NCT0265878 https://clinicaltrials.gov/ct2/show/NCT02658578

Keywords

upper extremity cerebrovascular accident rehabilitation sensory neuromodulation

Introduction

Increase in sensory input from the paretic hand in the form of repetitive peripheral sensory stimulation (RPSS) enhances motor performance in subjects with mild to moderate impairments.¹ Also, Carrico et al.² reported significantly bigger improvements in Wolf Motor Function Test (WMFT), Fugl–Meyer Assessment (FMA), and Action Research Arm Test after active RPSS compared to sham in subjects with moderate to severe motor impairments. Active RPSS or sham was administered for 2 h prior to 4 h intensive task-oriented motor (TOT) training over 10 days. Implementation of this protocol may be challenging in clinical practice, particularly in developing countries where most strokes occur.³

Another intervention that may boost effects of training on amelioration of upper limb motor function is functional electrical stimulation (FES).^4-9 Here, we compared effects of shorter durations of active RPSS or sham combined with FES and task-specific training (TST) in subjects with moderate to severe upper limb impairments in the chronic phase after stroke.

Methods

This single-center, randomized, placebo-controlled, parallel-group clinical trial compared effects of 18 sessions of active and sham RPSS followed by FES and TST of the paretic upper limb. Outcome assessors were blinded to group assignment and participants were naive to the experimental hypothesis. The protocol has been previously published.¹⁰

Subjects

Adults with stroke (> 6 months) and upper limb FMA motor scores between 7 and 50 were included. For details, see Ref. [4].

Interventions

In the active group, 1.5 hours of RPSS of the median, ulnar, and radial nerves was performed.¹⁰ In the sham group, the tibial, superficial peroneal, and sural nerves were stimulated. Average intensities of nerve stimulation (% of sensory threshold) were as follows: In the active group, 213±95% (median), 193±88% (ulnar), and 165±79% (radial). In the sham group, 92.6±52% (tibial), 174.8±48.6% (superficial peroneal), and 173.8±45.6% (sural). FES for 30 minutes, TST for 45 minutes, and instructions to perform functional tasks at home were administered to both groups.¹⁰ Additional information is reported in Supplementary Materials.

Outcomes

The primary outcome was the WMFT (WMFT-TIME and functional assessment scale, WMFT-FAS) after 6 weeks of treatment.

The secondary outcomes¹⁰ were the WMFT at 3 weeks as well as the following at 3 and 6 weeks: grasp and pinch strength; Motor Activity Log; active range of motion (ROM) of wrist extension and flexion; modified Ashworth scale; FMA; Barthel Index (BI); Stroke Impact Scale (SIS); Beck Depression Inventory Short Form (BDI).

Ethics

The protocol was approved by the institutional ethics committee (CAAE 70163217.5.0000.0068). All subjects provided informed consent.¹⁰

Sample Size

Our goal was to include 40 subjects in the study.¹⁰

Analysis

The data were analyzed with a generalized estimating equations¹¹ models with factors GROUP (active or sham) and TIME (baseline, 3, 6 weeks). All post hoc analyses were Bonferroni-corrected. Intention-to-treat (ITT) analysis was performed with and without the Last Observation Carried Forward (LOCF) for missing data. Per protocol (PP) analysis excluded subjects who participated in <80% treatment sessions. P-values ≤ .025 were considered statistically significant because 1 interim analysis was performed. Analyses of secondary outcomes were exploratory and not corrected for multiple comparisons. Additionally, we assessed attainment of Minimal Clinically Important Differences (MCID)¹² for WMFT-TIME (1.5 s) and WMFT-FAS (.2). Effect sizes (ES) were assessed with Cohen’s d.

Results

The flow of subjects is shown in Supplementary Material. The study was stopped early (n = 38) due to the COVID-19 pandemic. Characteristics of subjects (n = 38; Table 1) and attrition rates (29.1%, Supplementary Material) were comparable in the active and sham groups. For debriefing and adverse events, see Supplementary Material.

Table 1.

Participant Characteristics

Characteristic	Active (19)	Sham (19)	P-Value
Male, n (%)	10 (52.6)	11 (57.9)	.744^a
Age (years, mean ± SD)	50.3 ± 13.9	51.5 ± 15.3	.809^b
Education, n (%)			.888^c
1–4 years+	2 (10.5)	3 (15.8)
5–8 years	3 (15.8)	3 (15.8)
9 or + years	14 (73.7)	13 (68.4)
White, n (%)	6 (31.6)	10 (52.6)
Hypertension, n (%)	10 (52.6)	10 (52.6)	> .999^a
Diabetes mellitus, n (%)	2 (10.5)	4 (21.1)	.660^d
Charlson comorbidity index (median, range)	2 (1-5)	2 (1-7)	.665^e
Oldfield inventory (median, range)	100 (-100-100)	100 (38-100)	.729^e
Time since stroke, months (median, range)	18 (6-205)	36 (6-180)	.370^e
Thrombolysis/thrombectomy, n (%)	2 (10.5)	2 (10.5)	1.00^d
Fugl–meyer upper limb motor assessment (median, range)	41 (14-53)	35 (20-50)	.339^e
Wolf motor function test, time (seconds) (median, range)	58.3 (12.5-105.4)	58.7 (4.6;-113.2)	.506^e
Wolf motor function test, functional ability scale (median, range)	1.53 (.53-2.67)	1.4 (.27-3.27)	.506^e
Motor evoked potentials, n (%)	14 (77.8)	10 (66.7)	.697^d
Lesion side, right/left, n (%)	11 (57.8)/8 (42.1)	10 (52.6)/9 (47.3)	.744^a
Lesion site
Corticosubcortical	8 (42.1)	12 (63.2)	.194^a
Involved M1	5 (26.3)	7 (38.9)	.660^d
Involved internal capsule	14 (73.7)	11 (61.1)	.414^a
CST lesion load (%)	8.6 ± 11.4	8.7 ± 11.1	.878^e
Stroke etiology–TOAST			.117^c
Large-artery atherosclerosis	2 (14.2)	0 (0)
Small-vessel occlusion	3 (21.3)	1 (6.7)
Other determined etiology	1 (7.1)	0 (0)
Undetermined etiology^f	0 (0)	3 (20)
Undetermined etiology^g	8 (57.1)	11 (73.3)

SD: standard deviation. IQR: interquartile range. TOAST: according to criteria from the Trial of Org 10172 in Acute Stroke Treatment, applied to ischemic strokes.

^aChi-square test.

^bStudent’s t.

^cLikelihood ratio test.

^dFisher’s exact test.

^eMann–Whitney test.

^fComplete investigation.

^gIncomplete investigation. CST: corticospinal tract. For assessment of CST lesion load, please see the Supplementary Material.

Intention-to-treat results without LOCF are shown in Table 2 and Supplementary Material. There were significant interactions between “group” and “time” for WMFT-TIME, pinch, and grasp strength. WMFT-TIME improved significantly in both active and sham groups at 3 and 6 weeks compared to baseline (Supplementary Material) but there were no significant between-group differences. ES at 6 weeks were .22 in the active and .32 in the sham group.

Table 2.

Results of Intention-to-Treat Analysis Without Last Observation Carried Forward. Medians and Ranges are Shown.

Outcome	Active Group (n = 19)			Sham Group (n = 19)			GEE Results (P-values)
Outcome	Baseline	3 weeks	6 weeks	Baseline	3 weeks	6 weeks	Group	Time	Interaction
WMFT-TIME	58.3 (12.5; 105.4)	52.3 (8.4; 98.5)	48.9 (5.9; 99.4)	58.7 (4.6; 113.2)	57.9 (4.6; 105.6)	60.6 (4.4; 97.3)	.345	<.001	<.001
WMFT-FAS	1.53 (.53; 2.67)	1.87 (.67; 3.73)	2.07 (.53; 3)	1.4 (.27; 3.27)	1.67 (.47; 2.93)	1.77 (.67; 3.2)	.268	<.001	.074
Grasp force (N)	70.6 (23.5; 164.8)	76.5 (11.8; 205.9)	70.7 (23.5; 213.8)	68.6 (31.4; 168.7)	100 (36.3; 190.2)	97.1 (41.2; 194.2)	.774	.004	.001
Pinch force (N)	29 (10; 58.6)	33.5 (8.8; 85.9)	37.3 (10.8; 81.6)	32.2 (9.9; 70.1)	36.3 (19.6; 76.5)	38.7 (19; 70.3)	.959	<.001	<.001

GEE = generalized estimating equations. WMFT-TIME = Wolf Motor Function Test, time. WMFT-FAS = Wolf Motor Function Test, Functional Assessment scale. N = Newtons.

Grasp strength improved significantly in the active but not in the sham group at 3 and 6 weeks. ES at 6 weeks was .35 in the active group. Pinch strength improved significantly in both groups at 3, and only in the active group at 6 weeks (ES, .61) (Figure 1).

Figure 1.

Changes in grasp strength at 3 and 6 weeks, normalized to baseline, in each subject in the active (left) and sham (right) groups. *P ≤ .025.

There were significant effects of time in both groups, with no interactions for WMFT-FAS (ES: .3 active, .31 sham), FMA, Minimum Acceptance Level, Read-Only Memory of wrist extension, Manufacturing Advisory Service, BI, some SIS domains, and BDI (Supplementary Material).

Intention-to-treat with LOCF and PP results were similar to results of ITT without LOCF, except for a lack of significant effects for grasp at 6 weeks in the active, and for pinch at 3 weeks in the sham group (Supplementary Material).

At 6 weeks, average changes in scores surpassed MCID for WMFT-TIME in both groups, and for WMFT-FAS only in the active group (Supplementary Material). MCID for WMFT-FAS was reached in 71.4% of subjects in the active, and in 42.9% in the sham group.

Post hoc analysis (Supplementary Material) was performed to assess the relation between the presence of Motor Evoked Potentials in the abductor pollicis brevis (MEPs), or the corticospinal tract lesion load at baseline (Table 1), and changes in the primary outcome at 6 weeks. According to ITT analyses, subjects with MEPs improved more than those without. Lesion load was inversely correlated with improvement, but the results were not statistically significant.

Discussion

The main result of this study was that WMFT improved significantly in both groups after 18 sessions of treatment (2.75 hsession). MCID was reached, on average, in both groups for WMFT-TIME and only in the active group for WMFT-FAS. Changes were greater in both groups compared to those described by Carrico et al² (for comparisons, see Supplementary Material). Two differences between patients´characteristics may have contributed to these findings: subjects randomized by Carrico et al² had more severe motor impairments and were, on average, 10 years older than those included in our study.

In addition, in contrast with our findings of significant decreases in WMFT in the active as well as in the sham group, Carrico et al (n = 36) reported significant decreases only in the active group.² Likewise, in a larger study that delivered 10 sessions of 4 hour intensive TOT following active RPSS (n = 33) or sham (n = 22), WMFT-TIME only improved significantly in the active group.¹³ In both studies, no instructions to perform tasks at home were given. Conversely, another study from the same group¹⁴ (n = 19) found significant improvements in WMFT-TIME after active RPSS or sham followed by 4-hour modified constraint induced-therapy (CIMT) that included instructions to perform tasks at home and wear a mitt on the unaffected arm for 90% of waking hours. Together with the results of the present study, these findings suggest that the performance of motor tasks at home may have led to gains in WMFT-TIME in both groups. Moreover FES, delivered to both groups in the present study but not in previous work, may have enhanced effects of TST. More work is required to assess whether FES can augment effects of RPSS or training in subjects with moderate to severe upper limb impairments after stroke.

Modest improvement at 6 weeks in pinch and grasp strength in the active but not in the sham group according to ITT analysis were consistent with reports of increase in force after single sessions of peripheral stimulation^1,15 or 2 weeks of CIMT.¹⁶

The main weakness of this study is the >20% attrition rate in both groups. Compliance with rehabilitation sessions represents a challenge to clinical trials and routine patient care. Furthermore, despite the results of debriefing, subjects may have suspected that they were in an active or sham group. We opted for lower limb stimulation as previously described¹⁰ in order to mimic active treatment, without the same effect. Further studies are necessary to compare patients’ perceptions about different types of controls for RPSS.

Our hypothesis-generating findings should encourage larger trials to assess the efficacy of RPSS on strength in the chronic phase after stroke. Despite attrition and the shorter duration of supervised training compared to traditional CIMT,¹⁷ this study showed clinical benefit in WMFT scores with an intervention of shorter duration than prior reports in the literature in subjects with comparable motor impairments. It remains to be confirmed if the presence of MEPs in hand muscles may help select subjects more likely to respond to training.

Improvements in WMFT scores after 3 weeks of treatment indicate that a closer evaluation of effect time-course across a treatment regimen may shed new light about the possibility of decreasing the number of sessions as well as the duration of interventions, while still deriving clinical benefit. If confirmed by larger trials, these results will have implications to settings of limited duration of direct contact between therapists and patients—or instance, due to costs of therapy or concerns about SARS-CoV-2 transmission.

Supplemental Material

sj-pdf-1-nnr-10.1177_15459683211046259 – Supplemental Material for Repetitive Peripheral Sensory Stimulation as an Add-On Intervention for Upper Limb Rehabilitation in Stroke: A Randomized Trial

Supplemental Material, sj-pdf-1-nnr-10.1177_15459683211046259 for Repetitive Peripheral Sensory Stimulation as an Add-On Intervention for Upper Limb Rehabilitation in Stroke: A Randomized Trial by Adriana B. Conforto, André G. Machado, Nathalia H. V. Ribeiro, Ela B. Plow, Sook-Lei Liew, Claudia da Costa Leite, Artemis Zavaliangos-Petropulu, Isabella Menezes, Sarah M. dos Anjos, Rafael Luccas, Paul Hunter Peckham and Leonardo G. Cohen in Neurorehabilitation and Neural Repair

Footnotes

Acknowledgments

We thank Danielle Pires, Paloma de Freitas and Eduardo A. Mello for participation in data collection.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Machado reports other from Enspire DBS, outside the submitted work. In addition, Dr. Machado has a patent 8,190,263 issued to Cleveland Clinic. Dr. Liew reports grants from the National Institutes of Health during the conduct of the study. Dr. Conforto, Dr. Ribeiro, Dr. Menezes, Dr. Dos Anjos and Dr. Luccas received funding from the National Institutes of Health (grant R01NS076348-01) during the conduct of the study. The other authors declare that there are no conflicts of interest.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by the National Institute of Neurological Disorders and Stroke, National Institutes of Health (grant R01NS076348-01). The sponsor had no roles in study design, collection, analysis and interpretation of data, in the writing of this report and in the decision to submit the article for publication.

ORCID iDs

Adriana B. Conforto

Sook-Lei Liew

Supplementary Material

Supplementary material for this article is available online.

References

Conforto

Dos Anjos

Bernardo

, et al. Repetitive peripheral sensory stimulation and upper limb performance in stroke: A systematic review and meta-analysis. Neurorehabilitation and Neural Repair. 2018;32:863-871. DOI: 10.1177/1545968318798943.

Carrico

Chelette

II Westgate

, et al. Nerve stimulation enhances task-oriented training in chronic, severe motor deficit after stroke: A randomized trial. Stroke. 2016;47:1879-1884. DOI: 10.1161/STROKEAHA.116.012671.

Krishnamurthi

Ikeda

Feigin

. Global, regional and country-specific burden of ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage: A systematic analysis of the global burden of disease study 2017. Neuroepidemiology. 2020;54:171-179. DOI: 10.1159/000506396.

Kimberley

Lewis

Auerbac

Dorsey

Lojovich

Carey

. Electrical stimulation driving functional improvements and cortical changes in subjects with stroke. Exp Brain Res. 2004;154:450-460. DOI: 10.1007/s00221-003-1695-y.

Alon

Levitt

McCarthy

. Functional electrical stimulation enhancement of upper extremity functional recovery during stroke rehabilitation: A pilot study. Neurorehabil Neural Repair. 2007;21:207-215. DOI: 10.1177/1545968306297871.

Sullivan

Hedman

. A home program of sensory and neuromuscular electrical stimulation integrated with upper-limb task practice in a patient who is stable after a stroke. Phys Ther. 2004;84:1045-1054.

Vafadar

Côté

Archambault

. Effectiveness of functional electrical stimulation in improving clinical outcomes in the upper arm following stroke: A systematic review and meta-analysis. Biomed Res Int. 2015;2015:729768. DOI: 10.1155/2015/729768.

Eraifej

Clark

France

Desando

Moore

. Effectiveness of upper limb functional electrical stimulation after stroke for the improvement of activities of daily living and motor function: A systematic review and meta-analysis. Syst Rev. 2017;6:40. DOI: 10.1186/s13643-017-0435-5.

Howlett

Lannin

Ada

McKinstry

. Functional electrical stimulation improves activity after stroke: A systematic review with meta-analysis. Arch Phys Med Rehabil. 2015;96:934-943. DOI: 10.1016/j.apmr.2015.01.013.

10.

Conforto

Machado

Menezes

, et al. Treatment of upper limb paresis with repetitive peripheral nerve sensory stimulation and motor training: Study protocol for a randomized controlled trial. Front Neurol. 2020;11:196. DOI: 10.3389/fneur.2020.00196.

11.

Liang

Zeger

. Longitudinal data analysis using generalized linear models. Biometrika. 1986;73:13-22. DOI: 10.1093/biomet/73.1.1312.

12.

Lin

Hsieh

Chen

Jang

Liu

. Minimal detectable change and clinically important difference of the wolf motor function test in stroke patients. Neurorehabil Neural Repair. 2009;23(5):429-434. DOI: 10.1177/1545968308331144.

13.

Carrico

Westgate

Powell

, et al. Nerve stimulation enhances task-oriented training for moderate-to-severe hemiparesis 3-12 months after stroke: A randomized trial. Am J Phys Med Rehabil 2018;97:808-815. doi:10.1097/PHM.0000000000000971.

14.

Carrico

Chelette

Westgate

Salmon-Powell

Nichols

Sawaki

. Randomized trial of peripheral nerve stimulation to enhance modified constraint-induced therapy after stroke. Am J Phys Med Rehabil 2016;95:397-406. doi:10.1097/PHM.0000000000000476.

15.

Olsen

Signal

Niazi

, et al. Peripheral electrical stimulation paired with movement-related cortical potentials improves isometric muscle strength and voluntary activation following stroke. Front Hum Neurosci. 2020;14:156. DOI: 10.3389/fnhum.2020.00156.

16.

Alberts

Butler

Wolf

. The effects of constraint-induced therapy on precision grip: A preliminary study. Neurorehabil Neural Repair. 2004;18:250-258. DOI: 10.1177/154596830427137017.

17.

Wolf

Winstein

Miller

, et al. Excite investigators. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: The excite randomized clinical trial. J Am Med Assoc. 2006;296:2095-2104. DOI: 10.1001/jama.296.17.2095.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.74 MB