753681

research-article2018
NNRXXX10.1177/1545968317753681Neurorehabilitation and Neural RepairAlmuklass et al

Original Research Article

Neurorehabilitation and

Pulse Width Does Not Influence the Gains

Neural Repair
1­–10
© The Author(s) 2018
Achieved With Neuromuscular Electrical Reprints and permissions:
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Stimulation in People With Multiple DOI: 10.1177/1545968317753681

https://doi.org/10.1177/1545968317753681
journals.sagepub.com/home/nnr

Sclerosis: Double-Blind, Randomized Trial

Awad M. Almuklass, PhD1,2 , Leah Davis, MS1, Landon D. Hamilton, MA1,

Jeffrey R. Hebert, PhD3, Enrique Alvarez, MD, PhD3, and Roger M. Enoka, PhD1

Abstract
Background. Multiple sclerosis (MS) eventually compromises the walking ability of most individuals burdened with the
disease. Treatment with neuromuscular electrical stimulation (NMES) can restore some functional abilities in persons with
MS, but its effectiveness may depend on stimulus-pulse duration. Objective. To compare the effects of a 6-week intervention
with narrow- or wide-pulse NMES on walking performance, neuromuscular function, and disability status of persons with
relapsing-remitting MS. Methods. Individuals with MS (52.6 ± 7.4 years) were randomly assigned to either the narrow-pulse
(n = 13) or wide-pulse (n = 14) group. The NMES intervention was performed on the dorsiflexor and plantar flexor muscles
of both legs (10 minutes each muscle, 4 s on and 12 s off) at a tolerable level for 18 sessions across 6 weeks. Outcomes
were obtained before (week 0) and after (week 7) the intervention and 4 weeks later (week 11). Results. There was no
influence of stimulus-pulse duration on the outcomes (P > .05); thus, the data were collapsed across groups. The NMES
intervention improved (P < .05) gait speed and walking endurance, dorsiflexor strength in the more-affected leg, plantar
flexor strength in the less-affected leg, force control for plantar flexors in the less-affected leg, and self-reported levels of
fatigue and walking limitations. Conclusion. There was no influence of stimulus-pulse duration on the primary outcomes (gait
speed and walking endurance). The 6-week NMES intervention applied to the lower leg muscles of persons with mild to
moderate levels of disability can improve their walking performance and provide some symptom relief.

Keywords
multiple sclerosis, neuromuscular electrical stimulation, wide pulse, walking endurance, muscle strength, force steadiness

Introduction One of the factors that contributes to such discrepancies

The loss of mobility experienced by persons with multiple
sclerosis (MS) can be partially restored with exercise
training,1,2 especially for individuals with Expanded Disability
Status Scale (EDSS) scores <4.0.3 Some evidence suggests,
however, that persons with greater levels of disability can
experience gains in physical function when exercise train-
ing is combined with neuromuscular electrical stimulation
(NMES). For example, Coote et al4 reported that supple-
menting a 12-week progressive resistance program with
NMES (pulse width not reported) augmented the gains in
fatigue reduction, muscle endurance, and balance for indi-
viduals with MS who used a walking aid most of the time.
In contrast, Broekmans et al5 found similar gains in strength
but no changes in clinical tests of mobility for individuals
with MS (EDSS = 4.3 ± 02) who performed 20 weeks of
strength training exercises of the knee extensors either
alone or in combination with NMES (pulse width = 0.4 ms).
in NMES outcomes is differences in stimulus characteris-
tics. Conventional NMES protocols apply currents of <100
mA between electrodes placed on the skin over a target
muscle at stimulus frequencies of 40 to 100 Hz with narrow
pulse widths of 0.2 to 0.5 ms.5,6 Recent work has shown that
the capacity of NMES to influence the function of the ner-
vous system depends on the duration of each stimulus pulse.
Longer stimulus pulses (0.5-1.0 ms)—typically known as
1
University of Colorado, Boulder, CO, USA
2
King Saud bin Abdulaziz University for Health Sciences, Riyadh,
Saudi Arabia
3
University of Colorado Denver, Aurora, CO, USA
Corresponding Author:
Awad M. Almuklass, Department of Integrative Physiology, University of
Colorado, Boulder, CO 80309, USA.
Emails: awad.almuklass@colorado.edu; muklassa@ksau-hs.edu.sa
2 Neurorehabilitation and Neural Repair 00(0)
wide-pulse NMES—are able to produce more widespread
responses in the nervous system than shorter stimulus
pulses (0.2-0.4 ms)7-10 even after the stimulation has
stopped.11,12 The application of wide-pulse NMES, there-
fore, might elicit more consistent improvements in motor
function and disability status for individuals with MS.
The primary purpose of our study was to compare the
effects of narrow- and wide-pulse NMES on gait speed and
walking endurance of persons with relapsing-remitting MS.
Because of its greater engagement of sensory axons,7,9
wide-pulse NMES was expected to elicit more widespread
adaptations in nervous system function and to produce
greater gains in walking performance than conventional
narrow-pulse NMES. The secondary purpose was to deter-
mine the influence of the NMES protocols on the functional
capabilities of the stimulated leg muscles and on assess-
ments of disability status.
Because of the critical role of lower-leg muscles in deter-
mining walking ability in persons with MS,13-16 NMES was
applied to the dorsiflexor and plantar flexor muscles of each
leg, and their functional capabilities were assessed. In addi-
tion to measuring the strength of the dorsiflexor and plantar
flexor muscles in both legs, we measured the fluctuations in
force during steady isometric contractions (force steadiness17)
to derive an index of the neural drive to muscle.17
Previous reports suggest that NMES interventions have
mixed effects on disability status of persons with MS,4,5
but exercise programs can modulate some measures of
disability. We expected that the most likely disability mea-
sures to be influenced by the NMES protocols would be
the test of manual dexterity (grooved pegboard test),18,19
walking limitations,20 and level of fatigue.4,21,22
Materials and Methods
Individuals who expressed an interest in the study com-
pleted a screening questionnaire in which they affirmed a
diagnosis of relapsing-remitting MS, difficulty with walk-
ing, stable doses of MS-related medications, and the
absence of a relapse within the preceding 3 months, history
of seizure disorder, implanted biomedical devices or metal,
and skin disease. Participants were recruited from the prac-
tice of the Rocky Mountain MS Center and via newsletter
distribution along the Front Range of the Rocky Mountains.
The study enrolled 32 volunteers who signed a consent
form that was approved by the institutional review board at
the University of Colorado Boulder.
In a double-blinded, randomized design, participants
were assigned to 1 of 2 groups: narrow-pulse group (n = 13;
54.9 ± 4.5 years) or wide-pulse group (n = 14; 50.4 ± 9.0
years). Participants and evaluators were blinded to the type
of intervention. Each participant attended 3 evaluation ses-
sions and 18 NMES treatment sessions distributed over 6
weeks. Each evaluation session comprised 2 days of testing.
Evaluation sessions were performed before (week 0) begin-
ning the 6-week treatment, within 1 week after finishing the
treatment (week 7), and approximately 4 weeks after com-
pleting the treatment (week 11).
Evaluation Sessions
On the first day of the evaluation sessions, participants per-
formed the 2 walking tests (25-feet walk and 6-minute
walk), took a manual dexterity test (grooved pegboard),
completed 3 questionnaires, and were instructed on how to
measure daily levels of physical activity. Maximal walking
speed was measured as the time it took to walk 25 feet as
quickly as possible from a stationary start.20,23 The average
of 2 trials was used as the measure of maximal walking
speed. Walking endurance was characterized as the distance
walked in 6 minutes around a 140-m track. Participants
were encouraged to walk briskly, and the distance covered
at 1, 2, 4, and 6 minutes was recorded.24,25
The grooved pegboard test, the 3 questionnaires, and the
daily levels of physical activity were used to assess disabil-
ity status. Manual dexterity was quantified as the time taken
to complete the grooved pegboard test, which required par-
ticipants to place 25 pegs into holes on a pegboard as
quickly as possible.26 The questionnaires were the Patient
Determined Disease Steps (PDDS),27 Modified Fatigue
Impact Scale (MFIS),25,28 and MS Walking Scale-12
(MSWS-12).29,30 Physical activity was measured with the
GENEActive accelerometer (Activinsights Limited,
Cambridge, UK) for 7 consecutive days beginning on the
second day of evaluations and quantified during at least
24-hour days during that period. Participants were asked to
wear the waterproof sensors all the time but were permitted
to remove it at night if it disturbed their sleep. The monitor
was worn on the same wrist, and the data were sampled at
30 Hz. Custom software (Matlab R2015a, Mathworks,
Natick, MA) was used to filter the signals (band pass of 0.2
to 15 Hz), calculate an average gravity-subtracted signal
vector magnitude, quantify activity counts per second, and
identify nonwear times (>10 hours). Based on norms estab-
lished for healthy adults, maximal activity category cut-
points were set for sedentary (1.4), light (4.0), and moderate
(11.3) accelerations per second to estimate the proportion of
daily time spent performing different levels of physical
activity.31 The main reason for including this assessment
was to quantify the potential negative impact of the inter-
vention on daily levels of physical activity.
On the second day of the evaluation sessions, muscle
strength and force steadiness were measured. Participants
lay in a supine position, and a strap was placed around the
forefoot and connected to a strain-gauge transducer (MLP-
300, Transducer Techniques, Tenecula, CA). The measured
force was sampled at 2 kHz (Power 1401, Cambridge
Electronic Design, Cambridge, UK) and displayed on a
Almuklass et al 3
monitor that was placed ~1 m in front of the participant.
Muscle strength was quantified as the peak torque (N m)
achieved by the dorsiflexor and plantar flexor muscles of
each leg when participants gradually increased muscle
torque up to maximum and sustained it briefly. Participants
performed up to 5 trials until 2 maximal values were within
10% of each other; the greater value was designated as the
maximal voluntary contraction (MVC) torque. Participants
then performed submaximal isometric contractions with the
dorsiflexor and plantar flexor muscles to match target forces
of 10% and 20% MVC torque with the self-reported less-
affected leg. The task was to match the target force dis-
played on the monitor and then maintain a steady
contraction.32 The protocol comprised two 30-s trials at
each target force with each muscle group. Force steadiness
was measured as the coefficient of variation for force.
NMES Intervention
The NMES treatments were applied with an FDA-approved
clinical device (Vectra Genisys Therapy System, DJO
Global) that delivered symmetric, biphasic pulses of current
through pairs of electrodes (2 × 3.5 in or 2 × 5 in each)
placed on the skin overlying the muscles of each leg (Figure
1). NMES was applied to the dorsiflexor and plantar flexor
muscles (10 minutes each muscle, 4 s on and 12 s off) of
each leg. NMES was applied to one leg at a time in a coun-
terbalanced order across sessions. Stimulus frequency was
set at 100 Hz with a pulse width of 1 ms for wide-pulse
stimulation and at 50 Hz with a pulse of 0.26 ms for narrow-
pulse stimulation. To reduce the discomfort associated with
NMES, the participant was encouraged to contract the
involved muscles while the stimulation was being applied.
The stimulation was applied while the participant was
seated during the first and last 2 weeks (12 sessions) of the
intervention and while standing in the middle 2 weeks (6
sessions). In the seated position, the legs were lifted parallel
to the floor, and the participant pushed against a restraint
during application of NMES. In the standing position, par-
ticipants stood in a lunge position when NMES was applied
to the plantar flexors and with the heels placed on a plat-
form when the NMES was applied to the dorsiflexors
(Figure 1). Current was progressively increased across ses-
sions to the maximal tolerable level for each participant and
then tapered during the last 3 sessions. After ~19 evoked
contractions, the participant performed 3 passive stretching
exercises with the involved leg muscles. The treatment ses-
sions were performed or supervised by a physical therapist
with clinical experience in providing such treatments. Each
treatment session lasted ~50 minutes.
Data Analysis
The data were coded during analysis to maintain blinding.
The Shapiro-Wilk test was used to assess normality. Normally
distributed data were analyzed with mixed ANOVA, and
nonnormally distributed data were analyzed with the Kruskal-
Wallis test. Comparisons across time were examined with
either 1-way repeated-corrections ANOVA (parametric) or
Friedman’s test (nonparametric) with Bonferroni adjust-
ments. When group differences reached significance, post
hoc comparisons were performed with either paired, inde-
pendent t (parametric data), Wilcoxon sign ranked, or Mann-
Whitney U tests (nonparametric data). Post hoc comparisons
were made within groups, which involved 3 statistical
comparisons.
Effect size for group differences were quantified as η2
(parametric data) or as x 2 / N and z / n1 + n 2 (non-
parametric data). Effect sizes of 0.1 were considered small
and those ≥0.5 were deemed large. Pearson and Spearman
correlations were used to examine the associations between
the outcomes and PDDS score. All statistical procedures
were performed with SPSS (version 22.0; SPSS, Chicago,
IL), with α set to .05.
Results
Of the 32 individuals who were enrolled in the study, 5
were unable to complete the protocol because of time com-
mitments or an unrelated injury. Thus, 27 persons (mean ±
SD; 52.6 ± 7.4 years) completed the protocol. There were
no statistically significant differences between the 2 groups
in the baseline values for the outcome measures (walking
performance, leg muscle function, and disability status;
Table 1). The average scores (both groups combined) for
the 3 self-reported assessments indicate that the partici-
pants exhibited a range of disabilities: PDDS (range = 0-6),
MFIS (range = 0-76), and MSWS-12 (range = 17-57).
Based on the PDDS criteria, most participants were classi-
fied as either with gait disability (n = 13) or early cane
(n = 8), but 1 person self-reported a score of 0 (normal),
and 2 were essentially confined to a wheelchair.
There was no difference (Kruskal-Wallis test) between
the 2 groups (wide- and narrow-pulse NMES) in the gains
in the 2 primary outcome variables: 25-feet walk speed
(χ2 = 4.85; df = 3; P value = .18) or 6-minute walk distance
(χ2 = 0.25; df = 3; P = .94). However, both groups exhibited
an effect of time (weeks 0, 7, and 11), which was quantified
by combining the data for the 2 groups.
Walking Performance
25-Feet Walk.  Friedman’s test with Bonferroni adjustment
for post hoc comparison and adjusted P value (Table 2)
indicated significant improvements (P = .003 [effect size =
0.38]) in the 25-feet walk test at week 7 (7.9 ± 11.1 s, P = .043
[0.304]) and week 11 (7.8 ± 11.9 s, P < .01 [0.43]) com-
pared with week 0 (8.8 ± 13.9 s). The decrease in time it
took to walk 25 feet relative to week 0 was −0.90 ± 3.1 s
(5% ± 16%) at week 7 and −1.0 ± 2.3 s (8% ± 15%) at week 11.
4 Neurorehabilitation and Neural Repair 00(0)

Figure 1.  The intervention setup showing the stimulation pad locations over the plantar flexor (A) and dorsiflexor (D) muscles, the
standing positions when stimulation was applied to the plantar flexor (B) and dorsiflexor (E) muscles, and the sitting position when
stimulation was applied to the plantar flexor (C) and dorsiflexor (F) muscles.
Almuklass et al 5

Table 1.  Descriptive Statistics for the 2 Groups and Combined Group of Participants Prior to Beginning the Intervention.a

Wide (n = 14) Narrow (n = 13) Combined (n = 27)

b
Age (years) 54.0 ± 9.0 54.9 ± 4.5 55.0 ± 7.4b
6-Minute walk (m) 410 ± 131 345 ± 138 379 ± 136
25-Feet walk (s) 5.8 ± 2.1 6.3 ± 19.9b 6.0 ± 13.9b
Dorsiflexor torque (N m)  
  Affected leg 11.4 ± 7.7 9.6 ± 5.9 8.1 ± 6.8b
  Less-affected leg 15.2 ± 6.4 14.5 ± 6.8 14.9 ± 6.5
Plantar flexor torque (N m)  
  Affected leg 24 ± 14 22 ± 11 23 ± 12
  Less-affected leg 26 ± 13 24 ± 9 25 ± 11
Dorsiflexor steadiness (percentage MVC)
 10% 4.7 ± 5.3b 4.7 ± 5.2b 4.7 ± 5.1b
 20% 2.9 ± 3.6b 4.0 ± 6.4 3.6 ± 5.1b
Plantar flexor steadiness (percentage MVC)  
 10% 2.5 ± 3.1b 3.6 ± 1.9 2.7 ± 2.5b
 20% 2.8 ± 1.5 2.6 ± 2.1b 2.5 ± 1.8b
PDDS 3.0 ± 1.3b 3.0 ± 1.0b 3.0 ± 1.2b
MFIS score 42 ± 19 39 ± 21 41 ± 20
MSWS-12 42 ± 12 48 ± 12b 47 ± 11b
Grooved pegboard test (s) 99 ± 35 89 ± 44b 89 ± 39b

Abbreviations: MFIS, Modified Fatigue Impact Scale; MSWS, Multiple Sclerosis Walking Scale-12; MVC, maximal voluntary contraction; PDDS, Patient
Determined Disease Steps.
a
Values reported as mean ± SD. Steadiness values are coefficient of variation for force (%). There were no significant differences between groups.
b
Median ± SD.

Table 2.  Measures of Walking Performance and Disability Status at the 3 Time Points During the 6-Week Intervention.a

Week 0 Week 7 Week 11 P Value Effect Size

b b
6-Minute walk (m) 379 ± 136 (33-598) 415 ± 154 (60-674) 421 ± 160 (45-698) .001 0.29
25-Feet walk (s) 8.8 ± 13.9 (3.4-78) 7.9 ± 11.1b (3.4-63) 7.8 ± 11.9b (3.4-67) .003 0.38
PDDS 3.5 ± 1.2 (0-6) 3.1 ± 1.4 (0-6) 3.2 ± 1.5 (0-6) .19 0.07
MFIS score 41 ± 20 (0-76) 29 ± 16b (0-56) 31 ± 16b (0-66) .004 0.21
MSWS-12 43 ± 11 (17-57) 35 ± 13b (12-55) 38 ± 13b (16-55) .001 0.33
Grooved pegboard 103 ± 39 (57-199) 97 ± 34 (54-174) 93 ± 33b (55-167) .006 0.36
test (s)
Daily activity (%)
 Sedentary 77.9 ± 6.6 76.5 ± 5.2 78.4 ± 6.1 .171 0.12
 Light 15.4 ± 4.6 15.8 ± 3.9 15.1 ± 4.3 .546 0.04
 Moderate-Vigorous 7.2 ± 3.1 8.5 ± 4.2 7.3 ± 3.4 .059 0.19

Abbreviations: MFIS, Modified Fatigue Impact Scale; MSWS, Multiple Sclerosis Walking Scale-12; PDDS, Patient Determined Disease Steps.
a
Values are mean ± SD (range).
b
P <.05 relative to week 0.

Despite the variability in the changes in walking perfor-
mance among participants, Figure 2 indicates a relatively
consistent relation between the gains in the 2 walking tests
observed immediately after the intervention (week 7) and 4
weeks later (week 11).
6-Minute Walk.  One-way repeated-measures ANOVA with
Bonferroni adjustment indicated significant improvements
(P = .001 [0.29]) in the 6-minute walk distance (Table 2).
The increase (mean ± SD) in the distance walked in 6 min-
utes relative to week 0 was 37 ± 51 m (12% ± 21%) at week
7 and 43 ± 66 m (13% ± 21%) at week 11.
The gains in 6-minute distance and 25-feet time at week
7 were not significantly different from those at week 11,
whether the improvements were examined as either abso-
lute (6-minute: P = .27 [0.14]; 25-feet: P = .33 [0.13]) or
relative (6-minute: P = .5 [0.09]; 25-feet: P = .23 [0.16])
changes.
6 Neurorehabilitation and Neural Repair 00(0)
Figure 2.  The relative (%) improvement in the distance walked
in 6 minutes and time taken to walk 25 feet immediately at
weeks 7 and 11.
Leg Muscle Function
Muscle Strength.  Friedman’s test and 1-way repeated mea-
sures ANOVA with Bonferroni correction for post hoc
comparisons indicated significant improvements in the
MVC torque (N m) for 2 of the 4 tested muscle groups. The
strength of the dorsiflexors in the affected leg (Table 3)
increased (P = .016 [0.32]) at week 11 (13.5 ± 7.8 N m, P = .02
[0.38]), but not at week 7 (12.7 ± 7.4 N m, P = .08 [0.29]),
compared with week 0 (10.5 ± 6.8 N m). The increase in
dorsiflexor strength relative to week 0 was 66% ± 167% at
week 7 and 71% ± 148% at week 11.
Similarly, the strength of the plantar flexors in the less-
affected leg (Table 3) increased (P = .038 [0.29]) at week 7
(33.3 ± 18.8 N m, P = .04 [0.34]), but not at week 11 (28.3
± 10.4 N m, P = .2 [0.25]), compared with week 0 (25.0 ±
10.9 N m). The increase in plantar flexor strength relative to
week 0 was 39% ± 54% at week 7 and 26% ± 58% at week
11. There were no statistically significant changes in the
dorsiflexor torque of the less-affected leg (P = .48 [0.03]) or
the plantar flexor torque of the affected leg (P = .36 [0.04]).
These selective changes in muscle strength influenced
the between-limb differences in muscle strength. Although
the dorsiflexor muscles in the affected leg were stronger
after intervention, they remained weaker than those in the
less-affected leg (Table 3) at week 0 (P = .003 [0.31]), week
7 (P = .048 [0.15]), and week 11 (P = .045 [0.16]). In con-
trast, it was the plantar flexor muscles in the less-affected
leg that gained strength during the intervention (Table 3),
which made them even stronger than those in the affected
leg (P = .001 [0.47]).
Force Steadiness.  The coefficient of variation for force dur-
ing the steady isometric contractions (force steadiness)
differed with target force (10% and 20% MVC), muscle
group in the less-affected leg (dorsiflexors and plantar flex-
ors), and after the intervention. Force was more steady
(lower coefficients of variation values) for the dorsiflexor
muscles at 20% than at 10% MVC (Table 3) both at week 0
(P = .039 [0.32]) and week 7 (P = .003 [0.46]), but not at
week 11 (P = .18 [0.21]). The plantar flexors were steadier
at 20% than at 10% MVC (Table 3), but only at week 7
(P = .004 [0.44]) and not at week 0 (P = .31 [0.16]) or at
week 11 (P = .058 [0.29]). The plantar flexors were steadier
than the dorsiflexors across all time points and at both target
forces: 10% MVC, week 0 (P < .001 [0.53]), week 7 (P = .021
[0.36]), and week 11 (P < .001[0.52]); 20% MVC, week 0
(P = .008 [0.41]), week 7 (P < .001 [0.58]), and week 11
(P < .001[0.57]). Force steadiness improved (P = .005
[0.25]) for the plantar flexors at 20% MVC, but not at 10%
MVC, at week 7 (2.3% ± 1.1%, P = .027) and at week 11
(2.4% ± 1.5%, P = .028) compared with week 0 (3.2% ± 1.8%).
There were no statistically significant changes in force
steadiness for the dorsiflexors.
Disability Status
Grooved Pegboard Test. Friedman’s test with Bonferroni
adjustment for post hoc comparisons indicated significant
differences (P = .006 [0.36]) across the intervention (Table 2),
with significant differences (P = .005 [0.43]) between week
0 (103 ± 39 s) and week 11 (93 ± 33 s) but not (P = .088
[0.29]) at week 7 (97 ± 34 s). This result indicates a main
effect for time on the grooved pegboard times.
Self-reported Assessments. MFIS (P = .004 [0.212]) and
MSWS-12 (P = .001 [0.33]) scores were improved at
weeks 7 and 11 (Table 2), but the change in PDDS score at
week 7 and 11 were not statistically significant when com-
pared with that at week 0 (P = .19 [0.07]). However, there
was a statistically significant correlation (P < .05) between
PDDS score and the increase in distance (m) walked in 6
minutes at week 7 (r = −0.40); participants with greater
PDDS scores experienced lesser gains in 6-minute distance.
Daily Levels of Physical Activity. There were no statistically
significant changes in the daily levels of physical activity at
week 7 or at week 11 in any of the 3 categories of physical
activity (Table 2): sedentary (P = .17 [0.12]), light (P = .55
[0.04]), and moderate-vigorous (P = .06 [0.19]). The inter-
vention, therefore, did not compromise the daily levels of
physical activity of the participants.
Discussion
In a double-blind, randomized comparison of narrow- and
wide-pulse NMES, individuals whose mobility was impaired
by MS showed clinically significant improvements in
Almuklass et al 7

Table 3.  Strength for Muscles in the More-Affected and Less-Affected Legs and Force Steadiness for the Less-Affected Leg at the 3
Time Points During the 6-Week Intervention.a

Week 0 Week 7 Week 11 P Value Effect Size

Dorsiflexor torque (N m)
  Affected leg 10.5 ± 6.8 12.7 ± 7.4 13.5 ± 7.8b .016 0.32
  Less-affected leg 14.9 ± 6.5c 14.8 ± 6.5c 16.3 ± 10.0c .48 0.03
Plantar flexor torque (N m)
  Affected leg 22.6 ± 12.3 24.9 ± 11.6 25.8 ± 11.9 .357 0.04
  Less-affected leg 25.0 ± 10.9 33.3 ± 18.8b,c 28.3 ± 10.4 .038 0.29
Dorsiflexor steadiness (percentage MVC force)
 10% 6.9 ± 5.1 7.2 ± 6.2 6.3 ± 4.9 .26 0.18
 20% 5.9 ± 5.1d 4.6 ± 4.0d 5.3 ± 4.0 .13 0.23
Plantar flexor steadiness (percentage MVC force)
 10% 3.8 ± 2.5e 4.0 ± 2.6e 3.3 ± 2.4e .13 0.22
 20% 3.2 ± 1.8e 2.3 ± 1.1b,d,e 2.4 ± 1.5b,e .005 0.25

Abbreviation: MVC, maximal voluntary contraction.

a
Values are mean ± SD.
b
P <.05 relative to week 0.
c
P <.05 relative to affected side.
d
P <.05 relative to 10% MVC.
e
P <.05 relative to dorsiflexors.

walking endurance and maximal walking speed after the
6-week NMES intervention. In contrast to the hypothesis,
however, there was no influence of stimulus-pulse duration
on the primary outcomes.
The hypothesis was derived from studies that have dem-
onstrated a gradual increase in the torque evoked in lower-
leg muscles by wide-pulse NMES relative to the same
initial level of torque elicited by narrow-pulse NMES.7,9
The increase in torque is attributed to the progressive
recruitment of motor neurons resulting from the widespread
distribution of sensory input associated with wide-pulse
NMES.10,11,33 The relative activation of sensory and motor
axons, however, is influenced by the placement of the
NMES electrodes. When the electrodes are placed over a
peripheral nerve, wide-pulse NMES engages a greater pro-
portion of sensory axons compared with when the elec-
trodes are placed over the muscle belly.7 The results of our
study, however, suggest that pulse width had no influence
on the adaptations elicited by NMES when the electrodes
were placed over the dorsiflexor and plantar flexor muscles
of the study participants.34
Some of the findings from our study are similar to those
reported in other NMES interventions, but there are some
significant differences. Coote et al4 found that supplement-
ing a 12-week home-based resistance program with NMES
applied to the quadriceps muscles of individuals who were
moderately disabled by MS augmented the gains in muscle
endurance and self-reported level of fatigue (MFIS).
Critically, the NMES was applied to the weaker leg while
the participants performed the prescribed exercises. In con-
trast, the current study found that the 6-week NMES proto-
cols applied to lower-leg muscles (dorsiflexors and plantar
flexors) while the participants performed isometric contrac-
tions in seated and standing positions improved gait speed,
walking endurance, some measures of muscle strength and
force steadiness, fatigue (MFIS), and self-reported levels of
walking disability (MSWS-12 score).
The decrease in time to walk 25 feet (8.8 ± 13.9 to 7.9 ±
11.1 s) corresponds to a clinically significant improvement
(week 7: −5% ± 16%; week 11: −8% ± 15%) in maximal
gait speed (<8 s to walk 25 feet).35 However, the 25-feet
walk test at a fast speed is less responsive to changes pro-
duced by rehabilitation than the longer walk tests.20
Consistent with this conclusion, the improvement in 6-min-
ute walk distance (379 ± 136 to 415 ± 154 m) represents an
improvement (week 7: 12% ± 21%; week 11: 13% ± 21%)
that exceeded the minimally important change of 22 m.20
Moreover, the decline in MSWS-12 score (maximum = 60
points) at week 7 (7.6 ± 8.4 points) was similar to the
8-point reduction deemed to indicate a meaningful improve-
ment in walking disability,30 but the improvement began to
dissipate at week 11 (5.4 ± 9.5 points).
As expected, the NMES intervention produced some
limited improvements in measures related to disability sta-
tus. In addition to the decrease in the MSWS-12 score, the
self-reported level of fatigue (MFIS) declined by 11 ± 17
(maximum = 53) points at week 7 and by 8 ± 16 points at
week 11. As a symptom, an individual’s level of fatigue is
derived from 2 domains: performance fatigability and per-
ceived fatigability.36 The fatigue experienced by persons
with MS appears to be minimally influenced by perfor-
mance fatigability and appears to depend more on perceived
fatigability,37 which depends on the psychological state of
the individual and the capacity to accommodate challenges
8 Neurorehabilitation and Neural Repair 00(0)
to homeostasis.36 Our findings suggest that an NMES inter-
vention is able to modulate at least 1 mechanism related to
either psychological state or homeostasis that contributed to
perceived fatigability in persons with MS.
In contrast, the NMES intervention did not produce a
statistically significant change in PDDS score, although
there was an inverse relation between the increase in
6-minute walk distance and the initial PDDS score. This
association suggests that the impact on the NMES protocol
was greater for those participants who were mildly dis-
abled. However, the statistically significant decreases in
grooved pegboard times are consistent with central adapta-
tions produced by the 6 weeks of NMES. Moreover, the
intervention did not compromise the daily levels of physi-
cal activity as measured with a wrist-worn accelerometer.
Because of the association between habitual walking per-
formance and disability status,38 the absence of change in
the daily levels of physical activity is consistent with no
change in the PDDS score.
The current results provide some insight into adaptations
that likely contributed to the improvements in walking per-
formance. In a 2-year longitudinal study, Zackowski et al39
reported that the decrease in strength of the ankle dorsiflexor
muscles (3.3 lb/year) for persons with MS was associated
with an increase in the time it took to walk 25 feet; time
changed by 0.19 s for each 1 lb decline in strength. We found
that 18 sessions of NMES applied to the dorsiflexor and
plantar flexor muscles of both legs increased the strength of
the dorsiflexor muscles in the affected leg and elicited a tran-
sient increase in strength of the plantar flexors in the less-
affected leg. Given the critical role of the dorsiflexor muscles
in limiting walking performance in persons with neurologi-
cal disorders,13-15 it seems likely that at least some of the
improvements in walking endurance and maximal walking
speed in our study can be attributed to the increase in strength
of the dorsiflexor muscles of the affected leg.
Consistent with previous reports on healthy individuals
in which force steadiness is usually worse in weaker
muscles,40,41 the fluctuations in force during submaximal
isometric contractions with the dorsiflexors were greater in
our study than those for the plantar flexors at both target
forces. Compared with healthy individuals, however, the
force fluctuations (coefficient of variation for force) for the
dorsiflexors in the current study (5.9% ± 5.1%) were much
greater than those for both young (1.20% ± 0.62%) and
older adults (1.74% ± 0.69%). Similarly, force steadiness
for the plantar flexors was greater for individuals with MS
(3.8% ± 2.5% at 10% MVC and 3.2% ± 1.8% at 20% MVC)
than for healthy adults (mean ± SE at 10% MVC force =
0.93% ± 0.13%).42 These comparisons indicate that the neu-
ral drive to the dorsiflexor and plantar flexor muscles dur-
ing submaximal isometric contractions is more variable for
individuals with MS relative to healthy adults. Moreover,
force steadiness for the plantar flexors at 20% MVC, but not
the dorsiflexors, improved after the NMES intervention,
which suggests an adaptation in the neural drive to these
muscles that likely has consequences for motor
function.40-42
In contrast to expectations, there was no influence of the
NMES stimulus-pulse duration on the primary outcomes
(gait speed and walking endurance), and the data were com-
bined into a single group to examine the influence of the
NMES intervention. The 6-week intervention elicited clini-
cally significant improvements in the primary outcomes
and several secondary outcomes in individuals whose
mobility was compromised by MS. A major limitation,
however, is that the actual influence of NMES could not be
evaluated, because of the absence of a control group that
would have assessed a potential placebo effect. In addition,
we were unable to assess the outcomes during the interven-
tion and for a longer follow-up period. Secondary outcomes
suggest that the improvements in mobility likely involve
increases in muscle strength and the control of muscle force
for some of the involved muscles. These findings suggest
that several weeks of NMES applied to the lower-leg mus-
cles can improve walking performance and provide some
symptom relief for persons with mild to moderate levels of
disability caused by MS.
Acknowledgments
We thank Ryan Price for help with Figure 1 as well as 3 anony-
mous reviewers for their helpful suggestions.
Authors’ Note
Trial registry name: Neuromuscular Electrical Stimulation and
Mobility in Multiple Sclerosis. ClinicalTrials.gov Identifier:
NCT02152085; https://clinicaltrials.gov/ct2/show/NCT02152085?
term=nct02152085&rank=1.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: The
Eunice Kennedy Shriver National Institute of Child Health &
Human Development of the National Institutes of Health provided
support for the project (R03HD079508). Chattanooga Inc. kindly
loaned us 3 Vectra Genesys 2-channel systems that are Food and
Drug Administration approved for the delivery of neuromuscular
electrical stimulation to human volunteers. Almuklass was sup-
ported by a scholarship from the King Saud bin Abdulaziz
University for Health Science in Saudi Arabia.
ORCID iD
Awad M. Almuklass https://orcid.org/0000-0003-0189-5160
Almuklass et al 9
References
1. Sandroff BM, Sosnoff JJ, Motl RW. Physical fitness, walk-
ing performance, and gait in multiple sclerosis. J Neurol Sci.
2013;328:70-76.
2. Snook EM, Motl RW. Effect of exercise training on walking
mobility in multiple sclerosis: a meta-analysis. Neurorehabil
Neural Repair. 2009;23:108-116.
3. Motl RW, Pilutti LA. The benefits of exercise training in mul-
tiple sclerosis. Nat Rev Neurol. 2012;8:487-497.
4. Coote S, Hughes L, Rainsford G, Minogue C, Donnelly A.
Pilot randomized trial of progressive resistance exercise aug-
mented by neuromuscular electrical stimulation for people
with multiple sclerosis who use walking aids. Arch Phys Med
Rehabil. 2015;96:197-204.
5. Broekmans T, Roelants M, Feys P, et al. Effects of long-term
resistance training and simultaneous electro-stimulation on
muscle strength and functional mobility in multiple sclerosis.
Mult Scler. 2011;17:468-477.
6. Maffiuletti NA. Physiological and methodological consider-
ations for the use of neuromuscular electrical stimulation. Eur
J Appl Physiol. 2010;110:223-234.
7. Bergquist AJ, Wiest MJ, Collins DF. Motor unit recruitment
when neuromuscular electrical stimulation is applied over a
nerve trunk compared with a muscle belly: quadriceps femo-
ris. J Appl Physiol (1985). 2012;113:78-89.
22. Hebert JR, Corboy JR, Manago MM, Schenkman M. Effects
8. Knash ME, Kido A, Gorassini M, Chan KM, Stein RB.
Electrical stimulation of the human common peroneal nerve
elicits lasting facilitation of cortical motor-evoked potentials.
Exp Brain Res. 2003;153:366-377.
23. Motl RM, Cohen JA, Benedict R, et al; Multiple Sclerosis
9. Lagerquist O, Walsh LD, Blouin JS, Collins DF, Gandevia
SC. Effect of a peripheral nerve block on torque produced
by repetitive electrical stimulation. J Appl Physiol (1985).
2009;107:161-167.
10. Mang CS, Clair JM, Collins DF. Neuromuscular electrical
stimulation has a global effect on corticospinal excitability for
leg muscles and a focused effect for hand muscles. Exp Brain
Res. 2011;209:355-363.
11. Mang CS, Bergquist AJ, Roshko SM, Collins DF. Loss of
short-latency afferent inhibition and emergence of afferent
facilitation following neuromuscular electrical stimulation.
Neurosci Lett. 2012;529:80-85.
12. Stein RB, Everaert DG, Thompson AK, et al. Long-term
therapeutic and orthotic effects of a foot drop stimulator
on walking performance in progressive and nonprogres-
sive neurological disorders. Neurorehabil Neural Repair.
2010;24:152-167.
13. Dodd KJ, Taylor NF, Shields N, Prasad D, McDonald E,
Gillon A. Progressive resistance training did not improve
walking but can improve muscle performance, quality of life
and fatigue in adults with multiple sclerosis: a randomized
controlled trial. Mult Scler. 2011;17:1362-1374.
14. Manca A, Cabboni MP, Dragone D, et al. Resistance training
for muscle weakness in multiple sclerosis: direct versus contra-
lateral approach in individuals with ankle dorsiflexors’ dispar-
ity in strength. Arch Phys Med Rehabil. 2017;98:1348-1356.e1.
15. McLouglin JV, Lord SV, Barr CJ, Crotty M, Sturnieks DL.
Dorsiflexion assist orthosis reduces the physiological cost
and mitigates deterioration in strength and balance associated
with walking in people with multiple sclerosis. Arch Phys
Med Rehabil. 2015;96:226-232.
16. Wagner JM, Kremer TR, Van Dillen LR, Naismith RT.
Plantarflexor weakness negatively impacts walking in per-
sons with multiple sclerosis more than plantarflexor spastic-
ity. Arch Phys Med Rehabil. 2014;95:1358-1365.
17. Farina D, Negro F. Common synaptic input to motor neurons,
motor unit synchronization, and force control. Exerc Sport Sci
Rev. 2015;43:23-33.
18. Koch MW, Murray TJ, Fisk J, et al. Hand dexterity and
direct disease related cost in multiple sclerosis. J Neurol Sci.
2013;341:51-54.
19. Yozbatiran N, Baskurt F, Baskurt Z, Ozakbas S, Idiman E.
Motor assessment of upper extremity function and its relation
with fatigue, cognitive function and quality of life in multiple
sclerosis patients. J Neurol Sci. 2006;246:117-122.
20. Baert I, Freeman J, Smedal T, et al. Responsiveness and clini-
cally meaningful improvement, according to disability level,
of five walking measures after rehabilitation in multiple scle-
rosis: a European multicenter study. Neurorehabil Neural
Repair. 2014;28:621-631.
21. Dalgas U, Stenager E, Jakobsen J, et al. Fatigue, mood and
quality of life improve in MS patients after progressive resis-
tance training. Mult Scler. 2010;16:480-490.
of vestibular rehabilitation on multiple sclerosis-related
fatigue and upright postural control: a randomized controlled
trial. Phys Ther. 2011;91:1166-1183.
Outcome Assessments Consortium. Validity of the timed
25-foot walk as an ambulatory performance outcome measure
for multiple sclerosis. Mult Scler. 2017;23:704-710.
24. Goldman MD, Marrie RA, Cohen JA. Evaluation of the six-
minute walk in multiple sclerosis subjects and healthy con-
trols. Mult Scler. 2008;14:383-390.
25. Learmonth YC, Dlugonski D, Pilutti LA, Sandroff BM,
Klaren R, Motl RW. Psychometric properties of the Fatigue
Severity Scale and the Modified Fatigue Impact Scale. J
Neurol Sci. 2013;331:102-107.
26. Almuklass AM, Feeney DF, Mani D, Hamilton LD, Enoka
RM. Peg-manipulation capabilities during a test of manual
dexterity differ for persons with multiple sclerosis and healthy
individuals. Exp Brain Res. 2017;235:3487-3493.
27. Hohol MJ, Orav EJ, Weiner HL. Disease steps in mul-
tiple sclerosis: a longitudinal study comparing disease steps
and EDSS to evaluation disease progression. Mult Scler.
1999;5:349-354.
28. Amtmann D, Bamer AM, Noonan V, Lang N, Kim J, Cook
KF. Comparison of the psychometric properties of two fatigue
scales in multiple sclerosis. Rehabil Psychol. 2012;57:159-
166.
29. Goldman MD, Ward MD, Motl RW, Jones DE, Pula JH,
Cadavid D. Identification and validation of clinically mean-
ingful benchmarks in the 12-item Multiple Sclerosis Walking
Scale. Mult Scler. 2017;23:1405-1414.
30. Mehta L, McNeil M, Hobart J, et al. Identifying an important
change estimate for the Multiple Sclerosis Walking Scale-12
10 Neurorehabilitation and Neural Repair 00(0)
(MSWS-12v1) for interpreting clinical trial results. Mult Scler
J Transl Clin. 2015;1. doi:10.1177/20552173155969993.
31. Eslinger DW, Rowlands AV, Hurst TL, Catt M, Murray P,
Eston RG. Validation of the GENEA accelerometer. Med Sci
Sports Exerc. 2011;43:1085-1093.
32. Almuklass AM, Price RC, Gould JG, Enoka RM. Force
steadiness as a predictor of time to complete a pegboard test
of dexterity in young men and women. J Appl Physiol (1985).
2016;120:1410-1417.
33. Collins DF. Central contributions to contractions evoked by
tetanic neuromuscular electrical stimulation. Exerc Sport Sci
Rev. 2007;35:102-109.
34. Feiereisen P, Duchateau J, Hainaut K. Motor unit recruitment
order during voluntary and electrically induced contractions
in the tibialis anterior. Exp Brain Res. 1997;114:117-123.
35. Goldman MD, Motl RW, Scagnelli J, Pula JH, Sosnoff JJ,
Cadavid D. Clinically meaningful performance benchmarks
in MS: timed 25-foot walk and the real world. Neurology.
2013;81:1856-1863.
36. Enoka RM, Duchateau J. Translating fatigue to human perfor-
mance. Med Sci Sport Exerc. 2016;48:2228-2238.
37. Steens A, de Vries A, Hemmen J, et al. Fatigue perceived by
multiple sclerosis patients is associated with muscle fatigue.
Neurorehabil Neural Repair. 2012;26:48-57.
38. Gijbels D, Alders G, Van Hoof E, et al. Predicting habitual
walking performance in multiple sclerosis: relevance of
capacity and self-report measures. Mult Scler. 2010;16:618-
626.
39. Zackowski KM, Wang JL, McGready J, Calabresi PA,
Newsome SD. Quantitative sensory and motor measures
detect change over time and correlate with walking speed in
individuals with multiple sclerosis. Mult Scler Relat Disord.
2015;4:67-74.
40. Enoka RM, Christou EA, Hunter SK, et al. Mechanisms
that contribute to differences in motor performance between
young and old adults. J Electromyogr Kinesiol. 2003;13:
1-12.
41. Tracy BL, Mehoudar PD, Ortega JD. The amplitude of force
variability is correlated in the knee extensor and elbow flexor
muscles. Exp Brain Res. 2007;176:448-464.
42. Tracy BL. Force control is impaired in the ankle plantarflex-
ors of elderly adults. Eur J Appl Physiol. 2007;101:629-636.