REVIEW PHYSIOLOGY 35: 40 –56, 2020. Published December 4, 2019; doi:10.1152/physiol.00015.
2019
Electrical Stimulation of Muscle:
Electrophysiology and Rehabilitation
The generation of action potentials in intramuscular motor and sensory axons
in response to an imposed external current source can evoke muscle contrac-
tions and elicit widespread responses throughout the nervous system that
impact sensorimotor function. The benefits experienced by individuals ex-
posed to several weeks of treatment with electrical stimulation of muscle
suggest that the underlying adaptations involve several physiological systems,
but little is known about the specific changes elicited by such interventions.
central nervous system; electrical stimulation; electrophysiology; evoked
contractions; therapeutic benefits
Introduction
Physiologists have known about the existence of
electrical currents in nerves and muscle in humans
since at least 1843 (41). The first recordings of
electrical activity in muscle (116) and action cur-
rents in nerve (2), however, were not published
until the early 1900s. As reviewed in Duchateau
and Enoka (42), it soon became obvious to several
eminent physiologists that the activation signal
used by the nervous system to control muscle force
comprised unitary electrical events known as ac-
tion potentials. Moreover, they found that the ac-
tion potentials generated by each motor neuron
are distributed to a distinct set of muscle fibers,
which together form the motor unit (83). The mo-
tor unit came to be recognized as the final com-
mon pathway by which the electrical activation
signal is transmitted from the nervous system to
muscle and then transformed into contractile
activity.
After ~100 years since the discovery of the motor
unit, much has been learned about the organiza-
tion of motor unit activity during the performance
of voluntary actions. As summarized in several re-
views on motor unit physiology (42, 46, 61), we
know that motor units are recruited in a relatively
fixed order, the force produced by a muscle over
most of its operating range is controlled by con-
current adjustments in motor unit recruitment and
rate coding, the rate at which action potentials are
generated increases during faster contractions, the
peak discharge rates achieved during most volun-
tary contractions are less than those necessary to
produce maximal motor unit force, motor unit ter-
ritories are reorganized with advancing age and in
the presence of neurological diseases, and the ac-
40 1548-9213/20 Copyright © 2020 Int. Union Physiol. Sci./Am. Physiol. Soc.
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Roger M. Enoka,1
Ioannis G. Amiridis,2 and
Jacques Duchateau3
1
Department of Integrative Physiology, University of Colorado
Boulder, Colorado; 2Department of Physical Education and
Sport Sciences at Serres, Aristotle University of Thessaloniki,
Thessaloniki, Greece; and 3Laboratory of Applied Biology and
Neurophysiology, ULB Neuroscience Institute, Université Libre
de Bruxelles, Brussels, Belgium
enoka@colorado.edu
tivation of motor units can be compromised in
some conditions.
When the activation of motor units is compro-
mised, experimental and clinical studies have
demonstrated that it is possible to attenuate the
deficit by supplementing the activation with elec-
trical stimulation of muscle. The typical approach
is to pass an electric current between conductive
pads attached to the skin over a targeted muscle or
group of muscles. The outcomes from these stud-
ies, however, have demonstrated that the forces
and the adaptations evoked by the applied current
vary with the stimulus parameters. The purpose of
this brief review is to synthesize the findings on the
rehabilitation potential of protocols in which elec-
trical stimulation is applied percutaneously over
muscle to elicit action potentials in intramuscular
axons. Before reviewing this work, however, we
begin by discussing key details of the electrophys-
iology underlying the evoked activity.
Electrophysiology
Although the application of current over a muscle
in vivo can enable the contractile proteins to per-
form work, the activation signal is generated in
intramuscular axons and not in muscle fibers di-
rectly, at least with pulse durations of ⱕ1 ms. The
delivery of an electrical current either through
electrodes attached to the skin or through wires
inserted into the anterior thigh muscles of human
volunteers during a surgical procedure was not
able to evoke a muscle contraction after intrave-
nous administration of curare (68). Since curare
blocks synaptic transmission at the neuromuscular
junction, this observation indicates that electrical
currents evoke muscle contractions by eliciting ac-
tion potentials in intramuscular nerve fibers (100).

Moreover, Hultman and colleagues (68) found that
the current fields associated with intramuscular
electrodes engaged a greater number of sensory
axons than did percutaneous stimulation, even
though the current intensity delivered through the
surface electrodes was ~10 times greater. After ad-
ministration of local anesthetics into the muscle
proximal to the stimulating electrodes to block af-
ferent feedback, they found that the application of
electrical stimulation (frequency: 20 Hz; pulse du-
ration: 0.5 ms) through intramuscular electrodes
could evoke a force equal to the 70% of the peak
force achieved during a maximal voluntary con-
traction (MVC).
Intramuscular Distribution of Evoked
Responses Varies With Electrode Placement
Most rehabilitation protocols that include electri-
cal stimulation involve the delivery of current
through electrodes attached to the skin of the pa-
tient, which means the benefits are constrained by
the distribution of the current within the underly-
ing tissues. In an analytical model of a volume
conductor with three layers of tissue (skin ⫽ 1 mm,
fat ⫽ 1 mm, and muscle ⫽ 96 mm), Mesin and
Merletti (97) determined that the current density
decayed to 10% of the value applied to the skin at
a distance of 10 mm from the electrodes. Experi-
mental estimates of the intramuscular current con-
firm the marked decay in current density with
increases in distance from the source. For example,
Petrofsky et al. (113) estimated that the current
detected by a needle electrode at a depth of 0.5 cm
into the muscle (~2.5 cm from the skin surface) was
⬍1% of the current applied between electrodes (2
cm ⫻ 2 cm) attached to the skin over quadriceps
femoris. Increases in the current passed between
surface electrodes, therefore, result in a greater
spatial distribution of intramuscular currents to
elicit action potentials in the axons included within
a critical volume of the muscle. Petrofsky et al.
(113) found, for example, that a modest (20 mA)
sinusoidal current (30 Hz, 0.3 ms) evoked a quad-
riceps femoris force of 15% MVC, whereas a stron-
ger current (60 mA) produced a force of 75% MVC.
Critically, the volume of muscle activated by an
applied current varies with the distance between
the stimulating electrodes attached to the skin over
a target muscle (54).
The greater force evoked with stronger currents
is due to an increase in the number of activated
motor axons (98). The applied currents are distrib-
uted both into (transverse direction) and along
(longitudinal direction) the target muscles, with
conductivity being greater in the longitudinal di-
rection (97). Given the broad distribution of intra-
muscular axons (FIGURE 1), the capacity of
surface-applied currents to evoke strong forces
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REVIEW
likely depends most on the longitudinal distribu-
tion of the intramuscular currents. Although the
electrical stimulation presumably activates the
muscle fibers that have innervating axons located
in a current field that exceeds the threshold for
action-potential generation (76), it seems likely
that the action potentials can propagate anti-
dromically along motor axons from this location,
in addition to the expected orthodromic propaga-
tion, and thereby engage most of the muscle fibers
belonging to the motor unit. Evidence for this ex-
pectation is provided by the observation that the
generation of an action potential in a peripheral
motor axon by an electrical stimulus is propagated
antidromically back to the motor neuron where it
elicits an action potential that is then propagated
orthodromically back to the muscle, where it can
be recorded as an evoked response known as an F
wave (157).
Consistent with this interpretation, some evi-
dence suggests that the application of a current
through electrodes placed around the motor point
(20) may elicit action potentials in most of the
muscle fibers belonging to individual motor units
in tibialis anterior. The evidence is based on the
similarity of the shapes of action potentials ex-
tracted by spike-triggered averaging during the
performance of voluntary contractions and evoked
contractions (FIGURE 2). The purpose of the study
that compared the shapes of the action potentials
was to quantify the recruitment order for pairs of
motor units during voluntary and electrically
evoked contractions (49). Spike-triggered averag-
ing of the electromyographic (EMG) and force sig-
nals during voluntary contractions (FIGURE 2C)
yielded the action potential shapes and twitch re-
sponses of individual motor units (FIGURE 2, A
AND B). With careful grading of the applied cur-
rent to evoke a muscle contraction, the similarity
of the action potential shapes during the voluntary
and evoked contractions suggests that it was pos-
sible to determine the current needed to activate
the same two motor units (FIGURE 2D). The data
for the pair of motor units shown in FIGURE 2
indicate that a greater current was required to ac-
tivate motor unit 1 (MU 1), which had a lower
recruitment threshold during the voluntary con-
traction. Such reversal of recruitment order was
observed for 28 –35% of the motor unit pairs, de-
pending on pulse duration, suggesting that the re-
cruitment order of motor units is relatively random
during contractions evoked by electrical stimula-
tion applied over the muscle (49, 69, 76).
Most studies find that currents applied through
electrodes attached to the skin over a muscle tend
to activate the more superficial muscle fibers (98,
149), but some evidence suggests that surface stim-
ulation can activate deep regions within a muscle
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REVIEW
(1). In an elegant assessment of the spatial distri-
bution of muscle fiber activation evoked by surface
stimulation, Okuma et al. (108) measured the am-
plitude of the direct motor response (M wave) at
superficial (0.7 ⫾ 0.2 cm from the surface of the
muscle) and deep (2.0 ⫾ 0.3 cm) locations within
the tibialis anterior muscle. The intramuscular re-
cordings were made with fine-wire electrodes that
had 0.25 cm of the insulation removed from the tip
of the wire. The current was applied either through
pads that were trimmed to fit over the middle
one-third of each participant’s tibialis anterior
muscle or an electrode (3.2-cm diameter) attached
over the innervating nerve (common peroneal)
near the head of the fibula. The primary outcome
variable was an M-wave recruitment curve that
shows the relation between M-wave size (␮V·s) and
applied current (mA). When the current was ap-
plied through the electrodes attached over the
muscle, they found that a greater current was
needed to achieve specific M-wave sizes (5%, 50%,
and 95% of maximum) at the deep location than at
the superficial location. In contrast, when the elec-
trical stimulation was applied through the elec-
trodes placed over the nerve, there were no
statistically significant differences in the current
required to achieve the three M-wave sizes at the
two intramuscular locations.
These results indicate that the location of the
stimulating electrodes has a significant impact
on the spatial distribution of the activated mus-
cle fibers. Due to the widespread distribution of
intramuscular nerve branches in large muscles
(FIGURE 1) that can give rise to several motor
points (82, 124), multiple electrodes are necessary
to engage most of the motor units in a muscle (22).
In smaller muscles that have less intramuscular
nerve branching, however, a similar force can be
evoked by electrodes placed over the motor point
and the innervating nerve (62).
Although the terminal branches of intramus-
cular axons are distributed widely throughout a
muscle (FIGURE 1), over-the-muscle stimulation
presumably results in no more than modest
amounts of jitter in the arrival time of the action
potentials at the muscle fibers within and across
motor units, and this variability remains rela-
tively consistent across contraction intensities
(12, 33, 96). Consistent with a fundamental dif-
ference in the genesis of the activation signal

FIGURE 1. Branching of intramuscular nerves for three lower leg muscles in humans
The branching patterns were identified in cadaveric specimens (n ⫽ 8) using modified Sihler’s staining technique. The gray area in each panel indi-
cates the location of the distal attachment to the skeleton. A: tibialis anterior, innervated by branches of the deep fibular nerve. B: gastrocnemius,
the two heads (medial and lateral) are innervated by the tibial nerve. C: soleus, innervated by the tibial nerve, which branches into superficial and
deep compartments. Images are from Ref. 160 and used with permission from Surgical and Radiologic Anatomy.

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between voluntary and evoked contractions,
Jones et al. (69) found that an increase in the cur-
rent delivered to a hand muscle evoked stronger
contractions but did not alter the amplitude of the
fluctuations in the low-pass-filtered force (25 Hz)
in contrast to the signal-dependent noise observed
during voluntary contractions. The electrical stim-
ulation (25–30 Hz, 0.3 ms) was applied through
electrodes placed over the motor point of extensor
pollicis longus to elicit forces in the range of 20 –
70% MVC. FIGURE 3, RIGHT shows that the fluctu-
ations in the filtered force signal during multiple
trials of evoked contractions did not change across
three target forces. In contrast, the amplitude of
the force fluctuations during the voluntary con-
tractions increased with target force, which is at-
tributed to an increase in the variance of common
synaptic input to motor neurons (48, 105, 141) that
augments the jitter in the arrival times of the action
potentials at the muscle fibers.
Central Distribution of Evoked Responses
In addition to influencing the spatial distribution
of evoked responses within the muscle, placement
of the electrodes around the motor point or over
the nerve elicits action potentials in a broad range
of sensory axons that provide feedback received by
the central nervous system (103, 111, 118, 153). We
know from classic studies on the Hoffmann (H)
reflex that it is possible with a single-stimulus
pulse to evoke action potentials in large-diameter
REVIEW
sensory axons alone or a mixture of sensory and
motor axons when the stimulating electrodes are
attached to the skin close to a peripheral nerve (63,
64). At low intensities, the current initially elicits
action potentials in afferent axons— especially
group Ia fibers—that evoke excitatory post-synap-
tic potential in motor neurons and then engage a
spinal reflex pathway to produce an evoked re-
sponse (H reflex) in a target muscle (110, 114, 125)
and to recruit low-threshold motor units (33).
Gradual increases in current intensities will pro-
gressively activate motor axons to produce a direct
motor response (M wave) and eventually suppress
the H reflex completely (67). Although the stronger
currents still elicit action potentials in group Ia
afferents, the motor neurons are less responsive to
the synaptic input provided by the sensory fibers.
This occurs because the membrane potential be-
comes refractory due the antidromic propagation
of the action potential along the motor axon back
into the spinal cord, as indicated by the recruit-
ment curves for M waves and H reflexes (see Fig. 1
in Ref. 125).
H reflexes and M waves can also be recorded
when a train of electrical stimuli are used to evoke
a muscle contraction; this method of activating
muscle is known as neuromuscular electrical stim-
ulation (NMES) (89). For example, Collins et al. (27)
demonstrated that NMES delivered through large
pads (3–18 cm ⫻ 3.5 cm) placed over lower leg
muscles (tibialis anterior and triceps surae) was

FIGURE 2. Recruitment order for a pair of motor units during voluntary and electrically evoked
contractions
The recruitment order of two motor units (MU1 and MU2) in tibialis anterior during a voluntary contraction (C) and
the corresponding motor unit action potentials (1) and mechanical responses (2) as determined by spike-triggered
averaging (A, B). The same two motor units, based on the similarity of the action potential shapes (D), were acti-
vated by different currents delivered through electrodes attached to the skin over the motor point of tibialis ante-
rior (cathode: 0.8-mm diameter) and on the calf muscles (anode: 2 ⫻ 3 cm). Data are from Ref. 49 and used with
permission from Experimental Brain Research.

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REVIEW
able to elicit action potentials in sensory axons
(current set below motor threshold) alone or in
both sensory and motor axons (current set above
motor threshold). When the applied current (rect-
angular pulses) was set below motor threshold, the
electrical stimulation (100 Hz with 1-ms pulses)
elicited a muscle force that began at 1.5–5 s after
stimulus onset and continued for 2–10 s until it
reached a value of 2–10% of the MVC force. To
demonstrate that the evoked force was attributable
to sensory feedback, the response was abolished
after conduction along the nerve was blocked with
an anesthetic that was applied proximal to the site
of electrical stimulation (19, 81).
The magnitude of the feedback-evoked force
was greater when Collins et al. (27) increased the
current intensity to elicit action potentials in
motor axons and evoke an initial force that was
~5% of the MVC value. By the end of the 7-s
contraction, force had increased by 1.6-fold for
the dorsiflexors and 1.9-fold for the plantar flex-
ors, although there was considerable variability
in the magnitude of the response among partic-
ipants (16, 154). Collins et al. (27) found that the
capacity of the sensory feedback to augment the
applied force was greatest at a stimulus fre-
quency of 100 Hz compared with 25 Hz and 200
Hz and for 1-ms pulses compared with 0.05-ms
and 0.25-ms pulses.
Subsequently, Bergquist et al. (15) compared the
force evoked in the plantar flexors by NMES that
was delivered either through electrodes placed
over the peripheral nerve (tibial nerve in the pop-
liteal fossa) or over the muscles themselves. The
maximal amplitude of the M wave evoked in soleus
was similar for the two stimulus locations, but the
amplitude of the maximal H reflex normalized to
the maximal M-wave amplitude was greater for
electrodes placed over the tibial nerve (0.60 ⫾ 0.01)
than that evoked by electrodes placed over the
muscle (0.10 ⫾ 0.01). These findings suggest that
sensory feedback, at least that transmitted by
group Ia afferents, was greater when NMES was
delivered through electrodes placed over the nerve
compared with when the stimulation was delivered
over the muscle. Similar findings were reported by
the same group when the protocol was performed
on the quadriceps femoris muscles, although H-re-
flex amplitude relative to M-wave amplitude was
much less in quadriceps than in soleus (16).
However, augmentation of the applied force by
sensory feedback during over-the-muscle stimula-
tion does not rely exclusively on the activation of
group Ia afferents. For example, Blouin et al. (19)

FIGURE 3. Forces exerted by the thumb during voluntary and NMES-induced contractions to dif-
ferent target forces
The force was produced by the extensor pollicis longus muscle, which is solely responsible for extension of the dis-
tal phalanx of the thumb. NMES (25–30 Hz, 0.3 ms) was delivered through electrodes (cathode: 1 ⫻ 2 cm; anode:
5-cm diameter) placed around the motor point. Columns 1 and 3 show the complete force trace for the voluntary
(column 1) and NMES-evoked (column 3) forces. Columns 2 and 4 show the force fluctuations relative to average
force. The “4 s” bar indicates the absence of visual feedback. Data are from Ref. 69 and used with permission
from Journal of Neurophysiology.

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found that high-frequency stimulation (100 Hz,
rectangular 1-ms pulses) delivered through elec-
trodes placed over the motor point of a muscle
with weak homonymous Ia monosynaptic projec-
tions (flexor pollicis longus) was able to elicit extra
torque that was abolished with a nerve block. A
similar result was obtained for biceps brachii
(19) and for first dorsal interosseus (10), both of
which have stronger Ia monosynaptic connectiv-
ity. Moreover, the application of anesthesia to
the skin overlying first dorsal interosseus re-
duced the amplitude of the central response
(long-latency reflex in response to a fast stretch
of the muscle) that was augmented by electrical
stimulation (60 –100 s) applied to the skin at an
intensity less than motor threshold (10). These
findings were collectively interpreted as indicat-
ing that electrical stimulation applied over the
muscle elicits action potentials in both muscle
and non-muscle afferents.
When the current (2.5–10 mA; 1-ms rectangular
pulses) applied over the nerve is less than that
needed to elicit an H reflex in soleus, the activated
sensory axons can transmit sufficient excitatory
synaptic input to motor neurons that results in
some of them discharging action potentials. Dean
et al. (33) found that the activated motor units
began discharging action potentials at varying la-
tencies (0.5–29.6 s) after the onset of the electrical
stimulation, and these motor units were all re-
cruited at low forces during voluntary contrac-
tions. The recruitment latency (time from the onset
of electrical stimulation) decreased with an in-
crease in stimulus rate from 10 to 60 Hz during the
constant-frequency stimulation with no further re-
ductions at 80 and 100 Hz. Discharge rate at re-
cruitment was low (2–5 pps), but this increased to
a steady-state value (~8 pps) despite there being no
increase in the applied current. The discharge
times for 24% of the action potentials occurred at
an H-reflex latency, whereas the timing of most
action potentials was unrelated to that of the stim-
ulus pulse. These findings suggested that the acti-
vation of sensory axons with low currents enabled
adjustments in motor neuron excitability that re-
sulted in the generation of action potentials.
When the sensory response elicited by electrical
stimulation enters the spinal cord, it is dispersed to
both intraspinal networks and ascending path-
ways. Modulation of these pathways differs for vol-
untary actions and those evoked by electrical
stimulation. In response to a ramp-and-hold
stretch of a muscle, the reflex pathways produce
short-, medium-, and long-latency responses. After
a sustained MVC with a hand muscle that lasted
108 ⫾ 25 s, Balestra et al. (10) found that the am-
plitudes of the short- and medium-latency re-
sponses due to muscle afferents engaging spinal and
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REVIEW
supraspinal pathways was reduced but that the am-
plitude for the long-latency response mediated by
non-muscle afferents was unchanged. In contrast,
the changes in the amplitudes of these responses
differed when the fatiguing contraction (117 ⫾ 32 s)
was evoked by NMES (supramaximal pulses at 30 Hz
with a duration of 0.2 ms) applied over the muscle.
Despite a similar reduction in the applied force for
the two fatiguing contractions (~50% of the initial
value), the NMES condition resulted in no change in
the amplitudes of the short- and medium-latency
responses, and an increase in the amplitude of the
long-latency response. Augmentation of the long-
latency response after NMES was attributed to
feedback transmitted by cutaneous receptors in
response to electrical stimulation, whereas the ab-
sence of a change in the short- and medium-la-
tency responses was likely caused by the lack of a
decrease in the responsiveness of the Ia afferent
spinal and supraspinal reflex pathways following
the NMES-evoked contraction.
In addition to engaging short-latency spinal
pathways, the synaptic input projects to interneu-
rons that modulate the activity of motor neurons
innervating synergists and contralateral homolo-
gous muscles (7, 53, 66, 101, 102, 138). These ef-
fects can be observed when electrical stimulation is
delivered through pads attached over the muscles
of one arm while the same muscles in the other
arm perform a submaximal voluntary contraction.
Based on EMG signals recorded with a high-den-
sity electrode (4 ⫻ 8 detection points; 10-mm in-
terelectrode distance), for example, Hamilton et al.
(58) found that electrical stimulation (50 and 90
Hz, 0.2 and 1.0 ms) applied to the right biceps brachii
influenced both the discharge times of motor units
and the spatial distribution of EMG amplitude in the
left biceps brachii during a submaximal (10% MVC
force) isometric contraction. Although they found
that the specific adjustments varied with the fre-
quency, pulse width, and intensity of the applied
electrical stimulation, the most common response
was an increase in the activity of motor units in left
biceps brachii, as indicated by an increase in ab-
solute EMG amplitude (mV). However, these ef-
fects in the left biceps brachii were most often
observed after the 10 s of electrical stimulation
applied to the right arm had ended, which is con-
sistent with other reports of the effects outlasting
the interval during which electrical stimulation is
applied (7, 26, 33, 93).
The sensory feedback generated by electrical
stimulation of muscle also reaches supraspinal
centers. For example, NMES applied to muscle can
increase the responsiveness of corticospinal path-
ways, as demonstrated by changes in the amplitude
of the potentials evoked in muscle by transcranial
magnetic stimulation (TMS) applied over the motor
PHYSIOLOGY • Volume 35 • January 2020 • www.physiologyonline.org 45
REVIEW
cortex (24, 73, 77, 84), but the effect appears to de-
pend on the frequency, duration, and intensity of the
stimulation (25, 57, 94). Also, the change in respon-
siveness appears to differ for arm and leg muscles.
When NMES (100 Hz, 1 ms) was applied—the cur-
rent was set to elicit an M wave equal to 15% of the
maximal value—for 40 min (20-s on, 20-s off) over
the common peroneal nerve (tibialis anterior) and
over the median nerve (abductor pollicis brevis),
Mang et al. (93) found that the amplitude of the
motor evoked potential increased for both target
muscles (tibialis anterior, 45 ⫾ 6%; abductor pollicis
brevis, 56 ⫾ 8%) with mixed effects in other muscles.
The amplitude of the motor evoked potential in-
creased in both adjacent (soleus, 47 ⫾ 5%) and dis-
A
14
12
MEP amplitude (% Mmax)
tant (vastus medialis, 36 ⫾ 3%) leg muscles, but there
was no change in the amplitude of the potentials
evoked in either an adjacent hand muscle (first dor-
sal interosseus) or a muscle in the forearm (extensor
carpi ulnaris) (FIGURE 4). These findings were inter-
preted as indicating that NMES had a more global
effect on the cortical neurons that projected to motor
neurons innervating the involved leg muscles than
those related to the engaged arm muscles.
The specific cortical adjustments elicited by a
single session of NMES, at least for targeted hand
muscles (first dorsal interosseus), appear to in-
volve a reduction in short-latency inhibition and
an increase in short-latency facilitation (92).
These effects were demonstrated by comparing
the amplitudes of motor evoked potentials before
and after a conditioning stimulus was applied to
the ulnar nerve at the level of the wrist before the
test stimulus (transcranial magnetic stimulation

over the motor cortex). NMES eliminated the

10
short-latency depression (25%) in the conditioned
8 response and augmented (33%) the later condi-
tioned response, which suggests a net increase in
6 the excitation delivered by afferent fibers to corti-
cal neurons. Moreover, NMES (100 Hz, 1 ms) ap-
4
plied to a right forearm muscle (15% MVC force)
2
for 10 min (5-s on, 5-s off) has been shown to
increase the level of interhemispheric inhibition
0 from the left to the right primary motor cortex,
Before After Before After likely due to an increase in the excitability of tran-
Tibialis anterior Abducctor scallosal neurons in the left hemisphere (57). As
pollicis brevis
with the effects observed at the spinal level, the
central adjustments elicited by NMES of ⱖ40 min
B
continue after the stimulation has ended (26, 93,
135).
0.20 0.9
These studies demonstrate that the delivery of
an electric current through electrodes attached to
MEP amplitude (mV)

MEP amplitude (mV)

0.15 the skin over either a peripheral nerve or a limb

0.6
0.10
0.3
0.05
0.00
Before After
Leg
FIGURE 4. The amplitude of motor evoked potentials in leg and arm mus-
cles before and after NMES
The motor evoked potentials (MEPs) were evoked by transcranial magnetic stimulation
applied over the appropriate areas in the motor cortex. NMES (100 Hz, 1 ms) was ap-
plied for 40 min over the common peroneal nerve (tibialis anterior) and the median
nerve (abductor pollicis brevis). A: MEP amplitude (normalized to maximal M-wave am-
plitude) increased by 45 ⫾ 6% for tibialis anterior and by 56 ⫾ 8% for abductor pollicis
brevis after the application of NMES. B: MEP amplitude (mV) increased by an average
of 42 ⫾ 4% for both adjacent (soleus, 47 ⫾ 5%) and distant (vastus medialis, 36 ⫾ 3%)
leg muscles after NMES but did not change for either adjacent (first dorsal interosseus)
or distant (extensor carpi ulnaris) arm muscles. Data are from Ref. 93 and used with
permission from Experimental Brain Research.
muscle can elicit action potentials in sensory axons
that are propagated into spinal and supraspinal
networks (16, 19, 24, 26, 27, 58, 63, 64, 73, 77, 81, 92,
93, 135). These central effects are evident whether
the applied current is greater than or less than the
threshold required to evoke a muscle contraction
(10, 25, 58, 156). A number of studies have demon-
0 strated that the adjustments elicited by the sensory
Before After feedback vary with the stimulus parameters, such
Hand as pulse width, frequency, current amplitude, and
electrode location. These findings raise the ques-
tion of which set of parameters can elicit clinically
meaningful adaptations (134).
Rehabilitation
As indicated in the title of our paper, the second
half of this review focuses on the rehabilitation po-
tential of electrical stimulation applied to muscle.

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Moreover, we limit the discussion to non-invasive
approaches that are used to elicit sensorimotor ad-
aptations (99, 114, 117, 126, 129) and not electrical
nerve stimulation that is used to assist a specific
function [functional electrical stimulation (FES)].
For example, FES is used to supplement an inad-
equate muscle activation during such actions as
toe clearance during the gait cycle (99, 134, 135,
137), the leg extension phase of cycling (13, 44) and
rowing (40, 140), and reaching actions (59, 75).
Despite its primary function, FES also engages sen-
sory axons that distribute input throughout the
nervous system and produce adaptations that are
evident when the device is not in use (59, 117, 131,
135).
Similar to other investigators (126, 130, 142), we
distinguish between electrical-stimulation proto-
cols in which the applied current exceeds motor
threshold and evokes a muscle contraction and
those for which the current is less than motor
threshold and elicits action potentials primarily in
sensory nerve fibers. When the intensity of the
applied current is sufficient to evoke a muscle con-
traction, the protocol is typically referred to as
NMES. In contrast, protocols that apply a lesser
current and largely engage sensory axons are
known as transcutaneous electrical nerve stimula-
tion (TENS).
Neuromuscular Electrical Stimulation
NMES is used most often in clinical settings to
recover skeletal muscle mass and function after a
period of reduced use (29, 37, 38, 87, 89, 150, 158),
but sometimes it is used in healthy individuals to
augment the activation signal generated by the
nervous system (43, 56, 143). Despite the benefits
that can be achieved with NMES treatments (121),
the approach is not effective for some clinical co-
horts, such as individuals who have undergone
cardiac valve surgery [no effect on gait speed or
walking endurance (52)], those undergoing chemo-
therapy treatment for cancer [no effects on quad-
riceps muscle strength, thigh lean mass, or
physical activity (86)], those with mild-to-moder-
ate osteoarthritis [no effect on quadriceps muscle
strength (109)], intensive care survivors [no effect
on handgrip strength (112)], and critically ill pa-
tients [inability to elicit an adequate quadriceps
muscle contraction (128)].
As an example of an effective NMES protocol,
Stevens-Lapsley et al. (136) performed a clinical
trial to evaluate the capacity of NMES to attenuate
the depression of muscle activation that is ob-
served after total knee arthroplasty (145, 159). The
60 participants were randomized into two groups
that received standard-of-care rehabilitation either
alone (control group) or in combination with
NMES. All participants performed the same set of
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REVIEW
standardized exercises in inpatient (6 sessions in 3
days), home (6 sessions in 2 days), and outpatient
(10 –12 sessions in 6 wk) settings. In addition, one
group self-administered NMES (50 Hz, 0.25 ms;
biphasic, symmetrical stimulus pulse) applied
through large-pad electrodes attached to the skin
over the relaxed quadriceps muscle of the operated
leg while seated. The protocol involved 15 evoked
contractions (15-s on, 45-s off) at the maximal tol-
erated intensity. Evaluation sessions were per-
formed during the rehabilitation protocol (3.5 and
6.5 wk after the surgical procedure) and on three
subsequent occasions (13, 26, and 52 wk).
At the primary end point (3.5 wk), the NMES
group exhibited less of a decline in the strength of
the quadriceps and hamstrings muscles and less of
a reduction in performance on three functional
tests (6-min walk, stair-climbing test, and timed
up-and-go test). Subsequently, muscle strength re-
covered for both groups of participants but at 52
wk remained significantly less for the control
group relative to the NMES group (FIGURE 5). Sim-
ilarly, performance on the three functional tests
improved for both groups of participants, but the
gains were greater for the NMES group. Although
the measure of muscle activation (doublet-inter-
polation technique) also improved for both groups
of participants, NMES did not augment the capac-
ity of the nervous system to activate muscle as
indicated by the absence of a change in the level of
voluntary activation. Nonetheless, NMES greatly
attenuated the decline in performance on the func-
tional tests at the primary end point and aug-
mented the gains observed during the follow-up
period (FIGURE 5C). Moreover, NMES improved
the increase in the strength of the hamstring mus-
cles, even though the treatment was applied to the
quadriceps muscle. These findings suggest that
NMES elicited more global adaptations than those
expected from the contractions evoked in the tar-
geted muscle. The protocol developed by Stevens-
Lapsley et al. (136) was subsequently expanded as
the recommended approach for using NMES to
restore quadriceps muscle function in individuals
who undergo an orthopedic procedure (133).
Similar results have been obtained in other
NMES intervention studies, even with different
stimulation parameters. For example, Almuklass et
al. (5) performed a clinical trial in which they com-
pared the influence of two NMES protocols on the
gains in function experienced by persons living
with multiple sclerosis. Participants were ran-
domly assigned to receive a 6-wk treatment (18
sessions) of NMES applied at either 100 Hz with
1-ms pulses or at 50 Hz with 0.26-ms pulses to the
dorsiflexor and plantar flexor muscles of each leg.
Each muscle group was stimulated for 10 min (4-s
on, 12-s off) at the maximal tolerable intensity in
PHYSIOLOGY • Volume 35 • January 2020 • www.physiologyonline.org 47
REVIEW
each session. There were no statistically significant
differences in the outcomes for the two groups of
participants, which indicates that the two NMES
protocols had similar effects on the primary out-
comes. The 6-wk intervention elicited clinically
significant improvements with moderate effect
sizes in gait speed (time to walk 25 ft.) and walking
endurance (distance walked in 6 min), and these
gains were still present at 4 wk after the interven-
tion. The NMES treatment increased muscle
strength for the dorsiflexors of the affected leg and
the plantar flexors of the less-affected leg, but not
the other muscles. Consistent with a global influ-
ence of NMES, the intervention improved self-re-
ported levels of fatigue and walking limitations and
the time to complete a pegboard test of manual
dexterity. However, there were no changes in the
daily level of physical activity and the self-reported
measure of disability status. Given that two of the
major symptoms associated with multiple sclerosis
are fatigue and walking limitations, the NMES in-
tervention was successful in reducing the burden
of the disease.
Mani et al. (95) used a similar approach to com-
pare the outcomes produced by the two NMES
protocols in healthy older adults (74 ⫾ 5 yr). The
NMES protocols were similar to those used by Al-
muklass et al. (5), and there were no statistically
significant differences in the outcomes exhibited
by the two groups of participants (100 Hz, 1 ms vs.
50 Hz, 0.26 ms). In contrast to the study on persons
with multiple sclerosis, the time course of the ad-
aptations elicited in older adults by the NMES in-
tervention varied across the outcome measures.
The primary outcomes were mobility tests, which
included gait speed (time to walk 10 m), walking
endurance (time to walk 400 m), and dynamic bal-
ance (chair-rise test and rapid step test). Gait speed
and walking endurance had improved midway
through the 6-wk intervention, with no further
changes at weeks 7 and 10. Performance on the two
tests of dynamic balance improved progressively
up to the end of the intervention (week 7), with no

FIGURE 5. Recovery of muscle function after to-

tal knee arthroplasty
The clinical trial involved two groups of participants who
performed standard rehabilitation exercises alone (con-
trol group) or in combination with NMES applied to the
quadriceps muscle of the operated leg. NMES (50 Hz,
0.25 ms) was applied to the relaxed quadriceps muscle
at the maximal tolerable intensity twice daily for 6
weeks. A: change in quadriceps strength (torque normal-
ized to body mass) across the 52-wk study, which in-
cluded the rehabilitation treatment (first two time points
after week 0) and follow-up. B: change in the strength of
the hamstring muscles. C: change in the test of walking
endurance (6-min test). *Statistically significant (P ⬍
0.05) differences between groups. Data (means ⫾ SE)
are from Ref. 136 and used with permission from Physi-
cal Therapy.

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further change during the 4-wk follow-up period.
The strength of the plantar flexor muscles (average
of both legs) was increased at the end of the inter-
vention (week 7) and remained elevated at week 10.
There were no statistically significant changes in
the strength of the dorsiflexor, knee extensor, knee
flexor, and hip flexor muscles. The changes in mo-
bility, therefore, seem to be unrelated to the peak
forces achieved during maximal isometric contrac-
tions performed with these muscle groups. Sim-
ilarly, there were no statistically significant
changes in the amplitude of the force fluctua-
tions during steady submaximal contractions
with plantar flexor muscles, suggesting that the
modulation of motor unit activity was not influ-
enced by the NMES intervention (48, 105, 141).
One of the noteworthy outcomes of these three
studies (5, 95, 136) was that several weeks of NMES
applied to leg muscles was able to elicit significant
improvements in performance on clinical tests of
motor function. In all three studies, the applied
current was passed between pairs of electrodes
attached to the skin over target muscles (knee ex-
tensors, plantar flexors, or dorsiflexors). An alter-
native approach is to increase the number of
stimulation sites by placing multiple electrodes
over a single muscle group (50, 104, 121) or attach-
ing pairs of electrodes over many muscles (9, 11,
51). Two examples illustrate the types of adapta-
tions that can be achieved with this approach.
The first example demonstrates the capacity of
multiple-muscle NMES to improve performance of
healthy individuals. The study compared the gains
achieved by sedentary adults (48 ⫾ 12 yr) after a
6-wk intervention that involved five 1-h training
sessions each week (11). NMES (rhythmic contrac-
tions at 4 Hz) was delivered through large elec-
trodes embedded in tight-fitting shorts that evoked
contractions in the quadriceps, hamstrings, glu-
teal, and calf muscles. Stimulus intensity was con-
strained by subject tolerance and an increase in
heart rate of no more than 90% of heart-rate re-
serve during prescribed exercises. The intervention
elicited increases in peak oxygen consumption
(10.9 ⫾ 8.5%) during a treadmill test of aerobic ca-
pacity, walking endurance (6-min walk; 7.5 ⫾
4.0%), and the strength of the quadriceps muscles
(27 ⫾ 22%). One critical feature of this study was
that the response of each participant to the appli-
cation of NMES to multiple muscles was regulated
by trained personnel. Care is necessary with this
approach, since unsupervised use of multi-muscle
NMES systems has been reported to produce rhab-
domyolysis in some individuals (72, 91).
The second example involves that application of
multiple-muscle NMES to individuals with chronic
low-back pain (155). Participants were randomly
assigned to either a treatment group (multiple-
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REVIEW
muscle NMES) or a control group for the 12-wk
intervention. NMES (80 Hz, 0.35 ms) was applied to
8 –10 muscle groups concurrently in a single 20-
min (6-s on, 4-s off) session each week while par-
ticipants performed six movements with minimal
voluntary activity. The current was adjusted for
each muscle group to achieve a rating of ⱖ “hard”
on a Borg scale. The primary outcome was a self-
reported measure of pain intensity on a scale of 0
(no pain) to 10 (worst possible pain) during the last
4 weeks of the intervention. The pain score de-
creased significantly for the NMES group and was
accompanied by increases in the strength of the
trunk extensor and flexor muscles. There were no
statistically significant changes for the control
group. Given that pain representations are local-
ized to specific regions within the brain (77), the
multiple-muscle NMES intervention must have
modulated the pathways and networks that con-
tribute to the perception of pain.
These NMES studies demonstrate that the appli-
cation of electrical stimulation at an intensity suf-
ficient to evoke a muscle contraction can elicit
improvements in tests of muscle function and
performance on tests of motor function. The re-
sults suggest that many of the adaptations elic-
ited by the treatment occur within the nervous
system, but little is known about the specific
changes underlying the gains in function and
why the time course of the improvements varies
across outcome variables.
Transcutaneous Electrical Nerve
Stimulation
Transcutaneous electrical nerve stimulation (TENS)
is a form of stimulation in which the applied elec-
trical current is constrained to engage sensory
nerve fibers with no more than minimal evoked
muscle contractions. When the current is set at
around motor threshold (slightly above or below),
it elicits action potentials in a wide range of muscle
and non-muscle sensory axons (103, 110, 118, 153).
With mixed success, it is used clinically at various
frequencies [1–150 Hz (147)] to manage pain (106,
120), spasticity (47, 115, 132), and urinary inconti-
nence (142, 144). In this review, we briefly discuss
an additional application of TENS when it is ap-
plied to limb muscles: its capacity to improve sen-
sorimotor function.
As a rehabilitation technique, TENS can be used
to augment sensory feedback during the perfor-
mance of an action (18, 31, 78, 130, 147, 153) or it
can be used as a treatment to modify neural path-
ways and networks that are engaged during pre-
scribed tasks (23, 36, 127). As an example of using
TENS to augment sensory feedback during an ac-
tion, Almuklass and colleagues (4) assessed the
influence of TENS (50 Hz, 0.2 ms) applied to the leg
PHYSIOLOGY • Volume 35 • January 2020 • www.physiologyonline.org 49
REVIEW
muscles of persons with multiple sclerosis (MS) on
their performance of standard clinical tests. Some
of the earliest signs of the damage caused by MS
are changes in sensory function, which in the legs
is reported as numbness, tingling, pins-and-nee-
dles, and sleepy leg (8, 14, 139). The significance of
the sensory impairments is underscored by find-
ings of meaningful associations between loss of
sensation and declines in motor function, such as
decreases in vibration sensation and increases in
the time to walk 25 ft. over a 2-year period (162).
Critically, much of the variance in vibration sensa-
tion was explained (R2 ⫽ 0.54) by MRI-detected
abnormalities in the dorsal column and diagnosis
subtype (161), which suggests that the accumula-
tion of sensorimotor disabilities in MS is strongly
associated with spinal cord abnormalities (34).
The rehabilitation potential of targeting sensory
axons was assessed by Almuklass et al. (4) when
they compared the influence of TENS on the
performance of individuals with MS who had mild-
to-moderate levels of disability with an age- and
sex-matched control group on measures of gait
speed (time to walk 25 ft.), walking endurance (dis-
tance walked in 6 min), and dynamic balance
(chair-rise test). TENS (50 Hz, 0.2 ms) was deliv-
ered through large electrodes attached to the skin
over the ankle dorsiflexor muscles and the anterior
thigh muscles of the more affected leg and was
applied continuously during the performance of
each test. The intensity was set at just above motor
threshold and was applied continuously during the
performance of each test. The increase in sensory
feedback elicited by TENS produced clinically
FIGURE 6. Percent changes in clinical outcomes elicited by TENS in per-
sons with multiple sclerosis
The green bars show statistically significant differences (means ⫾ SE) in performance
for 13 individuals between a sham condition and when each test is completed with the
concurrent application of TENS (4). Positive values denote an improvement in perfor-
mance. The blue bars show the change from before to after a 3-wk intervention (9 ses-
sions) for 12 individuals (3). The 25-ft. data indicate maximal gait speed; the 6-min
values are the distance walked in 6 min (4) or 2 min (3); the Chair scores are for the
chair-rise test; GPT refers to the grooved pegboard test; fatigue was measured with
the Modified Fatigue Impact Scale; and Walking refers to the self-reported assessment
of walking limitations (Multiple Sclerosis Walking Scale-12). With the exception of the
GPT, all changes (blue bars) were statistically significant. Data are from Refs. 3, 4 and
used with permission from the American Society of Biomechanics.
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significant improvements (FIGURE 6) in gait speed,
walking endurance, and dynamic balance for the
MS group (52 ⫾ 8 yr). There were no statistically
significant effects for the control group (52 ⫾ 9 yr),
except for an improvement in walking endurance
(distance walked in 6 min). The specific adjust-
ments underlying these transient improvements in
mobility remain to be determined.
Work on the capacity of TENS to modify neural
pathways and networks has examined the influ-
ence of its application either immediately before
performing a prescribed task or as a treatment
administered over several sessions. Cohen and col-
leagues have performed several studies in which
they assessed the influence of a single session of
prolonged electrical nerve stimulation on hand-
arm function in stroke survivors (23, 156). The
TENS was delivered through electrodes attached to
the skin over peripheral nerves (median, radial,
and ulnar) of the paretic hand and leg (peroneal,
sural, and tibial nerves) at an intensity just below
(156) or above (23) motor threshold. The electrical
stimulation involved bursts of 5 pulses (1 ms each)
at 10 Hz (0.5 s of stimulation) once each second for
2 h. The primary functional outcome was the time
to complete the Jebsen-Taylor Hand Function
Test, which comprises seven tests that quantify
manipulation and dexterity. Time to complete the
test was reduced immediately after the electrical
nerve stimulation and at 1 and 24 h later, with the
greatest improvements exhibited by those partici-
pants with more pronounced impairments. More-
over, the benefit was observed only when the
stimulation was applied at two sites on the arm
concurrently and not when it was applied to the
paretic leg. Consistent with other studies on the
central effects of TENS (60, 88), Celnik et al. (23)
found that their protocol of electrical nerve stim-
ulation reduced the TMS-estimated level of short-
interval intracortical inhibition, which is mediated
by GABAergic neurotransmission. A subsequent
study found that the improvement in the accuracy
of a tracking task by healthy adults after applica-
tion of this TENS protocol for 20 min was accom-
panied by increases in EEG-derived estimates of
activity and connectivity within the sensorimotor
cortex (151).
In a series of studies on several different cohorts,
Dinse and colleagues have examined the effective-
ness of somatosensory stimulation applied to the
fingertips on arm and hand function (71, 85, 127).
In one of these studies, Kattenstroth et al. (71)
assessed the influence of 10 sessions of a TENS
protocol on the motor function of individuals in
the subacute phase after a unilateral ischemic
stroke. The study involved two groups: a TENS
group and a sham group. TENS was applied to
the fingertips of the more-affected hand and

comprised bursts (1.4-s on, 5-s off) of electrical
stimuli (20 Hz, 0.2 ms) at an intensity above sen-
sory threshold (median nerve: 10.0 ⫾ 3.9 mA; ulnar
nerve: 6.7 ⫾ 3.5 mA) for 45 min each session. The
outcomes included measures of light-touch and
tactile discrimination, proprioception, dexterity,
grip force, and the Jebsen-Taylor Hand Function
Test. The TENS group experienced significantly
greater improvements in all measures of sensori-
motor function, but the effect size (Cohen’s
d ⫽ 0.72) was greatest for the measures of sensory
function (tactile performance). There were also sig-
nificant improvements in motor function, as re-
ported in a parallel study by the same group (85).
Consistent with the results reported for a single
TENS session (23), the gains experienced by the
participants were greater for those who were more
impaired (71).
In contrast to employing TENS as a stand-alone
treatment, Shimodozono et al. (130) assessed the
influence of the concurrent application of TENS (20
Hz, 0.25 ms) during the performance of therapeutic
exercises by individuals with severe impairments in
arm function due to post-stroke hemiplegia. The
4-wk treatment, which was performed 40 min/day
on 5 days/wk (20 sessions), comprised 100 –150
repetitions of standardized movements about the
shoulder, elbow, and wrist joints of the affected
arm. TENS was applied continuously during the
exercises at an intensity slightly above motor
threshold, similar to the protocol used by Al-
muklass et al. (4). The primary outcome was the
change in the Fugl-Meyer Assessment Scale for the
arm, with secondary outcomes being the range of
motion about the involved joints. The group that
performed the exercises with TENS experienced a
clinically significant improvement in the Fugl-
Meyer score, whereas the change for the group that
performed exercises without TENS did not differ
from that for the control group. Also, the TENS
group exhibited a significant increase in the range
of motion for elbow extension but not for shoulder
flexion or wrist flexion. The gains, however, were
not accompanied by changes in the scores for
spasticity.
These studies on the effectiveness of TENS indi-
cate that the outcomes are relatively insensitive to
the duration of the stimulus pulse (range: 0.05–1.0
ms), stimulus frequency (range: 10 –50 Hz), and the
intensity of the applied current, provided it evokes
no more than weak contractions (23, 80, 156).
However, other details of the protocol appear to be
more critical. For example, some studies have
found that the outcomes are beneficial when TENS
is applied continuously during an action (4, 18,
130, 153), whereas others have observed significant
gains when TENS is delivered in low-frequency
bursts of pulses during a conditioning treatment
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REVIEW
for durations that range from 15 min to 2 h (36,
151, 156) or as an intervention administered for
several weeks (3). Also, it requires an appropriate
placement of the stimulating electrodes (4, 23,
156). For example, synchronous activation of the
median and ulnar nerves elicited more beneficial
effects on motor function than did electrical stim-
ulation applied to one nerve (23). Moreover, the
TENS electrodes need to be placed over the weak-
est muscles of the more affected leg of individuals
with multiple sclerosis to elicit clinically significant
improvements in walking performance (4). Criti-
cally, the responsiveness of axons and neuromus-
cular junctions tends to decline with prolonged
high-frequency stimulation (74, 107), which neces-
sitates some variability in the stimulus protocol
(31). This diversity of protocols suggests that some
work is needed to identify the optimal set of pa-
rameters needed to elicit clinically meaningful ad-
aptations in specific cohorts.
Although some studies have explored the under-
lying neurophysiology responsible for the benefits
achieved with TENS, these have largely focused on
changes at the cortical level (18, 30, 85, 127, 151).
Given the capacity of TENS to improve motor func-
tion, the gains must be mediated by adjustments in
the output from the spinal cord. Work is needed to
characterize the changes in muscle activation pro-
duced by TENS and then to determine the path-
ways and networks that are modulated by TENS to
generate the observed gains.
Future Directions
Whether the current applied during electrical stim-
ulation is greater than (NMES) or less than (TENS)
motor threshold, it is capable of improving senso-
rimotor function in healthy adults and some clin-
ical cohorts. The key issues that need to be
resolved include identifying the stimulation details
that maximize the benefits associated with each
protocol and characterizing the adaptations un-
derlying the improvements in performance.
Although electrical stimulation—especially NMES—
is typically applied when the person is not active
(3, 5, 95, 136), some studies suggest that the gains
may be more substantial when the intervention is
applied during the performance of prescribed ac-
tions (147). In some of these studies, the stimula-
tion is synchronized with a particular event in the
action (18), whereas, in other studies, the stimula-
tion is applied continuously (21, 29, 51, 130, 153).
The relative capacity of these two approaches to
elicit clinically significant adaptations remains to
be determined. Moreover, it would be of interest
to determine the degree of similarity between the
adjustments elicited in a single session in which
the electrical stimulation is applied concurrently
PHYSIOLOGY • Volume 35 • January 2020 • www.physiologyonline.org 51
REVIEW
during the performance of an action and the
adaptations evoked by several sessions of NMES
or TENS (FIGURE 6).
The studies cited in our review indicate that the
rehabilitation potential of electrical stimulation
can range from the modulation of motor function
in various groups of individuals to the reduction in
symptom severity in clinical cohorts. In the sim-
plest case, it is not surprising that several sessions
of NMES can increase the strength of target mus-
cles (6, 11, 28, 43, 50, 136), but this result can be
quite variable (4, 21, 39, 95, 122). Although the
strength gains appear to be mediated by increases
in the level of muscle activation (6, 39, 70, 90),
several weeks of NMES can induce adaptations in
muscle-fiber properties (55, 152). One unexpected
outcome of these interventions is the capacity of
NMES to increase the strength of non-targeted
muscles. For example, an NMES protocol that tar-
geted the knee extensor muscles increased the
strength of both the knee extensors and knee flex-
ors (136). Similarly, NMES training of the dorsi-
flexor muscles resulted in an increase in the EMG
activity of medial gastrocnemius during the perfor-
mance of postural tasks (6). Even the strength of
muscles in the contralateral limb can be increased
by the application of NMES to one limb (17, 65).
Moreover, the application of NMES to leg muscles,
whether in the thigh or the lower leg, can improve
performance on a test of walking endurance (6-
min walk) (4, 11, 95, 136, 152), which suggests the
improvements in mobility involve other adapta-
tions besides increases in muscle strength. Rela-
tively few studies, however, have probed the
physiological adaptations responsible for these off-
target improvements in function.
Even more interesting is the capacity of low lev-
els of electrical nerve stimulation to reduce the
intensity of self-reported symptoms, such as pain
and fatigue. TENS can be effective in some clinical
settings for the treatment of pain (32, 119, 146),
which it accomplishes by evoking the local release
of opioids to dampen inflammation-induced hy-
peralgesia (123, 148) and activating central inhibi-
tory pathways (32, 35). Although both NMES and
TENS can reduce self-reported levels of fatigue in
various groups of individuals (FIGURE 6) (3, 5, 29,
32, 95), much less is known about the adaptations
responsible for a decrease in the level of fatigue.
Current taxonomies of fatigue suggest that the
level of fatigue reported by an individual can be
modulated by factors that contribute to perceived
and performance-based measures of fatigability
(45, 163). Of these two domains, it seems more
likely that the factors contributing to perceived fa-
tigability—maintenance of homeostasis and psycho-
logical state—are the ones that respond to the
sensory feedback associated with electrical stimula-
52 PHYSIOLOGY • Volume 35 • January 2020 • www.physiologyonline.org
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tion. However, we know essentially nothing about
these interactions. In contrast, our knowledge on
pain is much more advanced as methods are being
developed that can derive predictive models from
neuroimaging data to interpret mental constructs
(79). A parallel approach would generate new knowl-
edge on fatigue and its modulation by electrical stim-
ulation of muscle.
Clinical and experimental findings have demon-
strated that electrical stimulation can provide a
number of therapeutic benefits, underscoring its
utility as a rehabilitation tool. Although some at-
tempts have been made to standardize effective
protocols (133), many of the details remain to be
established. Critically, our understanding of the re-
sponses elicited in the nervous system by the appli-
cation of electrical stimulation to muscle is quite
rudimentary. 䡲
No conflicts of interest, financial or otherwise, are de-
clared by the author(s).
R.M.E. and J.D. conceived and designed the review;
R.M.E. and J.D. prepared figures; R.M.E. and J.D. drafted
manuscript; R.M.E., I.G.A., and J.D. edited and revised
manuscript; R.M.E., I.G.A., and J.D. approved final version
of manuscript.
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