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Cell Transplantation, Vol. 24, pp.

429446, 2015
Printed in the USA. All rights reserved.
Copyright 2015 Cognizant Comm. Corp.

0963-6897/15 $90.00 + .00

E-ISSN 1555-3892

Electrical Stimulation and Motor Recovery
Wise Young
W. M. Keck Center for Collaborative Neuroscience, Rutgers, State University of New Jersey, Piscataway, NJ, USA

In recent years, several investigators have successfully regenerated axons in animal spinal cords without locomotor
recovery. One explanation is that the animals were not trained to use the regenerated connections. Intensive locomotor training improves walking recovery after spinal cord injury (SCI) in people, and >90% of people with incomplete SCI recover walking with training. Although the optimal timing, duration, intensity, and type of locomotor
training are still controversial, many investigators have reported beneficial effects of training on locomotor function.
The mechanisms by which training improves recovery are not clear, but an attractive theory is available. In 1949,
Donald Hebb proposed a famous rule that has been paraphrased as neurons that fire together, wire together. This
rule provided a theoretical basis for a widely accepted theory that homosynaptic and heterosynaptic activity facilitate
synaptic formation and consolidation. In addition, the lumbar spinal cord has a locomotor center, called the central
pattern generator (CPG), which can be activated nonspecifically with electrical stimulation or neurotransmitters to
produce walking. The CPG is an obvious target to reconnect after SCI. Stimulating motor cortex, spinal cord, or
peripheral nerves can modulate lumbar spinal cord excitability. Motor cortex stimulation causes long-term changes
in spinal reflexes and synapses, increases sprouting of the corticospinal tract, and restores skilled forelimb function
in rats. Long used to treat chronic pain, motor cortex stimuli modify lumbar spinal network excitability and improve
lower extremity motor scores in humans. Similarly, epidural spinal cord stimulation has long been used to treat pain
and spasticity. Subthreshold epidural stimulation reduces the threshold for locomotor activity. In 2011, Harkema et
al. reported lumbosacral epidural stimulation restores motor control in chronic motor complete patients. Peripheral
nerve or functional electrical stimulation (FES) has long been used to activate sacral nerves to treat bladder and pelvic dysfunction and to augment motor function. In theory, FES should facilitate synaptic formation and motor
recovery after regenerative therapies. Upcoming clinical trials provide unique opportunities to test the theory.
Key words: Functional electrical stimulation (FES); Central pattern generator (CPG); Spinal cord injury (SCI);
Synaptic formation; Motor recovery

In the past decade, several prominent laboratories have
shown axonal regeneration in animal spinal cord injury
(SCI) models, but locomotor recovery did not follow regeneration (277). For example Lu et al. (159,160) and Hes
group (156,282) regenerated many axons that synapsed
with neurons in the lower spinal cord, but the animals did
not recover walking. To explain the lack of locomotor
recovery, the investigators assume that insufficient numbers of regenerated axons have formed synapses with
appropriate neurons in the lower spinal cord to support
locomotion. Another explanation for the lack of locomotor
recovery after complete SCI and regeneration is that the animals did not learn to use their newly regrown connections.

Regenerated fibers are very unlikely to be contacting the

same neurons they used to. To walk again, animals must
not only establish synaptic connections with appropriate
lumbosacral neurons but also learn to turn on different
neurons to control locomotion.
Locomotor recovery is common after incomplete SCI.
Dobkins et al. (54) found that >90% of people with
incomplete SCI recover independent locomotion within a
year, whether they undertake treadmill or conventional
overground walking training. Many groups have reported
that locomotor training improves walking recovery in people
with chronic incomplete SCI (92,97,99,100,115,126,143,
162,258,262266). In 2008, Behrman et al. (19) described
a 4-year-old child who recovered walking with intensive

Received December 9, 2014; final acceptance January 27, 2015. Online prepub date: February 2, 2015.
Address correspondence to Wise Young, Ph.D., M.D., Distinguished Professor of Cell Biology and Neuroscience,
The Richard H. Shindell Chair in Neuroscience, and Founding Director of the W. M. Keck Center for Collaborative Neuroscience, Rutgers,
State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854-8082, USA. E-mail:



locomotor training and continued to improve 2 years after

severe incomplete SCI (68).
Few investigators, however, have observed improved
walking in people with complete SCI. Murillo et al.
(181) recently described a 15 year old with complete SCI
who recovered walking after locomotor training. Knikou
et al. (136) trained 16 subjects with incomplete and complete SCI in 45 sessions, 1 h/day, 5 days a week, and
found that the training promoted intralimb and interlimb
coordination and reduced cocontraction of knee and ankle
antagonists in both incomplete and complete subjects.
However, the complete subjects were not walking.
In the last 3 years, several groups reported that epidural stimulation (57,58,180,244) of the spinal cord of people with chronic severe SCI restore weight-bearing (9,220)
and voluntary motor function (5,98). Many clinical studies
suggest that both central and peripheral electrical stimulation improve long-term motor (90) and sensory recovery
(204), including standing (48), walking (96,105,130,204),
and hand function (106,129).
The mechanisms underlying stimulus-induced recovery
are not well understood. In this review, I will critically
assess the role of training, the central pattern generator
(CPG), Hebbian mechanisms of synaptic facilitation, and
various stimulation paradigms used to facilitate recovery of
motor function after SCI, including epidural cortical stimulation, epidural spinal stimulation, and functional electrical stimulation (FES) of peripheral nerves.
Locomotor training should activate diverse descending
tracts entering the spinal cord, including regenerated motor
axons. In theory, stimulation of peripheral nerve of arms
and legs should activate ascending volleys of afferents that
would facilitate synapses made by regenerating axons on
appropriate interneurons and motoneurons. If patients were
to try to move their arms or legs in synchrony with FES
activating hand grasp and foot flexion, we should see
improved motor control of these important muscles.
This theory should be straightforward to test in animals
and in humans treated with regenerative therapies. In animals, descending volleys can be activated by either motor
cortex stimulation or epidural stimulation of the spinal cord,
timed to coincide with antidromic and afferent volleys
elicited by peripheral nerve stimulation. In humans, FES can
be used to activate hand grasp and foot flexion repeatedly,
while the person attempts to move the hands or feet in
synchrony. Upcoming clinical trials assessing regenerative
therapies such as mononuclear cells and neural stem cell
transplants provide opportunities to test this theory.
Treadmill training improves locomotor recovery in
animals (124,164). For example, Ward et al. (257) studied
rats that received a T10 spinal cord contusion and then
trained for 1 h/day to walk. After 3 months of training, the


rats improved limb kinetics, gait, and hindlimb flexor

extensor bursting patterns compared to nontrained controls.
The training increased expression of nerve growth factor,
but not brain-derived neurotrophic factor or neurotrophin-3.
The rats not only improved locomotor function but also
improved bladder function and neuropathic pain. Shin et al.
(228) did gene expression profiling of the rat lumbar spinal
cord at 1 and 3 weeks after contusive SCI at T9 and locomotor training. Treadmill training did not influence injuryinduced upregulation of inflammation-related genes, but
increased the expression of genes associated with neuroplasticity (activity-regulated cytoskeleton-associated protein, neuronal cell adhesion molecule) and angiogenesis [a
disintegrin and metalloproteinase domain 8 (Adam8), tyrosine kinase with immunoglobulin-like and epidermal growth
factor-like domains 1 (Tie1)]. Locomotor training increased
the regeneration of the soleus muscle (124).
Wernig et al. (162,258266) first reported that weightsupported treadmill walking improves locomotor function
of people with incomplete SCI (92,97,99,100,115,126,143).
Many investigators have reported beneficial effects of automated (222,270), electromechanical (22), robotic (185,234,
275), cable-driven (274), conventional treadmill training
(61), daily passive cycling (45), exoskeletal robotic orthoses (110,175), and other activity-based training (157) on
locomotor function and balance (67), spasticity (28,163),
gait impairment (113), and respiratory function (247). Less
intensive locomotor training (twice a week) also appears
to be beneficial (187). Morrison et al. (178,179) estimated
that locomotor training reduced lifetime care costs. Two
reviews (169,176) suggested that while some of these
approaches show potential for ambulatory improvement,
randomized clinical trials are needed to show that these
instrument-intensive programs are better than progressive
overground training (55).
Despite many studies, however, the best approach, intensity, timing, and duration of locomotor training are still controversial (176). In Australia, a randomized controlled trial
has started to compare regular and intense activity-based
training (70). Laburuyere and van Hedel (148) studied
nine subjects with chronic incomplete SCI, randomized
to 16 sessions of robotic assisted gait training (RAGT)
over 4 weeks followed by 16 sessions of strength training or the reverse order of strength training followed by
RAGT. Strength training improved maximal walking speed
(10MWT) more than RAGT, and both interventions
reduced pain. Behrman et al. (19,68) reported a 4.5-yearold child who recovered walking with intensive locomotor training and continued to improve 2 years after severe
incomplete SCI.
Locomotor training may help patients with complete SCI
as well. Knikou et al. (136) studied 16 patients with complete and incomplete SCI after 45 locomotor training sessions, 5 days a week and 1 h/day. The training potentiated


homosynaptic depression, promoted intralimb and interlimb

coordination, and altered cocontraction of knee and ankle
antagonistic muscles in both complete and incomplete
patients. Presynaptic facilitation of soleus Ia afferents
occurred only in patients with incomplete SCI. Murillo
et al. (181) likewise described a 15 year old with complete
SCI who recovered walking after locomotor training.
Perhaps the most impressive training effect on locomotor
recovery was reported by Zhu et al. (281) in 2008. They
recruited 30 subjects within several weeks of complete SCI,
that is, American Spinal Cord Injury/International Spinal
Cord Society Impairment Scale A (AIS/ISCOS A), decompressed the spinal cord by removing adhesions between the
spinal cord and surrounding tissues and then trained the
subjects to walk 6 h a day, 6 days a week, for 3 months.
Before surgery, none of the subjects could stand without help. By 17 days after surgery, without rehabilitation,
10 subjects (33%) were walking using a rolling walker
without assistance. Over 3 months, 18 subjects (60%)
recovered walking in a rolling walker without assistance.
Dobkin et al. (54) showed that 90% of patients with
motor incomplete (AIS/ISCOS C) will recover unassisted
walking within a year after SCI, regardless of the type of
locomotor training program. The patients were randomized to either treadmill walking or overground walking for
3 months after injury. The two groups showed no significant difference, but 92% of motor incomplete patients
with AIS/ISCOS C recovered unassisted walking, while
100% of patients with AIS/ISCOS D recovered unassisted walking.
In 1949, Donald Hebb (102) wrote on page 63 of his
famous book The Organization of Behavior; a Neuropsychological Theory:
Let us assume that the persistence or repetition of a reverberatory activity (or trace) tends to induce lasting cellular changes that add to its stability When an axon of
cell A is near enough to excite a cell B and repeatedly
or persistently takes part in firing it, some growth process or metabolic change takes place in one or both
cells such that As efficiency, as one of the cells firing
B, is increased.

This rule is sometimes summarized as cells that fire

together, wire together, but this summary is a gross oversimplification. As Caporale and Dan (37) pointed out, the
synaptic modification has critical windows of tens of milliseconds and involves homosynaptic and heterosynaptic
mechanisms, including long-term potentiation (LTP) due
to trains of activity, release of neurotransmitters such as
serotonin, and neuromodulatory heterosynaptic interactions between synapses that involve both facilitation
and depression.


In 2000, Bailey et al. (10) wrote an article entitled, Is

heterosynaptic modulation essential for stabilizing Hebbian
plasticity and memory? Homosynaptic facilitation or LTP
is primarily for learning and short-term memory, while
heterosynaptic facilitation involves long-term memory that
requires protein synthesis and synaptic formation. Bailey
et al. (11) showed that synaptic connections between
glutamatergic sensory neurons and motoneurons could be
facilitated by heterosynaptic mechanisms or repetitive homosynaptic activation. Serotonin mediates long-term facilitation in Aplysia, converting short-term Hebbian plasticity
into persistent, protein synthesis-dependent synapses. Both
homosynaptic and heterosynaptic activity may be necessary
to consolidate regenerated synapses, explaining why intensive locomotor activity or epidural stimulation enhances locomotor recovery, by ensuring descending activity to establish
synapses on lumbosacral neurons. However, specifically
timed heterosynaptic activation may be necessary to consolidate synapses for volitional activation of individual muscles.
Since the classic experiments of Hubel and Wiesel, who
found that formation of ocular dominance columns requires
visual experience, most scientists have accepted that neuronal activity maintains and refines synaptic connections
through Hebbian and other competitive mechanisms. While
synaptogenesis can proceed without neuronal activity (253)
or neurotransmitter release (255), neuronal activity also
regulates synaptic formation (4). Using live imaging and
genetic control of tetanus toxin, Soto et al. (233) showed
that increased spontaneous activity selectively increases synaptic formation in the developing retina.
In 2003, Rushton (215) proposed an interesting hypothesis. He pointed out that FES used to mimic or augment a
weak or paralyzed muscle sometimes is followed by specific recovery of voluntary power. He proposed that FES
may somehow promote adaptive changes in cortical connectivity, specifically that the corticospinal to neuronal synapses were a Hebb-type modifiable synapse (i.e., one that
is strengthened by coincidence of presynaptic and postsynaptic activity, then FES, combined with coincident voluntary effort through a damaged pyramidal motor system
should facilitate synaptic formation and modification).
In 2010, Everaert et al. (62) pointed out that long-term
use of foot-drop stimulator applying FES to the common
peroneal nerve improves walking performance even when
the stimulator is off. They hypothesized that this therapeutic
effect may be a result of neuroplastic changes in the spinal
cord, related to Hebbian plasticity. They studied 10 patients
with nonprogressive (such as stroke) and 26 people with
progressive disorders (such as multiple sclerosis) who used
a foot-drop stimulator for 312 months while walking in
the community. They recorded surface electromyograms
(EMGs) of the tibialis anterior muscle elicited by stimulating motor-evoked potentials (MEPs) using transcranial
magnetic stimulation, by maximum voluntary contraction


(MVC), and maximum motor wave from stimulating the

common peroneal nerve. They found that FES significantly improved MEPs and MVCs by 50% and 48% in
the nonprogressive and progressive groups, respectively.
Walking speed also increased.
A lumbar spinal cord motor center that controls locomotion was postulated over a century ago by GrahamBrown (80) who pointed out that hindlimb locomotion
(then called progression) may be elicited in late spinal
animals (p. 308) and that a mechanism confined to the
lumbar part of the spinal cord is sufficient to determine in
the hind limbs an act of progression, which is probably very
nearly a normal one . . . the act of progression is automatic
and conditioned by the integration of reflex movements
which follow each other successively, and each of which
determines the stimulus which calls the following movement into being.
Sherrington (225) had earlier noted in 1910 that cutting
of superficial sensory nerves of the foot (carrying information from the skin) did not abolish the reflexive stepping
and trotting. Graham-Brown (80) created a decerebrate low
spinal animal preparation by cutting the spinal cord at T12
and demonstrated that regular walking motions continued
and that only proprioceptive information from the muscles
is necessary and sufficient for walking and trotting. Cats
recover hindlimb locomotion 23 weeks after a hemisection
and then rerecover such walking after the spinal cord is
transected 3 weeks later.
In 1981, Dimitrijevic and Larsson (53) pointed out the
importance of the CPG in human recovery of locomotion.
In 1998, Dimitrijevic et al. (51,202) provided the first direct
evidence for the presence of the CPG in the second lumbar
segment of the spinal cord. Minassian et al. (173,174)
showed that stepping-like movements could be activated in
humans with complete SCI with extrinsic tonic input, showing that the CPG can convert continuous 5- to 15-Hz epidural stimulation to rhythmic walking activity.
The CPG can be activated by intrathecal administration
of the neurotransmitter serotonin in lamprey (101), neonatal rats (43,235), and adult rats with SCI (6,231). FeraboliLohnherr et al. (63,64) showed the sublesional transplants
of serotonergic neurons could restore locomotor function
in rats with chronic SCI. In fact, Guertin et al. (89)
showed that oral administration of buspirone, levodopa,
tand carbidopa could activate locomotor activity in paraplegic mice. Koopmans et al. (137) studied functional recovery,
lumbar serotonergic sprouting, and increased endogenous
progenitors in rats exposed to delayed environment enrichment after SCI. They concluded that environmental enrichment improves interlimb coordination associated with
serotonergic innervation of the L1L2 segments, where the
CPG is located.


Activation of the CPG can be nonspecific. As shown

in Figure 1, descending brain and incoming sensory activity can initiate CPG activity. For example, walking starts
with hip extension, knee extension, foot extension, then
foot flexion, knee flexion, and hip flexion. Tail stimulation can activate cats to walk (280), and vibration applied
to the foot alone can elicit step-like behavior in people
with chronic motor incomplete SCI (66). Activation of
CPG can initiate locomotor behavior even when subjects
cannot activate individual muscles. The CPG is located at
the top of the lumbar spinal cord, a shorter distance for
regenerating axons to reach. Finally, CPG can initiate
walking movements in both legs in the case of hemiplegia or unilateral regeneration.
In 2006, Righetti et al. (209,210) pointed out that nonlinear oscillating circuits, such as the CPG, are particularly susceptible to Hebbian type of learning. They showed
that the learning of rhythms is successful even when the
teaching signal is noisy and that the encoded trajectory,
once practiced, is stable against perturbations. Many
rhythms of locomotion are intrinsic properties of oscillatory networks, including biped gaits of two-legged hop,
run, and gallop (203) that can be reinforced with simple
Hebbian rules (3). Therefore, it is reasonable that the CPG
should be sensitive to training, that is, repeated walking
motions to reinforce patterns.
Given the likelihood that walking training can reinforce locomotor rhythms and that nonspecific activation
of the lumbar spinal cord can activate the CPG, it would
seem to be a natural target for regenerating axons. Much
evidence suggests that the CPG can be entrained even in
people with complete SCI. If even a small number of
axons were to reach the CPG and were able to release
neurotransmitters to activate it, people should be able to
recover walking. This may explain why most people with
incomplete SCI recover walking (54).
Spinal cord activity can be influenced in several ways.
One way is of course to shower the spinal cord with
activity in descending spinal tracts. Locomotor training
should stimulate descending activity of many pathways.
Another way is to stimulate the motor cortex, which in
turn can activate midbrain, brainstem, and spinal cord.
The motor cortex can be readily activated with epidural
electrodes or transcranial electrical currents or magnetic
fields. Subthreshold motor cortex stimuli are not particularly uncomfortable or painful but can activate the motor
cortex without overt movements.
Motor cortex stimulation has long been used to treat pain
(31,177,183,273). In 2004, Lefaucheur et al. (151) reported
successful repetitive transcranial stimulation treatment of
subjects with drug-resistant intractable pain due to stroke,
SCI, brachial plexus injury, or trigeminal injury, compared



Figure 1. CPG for locomotor function. Located in the lumbar spinal cord (L2), the locomotor CPG contains programs that control
movement of hip, knee, and foot muscles. The CPG activates walking by first causing hip extension, then knee extension, then foot
extension, followed by foot flexion, knee flexion, and hip flexion. This sequence of activation can be initiated by activating the
CPG and subsequent reflexive and sensory inputs resulting from the walking motions. Likewise, running, hopping, skipping,
jumping, and dancing motions can be initiated, sustained, and modulated by the brain without direct activation of motoneurons. The
leg muscle illustration was adapted from

to sham stimulation. Tani et al. (243) successfully used

bilateral cortical stimulation to treat a woman with neuropathic pain after SCI. Fregni et al. (69) did a phase II
clinical trial to assess transcranial direct current to alleviate central pain after SCI, showing that active anodal
stimulation of the motor cortex reduced pain compared to
sham stimulation.
In 2012, Wang et al. (256) showed that weak electrical
stimulation of rat sensorimotor cortex causes long-term
changes in spinal H-reflexes and motoneuron g-aminobutyric
acid (GABA) receptors. Within weeks of initiating stimulation, the numbers and sizes of GABAergic spinal interneurons increased, while GABAA and GABAB receptor
labeling on soleus motoneurons decreased. Several months
after terminating stimulation, the interneuronal and GABA
terminal changes disappeared, but the H-reflex increase
and receptor decreases remained. Ahmed and Wieraszko
(2) found that trans-spinal direct current enhances corticospinal output and evoked release of glutamate analog
dehydroascorbic acid in the spinal cord in rats. Hou et al.
(113) found that combined treadmill and transcranial magnetic stimulation improved locomotor recovery in rats.
Carmel et al. (32,33,39,41,42) stimulated rat motor cortex after unilateral section of the corticospinal tract, finding

that 10 days of electrical stimulation leads to increased

sprouting of spinal axons that partially restores the sectioned corticospinal tract as well as cortical projection to
the magnocellular red nucleus (40), which projects the
rubrospinal tract to the spinal cord. The stimulation also
restored skilled motor function in the forelimbs of the rats,
bringing error rates of food retrieval to prelesion levels.
Reversible inactivation of the stimulated motor cortex reinstated the impairment.
Roche et al. (212) have assessed the effects of
transcranial direct current simulation in 15 healthy human
subjects, showing that such stimulation can modify
lumbar spinal network excitability and decrease cervical
propriospinal system excitability. Stein et al. (236) reported
similar results. Rebesco and Miller (208) showed that cortical stimulation can be used to produce Hebbian conditioning within the cortex in healthy subjects. Solopova
et al. (232) used transcranial magnetic stimulation to facilitate voluntary control and triggering of stepping behavior.
Benito et al. (21) used high-frequency repetitive transcranial
magnetic stimulation in patients with motor incomplete
SCI and found improved lower extremity motor scores.
Thus, motor cortex stimulation is not only feasible but also
safe and may improve motor function.


Motor cortical stimulation, however, has several drawbacks. First, having electrodes or magnetic paddles on the
head requires a helmet or some kind of head covering.
Second, electrical activation of the motor cortex may interfere with daily activity. Third, the effects of motor cortical
stimulation are relatively nonspecific and therefore should
be coupled with exercise or stimulation of the impaired
limb. On the other hand, it is not difficult to imagine people placing a helmet on while exercising their impaired
limbs for several hours a day. If this is effective in restoring motor control, this would be worth the trouble.
Epidural spinal cord stimulation has long been used to
treat intractable pain in patients (29,111,116,145,146,149,
177,183,188,227,230). Sayenko et al. (220) showed that
lumbosacral epidural stimulation activated widespread rostral and caudal areas of the lumbar spinal cord, involving
afferent and efferent pathways, in a patient with chronic
SCI. Maruyama and Shimoji (165) showed that epidural
spinal cord stimulation in 105 patients inhibited segmentally evoked spinal cord potentials and reduced cerebrospinal fluid norepinephrine concentrations.
Epidural stimulation activates widespread activity in
the spinal cord. Sato et al. (218) compared 0.5-h and 6-h
stimulation at 50%, 75%, and 90% motor threshold in
rats, showing that stronger and longer stimulation showed
the largest increase in mechanical withdrawal threshold.
Ichiyama et al. (118) showed that epidural stimulation
enhanced hindlimb stepping in rats with complete spinal
cord transections. Gerasimenko et al. (75) and Ichiyama
et al. (117) used a combination of epidural stimulation
and quipazine administration to facilitate walking in rats.
In 1980, Sherwood et al. (226) used epidural stimulation
to augment motor performance in 28 patients with upper
motor neuron disorders. In 1985, Barolat-Romana et al.
(18) reported that epidural spinal cord stimulation reduced
intractable spasms in six patients after SCI and spasticity
(15,17), while enhancing voluntary motor function (16).
Campos and Dimitrijevic (36,52) have reported that epidural stimulation have a long-lasting effect on spasticity,
while others (171) found that the treatment lacks long-term
efficacy and is not cost-effective.
Subthreshold epidural stimulation improves locomotor
function in patients with incomplete SCI. In 1998, Herman
et al. (104) used epidural electrodes to activate the lumbar
CPG in a patient with severe incomplete SCI. When the
stimulation was on, the subject walked faster and expended
less energy over 15 m. After a few months of training, the
subject walked longer distances of 50250 m and performed
multiple functional tasks within the home and community
with epidural stimulation (114). Other investigators have
used epidural lumbar stimulation (9,144,180) to reduce the
motor threshold for locomotor activation.


In 2011, Harkema et al. (57,98) reported that lumbosacral epidural stimulation restored lower extremity voluntary
control in chronic motor complete patients (5,9,98,214,220).
Four individuals are able to move their legs voluntarily
even when the stimulation was not on. However, none of
the subjects were able to walk. Although the mechanisms
of the voluntary recovery are not well understood, one
attractive possibility is that epidural stimulation enhances
sprouting and causes both homosynaptic and heterosynaptic
facilitation of synapses.
Epidural stimulation has several advantages over cortical stimulation. First, implanted epidural electrodes are
unobtrusive, and the stimulus can be left on through the
day and even at night. Second, especially for people with
SCI with reduced motor and sensory function in the lower
body, the stimulation should not interfere with daily activities. Third, although surgically placed epidural electrodes
may be associated with some complications (77,158), many
thousands of people have had epidural electrodes without
problems. Finally, Hofstoetter et al. (107) showed that noninvasive transcutaneous spinal cord stimulation can ameliorate spasticity in people with incomplete SCI. Electrodes
can also be introduced percutaneously (135). Such stimulation directly activates sensory and motor roots (213) and
can also activate locomotor circuits (168,172).
The mechanisms by which epidural stimulation improve
motor function are not well understood. However, one
attractive hypothesis is that widespread activation of both
ascending and descending activity in the spinal cord may
strengthen synaptic activity in lumbosacral motor centers
through Hebbian mechanisms, including walking, micturition, and defecation. Recent unconfirmed reports (46,123,
170,278) suggest epidural stimulation may improve sexual
function, another programmed activity of the lower spinal
cord. If confirmed, epidural stimulation is likely to become
a popular approach for this purpose. At least one company
has patented such a device (268).
Sacral nerve stimulation (SNS) has been used since
1967 to activate bladder voiding (91,132,182,241), to treat
bladder incontinence (20,34,44,59,78,108,119,120,122,
221,229), to alleviate pelvic pain (1,38,190,279), to prevent
fecal incontinence (50,7274,103,153), and to relieve constipation (56,128,133,134,161,166,167,186,189,248,252,272).
In 1998, Hamdy et al. (93) discovered that transcranial
motor cortex stimulation modifies anal sphincter electromyographic responses evoked by SNS in 11 healthy subjects, suggesting direct cortifugal pathways to sacral motor
centers. In 2005, Sheldon et al. (224) found that SNS
depressed corticoanal excitability for as long as 2 weeks
after SNS cessation.
In 1980, Peckham and Mortimer (194) used implanted
electrodes to stimulate forearm musculature of a quadriplegic


patient. In 1981, Dimitrijevic and Larson (53) stimulated

peripheral nerves to modify locomotion. In 1984, Kralj et al.
(141) applied multichannel stimulation to strengthen muscles
for standing and to assist gait. Petrofsky and Phillips (197)
developed a feedback-based stimulator for an isokinetic
leg trainer and exercise bicycle. Bajd et al. (12) used surface electrodes to restore reciprocal walking in patients with
incomplete SCI. Krajl et al. (139) stimulated quadriceps
to enhance locking of knee joints (140) during walking in
people with incomplete SCI.
The advent of commercially available stimulators, feedback, and computers that control multichannel systems (87,
112,138,147,198,199,219) led to many devices (152,201)
for improving walking (81,237), activating hand function
(24) through voice commands (94), enhancing coughing
(154), and even relieving seating pressures (65). Called
neuroprostheses (25,193), these devices often are designed
to correct specific deficits, such as foot drop (27,217,245)
and hand grasp weakness (47,249,267). Other devices, such
as the Parastep (71), use multichannel stimulators to activate
leg muscles for standing and walking (184,238,239,242).
FES implies electrical stimuli applied to skin surface
over muscles, usually activating local nerves innervating
muscle. For this reason, FES cannot be used to stimulate
denervated muscles (79). For many years, most physicians
regarded FES as a means of activating muscle (192,195,200)
to exercise paralyzed limbs (206,207) and to rebuild muscle
(86,127), bone (95,150), and joints (23). Many FES devices
have been approved for exercise (109,121,142,196,216).
The usefulness of FES devices varies. Taylor et al.
(245) evaluated 126 patients who used a common peroneal nerve stimulator activated by a heel switch for 3.6
years and 33 who continued to use the device after 11.1
years. The stimulator allowed people with stroke to walk
45% faster and 52% of the subjects to improve their functional walking, for an average cost of 3,095. Hitzig et al.
(76,105) randomized 34 subjects with incomplete SCI to
thrice weekly stimulation-assisted and resistance training
programs. At 12 months, the former group showed a significant increase in muscle bulk and had improved SCIM
mobility subscores, but did not otherwise improve walking. Karimi et al. (130,131) reviewed the literature and
found that user performance with mechanical orthoses
was generally better than hybrid FES orthoses.
Several recent clinical trials, however, have reported
that FES combined with activity-based therapies can contribute to walking recovery in people with chronic SCI.
Jones et al. (125) randomized 48 subjects with chronic
incomplete SCI to early or delayed activity-based therapy,
including developmental sequencing, resistance training,
repetitive pattern motor activity, and task-specific locomotor training for 9 h a week for 24 weeks. FES was part of
the training. Trained subjects had significant increases
in total motor scores and lower extremity motor scores,


as well as walking speeds, and total distances walked.

Kapadia et al. (129) studied eight participants with subacute cervical SCI. Five received 39 h of FES training of
hand function over 1316 weeks and three did not. The
FES-treated group improved their hand scores and selfcare scores. Hoffman et al. (106) compared FES and
somatosensory stimulation and found that both were associated with improved hand use and corticomotor control
in subjects with chronic tetraplegia.
Peripheral stimulation has central effects (26,88,211,246).
In 1992, Ragnarsson (205) pointed out that FES suppresses
spasticity. FES also causes endocrine changes, including increases in b-endorphin-like immunoreactivity and
cortisol levels (82,251). Likewise, FES induces autonomic
dysreflexia (7). In 1994, Barbeau and Rossignol (14) proposed that FES should have long-term beneficial effects on
locomotor recovery.
Many studies have reported that FES can improve
long-term motor (90) and sensory recovery (204) in people, including standing (48), walking (105,130), and hand
function (106,129). In 2007, Hardin et al. (96) reported a
22-year-old patient who was 18 months after a C56
incomplete (AIS/ISCOS C) SCI and had an implanted
eight-channel FES system for walking. After 12 weeks of
overground locomotor training, his maximal walking distance increased from 14 m to 309 m, maximal walking
speed increased by 10-fold, and the physiological cost
index fell fivefold. Before implantation of stimulating
electrodes, he underwent 36 preparatory sessions using
surface FES in a robotically assisted treadmill device that
bore 60% of his body weight.
In 2014, Possover et al. (204) described four patients
who had neuroprosthetic devices implanted to assist locomotor training combined with continuous low-frequency
pelvic lumbosacral stimulation. Two subjects were sensory incomplete (AIS/ISCOS B), one was motor incomplete (AIS/ISCOS C), and one was complete with flaccid
paralysis (AIS/ISCOS A). All four subjects recovered sensory and voluntary motor function: three recovered voluntary weight-bearing standing and walking a few meters
using a walker without FES, one patient was able to walk
900 m with two crutches and electrical stimulation and
30 m without stimulation.
Edgerton et al. (68) have long claimed that animals
with complete spinal cord recover weight-bearing stepping capability without reconnection of supraspinal tracts.
Askari et al. (8) studied the timing effects of electrical
stimulation during robotic treadmill training (RTT) of rats
with severe SCI. The rats that had FES synchronized to
RTT had much more (112%) EMG activity during the
early swing phase of the gait cycle, exhibited burst-to-step



latencies that were shorter (41%), and had greater ankle flexion than rats that received random stimulation. Tillakaratne
et al. (250) reported that such stepping recovery in rats
after complete neonatal spinal cord transection is not due
to regrowth across the injury site.
FES not only stimulates peripheral motor axons to
activate muscles but also sensory axons that return to the
spinal cord and activate both motoneurons and interneurons,
as well as the brain. If sensory activation coincides with
descending supraspinal activity, heterosynaptic facilitation
of synapses on spinal cord motoneurons and interneurons
may occur. In addition, peripheral nerve stimulation also
cause antidromic activation of motoneurons and Renshaw
neurons (254), which may facilitate synapse formation
(13,35,60,223,269) and release neurotransmitters that facilitate synaptic consolidation (240). Figure 2 illustrates how
descending supraspinal activity and incoming afferent activation may facilitate synapses. Hebbian facilitation of synapses can occur at multiple levels in the cortex, brainstem,
and spinal cord, as shown in Figure 3.
Not all FES-induced effects on the central nervous system are desirable. In 1986, Woolf and Wall (271) showed
that stimulation of C-fibers can have long-lasting effects
on flexor responses. Young et al. (276) described how neonatal hindpaw injury disrupts acquisition of instrumental
responses in adult spinal cords. Grau et al. (49,8385,
155,191) showed that noncontingent painful stimulation
of the legs markedly impairs locomotor learning. The timing of exercise therapy and intervention is important (30).
When combined with appropriate exercises synchronized
to the timing of stimulated activity, FES should induce longlasting changes in motor function, especially in situations
when new synapses are being formed by regenerating axons.
The theory that FES stimulation can induce Hebbian-type
facilitation of synapses formed by regrowing axons can be
tested in upcoming clinical trials that are planning to test
regenerative therapies. Not only will FES and exercise
improve the results of such trials but also the trials should
be able to ascertain whether Hebbian mechanisms are
involved in FES-induced recovery of motor function.
Electrical stimulation of the motor cortex, the spinal
cord, and peripheral nerves has long-lasting effects on motor
function in people with SCI. Many investigators have
reported beneficial effects of locomotor training after SCI.
Despite many studies, the best approach, timing, duration,
and intensity of locomotor training are still controversial.
A few patients with complete SCI have been reported to
recover walking.
In 1949, Donald Hebb (102) presciently proposed that
close timing of activation of a target neuron by two neurons
enhances synaptic connections of the neurons with the target neuron. This Hebbian rule, sometimes summarized as

Figure 2. Diagram of spinal cord circuits that may be affected

by functional electrical stimulation. Action potentials activated by
peripheral nerve stimulation descend to the muscles, ascend antidromically to activate motoneurons, and ascend orthodromically
in sensory Ia afferents to enter the spinal cord and activate
interneurons and motoneurons. Descending supraspinal tracts
from motor cortex and brainstem activate the motoneurons and
interneurons (not shown).

cells that fire together, wire together, has been extended

to include heterosynaptic and homosynaptic facilitation
and depression. Many studies have confirmed that neuronal
activity regulates synaptic formation and consolidation.
The lumbar spinal cord contains the CPG. Postulated
more than a century ago by Graham-Brown (80) and
Sherrington (225), the CPG plays an important role in locomotor recovery in humans. The CPG can be nonspecifically activated by epidural and peripheral nerve stimulation,



Epidural stimulation has long been used to treat intractable pain and spasticity, by evoking widespread spinal
cord and peripheral nerve activation. Subthreshold epidural stimulation reduced the threshold for activation of the
CPG. In 2011, Harkema et al. reported that lumbosacral
epidural stimulation can restore lower extremity voluntary
control (98). Others have reported that the spinal cord can
be activated with electrodes placed on the skin surface.
Peripheral nerve stimulation has similar effects to epidural stimulation. SNS, for example, has been used since
1967 to activate bladder voiding, to treat bladder incontinence, to alleviate pelvic pain, to prevent fecal incontinence, and relieve constipation. FES has been used to
stimulate arm and leg activity for exercise and to augment
function. For many years, physicians considered FES as
an electrical means of exercise.
FES can have long-term effects on motor recovery. In
theory, FES should facilitate and consolidate synapses
formed by regenerating axons. This hypothesis should be
readily testable in animal studies and human clinical trials
involving regenerative therapies. For example, it would be
of interest to assess the effects of FES stimulation on hand
grasp and foot flexors synchronized with voluntary efforts.
ACKNOWLEDGMENT: The author declares no conflict of


Figure 3. Multiple levels of Hebbian learning in the brain and

spinal cord. Hebbian learning can occur in the brain, brainstem,
and spinal cord. Cortical stimulation (A) can reinforce incoming
sensory activity coming from the dorsal column pathway through
the nucleus gracilis and thalamus. Brainstem cell stimulation (B)
can reinforce descending connections to the central pattern generator. Epidural stimulation or peripheral nerve stimulation can
reinforce descending connections to motoneurons (C) or to lumbosacral spinal cord (D).

and even by intrathecal and oral neurotransmitter administration. It is an obvious target locomotor recovery mechanism.
Spinal cord activity can be influenced by stimulating the
motor cortical, spinal cord, and peripheral nerves. Motor
cortex stimulation has long been used to treat pain. Such
stimulation affects spinal reflexes, changes spinal circuits,
enhances sprouting and synapse formation, and restores
skilled forelimb function in rats after corticospinal lesions.
Transcranial magnetic stimulation improves lower extremity motor scores in people with SCI.

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