Anda di halaman 1dari 18

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


DOI: http://dx.doi.org/10.3727/096368915X686904
E-ISSN 1555-3892
www.cognizantcommunication.com

Review
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

INTRODUCTION
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: wisey@pipeline.com

429

430

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.
IMPORTANCE OF LOCOMOTOR TRAINING
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

YOUNG

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

ELECTRICAL STIMULATION AND MOTOR RECOVERY

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.
ACTIVITY DEPENDENCE
OF SYNAPTIC FORMATION
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.

431

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

432

(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.
LUMBAR CENTRAL PATTERN GENERATOR
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.

YOUNG

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).
MOTOR CORTEX STIMULATION
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

ELECTRICAL STIMULATION AND MOTOR RECOVERY

433

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 http://www.irishhealth.com/content/image/2262/Image1.jpg.

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.

434

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
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.

YOUNG

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).
PERIPHERAL NERVE STIMULATION
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

ELECTRICAL STIMULATION AND MOTOR RECOVERY

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,

435

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.
MECHANISMS OF FES-MEDIATED
MOTOR CONTROL
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

436

YOUNG

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.
CONCLUSIONS
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,

ELECTRICAL STIMULATION AND MOTOR RECOVERY

437

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
interest.

REFERENCES

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.

1. Aboseif, S.; Tamaddon, K.; Chalfin, S.; Freedman, S.;


Kaptein, J. Sacral neuromodulation as an effective treatment for refractory pelvic floor dysfunction. Urology 60(1):
5256; 2002.
2. Ahmed, Z.; Wieraszko, A. Trans-spinal direct current
enhances corticospinal output and stimulation-evoked release
of glutamate analog, D-2,3-(3)H-aspartic acid. J. Appl.
Physiol. 112(9):15761592; 2012.
3. Akio, S.; Masaki, Y. Design of a novel central pattern generator and the Hebbian motion leaning. 18th IEEE International Conference on Control Applications, Part of the
2009 IEEE Multi-conference on Systems and Control. St.
Petersburg, Russia: IEEE; 2009:16551660.
4. Andreae, L. C.; Burrone, J. The role of neuronal activity
and transmitter release on synapse formation. Curr. Opin.
Neurobiol. 27C:4752; 2014.
5. Angeli, C. A.; Edgerton, V. R.; Gerasimenko, Y. P.;
Harkema, S. J. Altering spinal cord excitability enables
voluntary movements after chronic complete paralysis in
humans. Brain 137(5):13941409; 2014.
6. Antri, M.; Orsal, D.; Barthe, J. Y. Locomotor recovery in
the chronic spinal rat: Effects of long-term treatment with
a 5-HT2 agonist. Eur. J. Neurosci. 16(3):467476; 2002.
7. Ashley, E. A.; Laskin, J. J.; Olenik, L. M.; Burnham, R.;
Steadward, R. D.; Cumming, D. C.; Wheeler, G. D. Evidence of autonomic dysreflexia during functional electrical
stimulation in individuals with spinal cord injuries. Paraplegia 31(9):593605; 1993.
8. Askari, S.; Chao, T.; de Leon, R. D.; Won, D. S. The
effect of timing electrical stimulation to robotic-assisted
stepping on neuromuscular activity and associated kinematics. J. Rehabil. Res. Dev. 50(6):875892; 2013.

438

9. AuYong, N.; Lu, D. C. Neuromodulation of the lumbar


spinal locomotor circuit. Neurosurg. Clin. N. Am. 25(1):
1523; 2014.
10. Bailey, C. H.; Giustetto, M.; Huang, Y. Y.; Hawkins,
R. D.; Kandel, E. R. Is heterosynaptic modulation essential
for stabilizing Hebbian plasticity and memory? Nat. Rev.
Neurosci. 1(1):1120; 2000.
11. Bailey, C. H.; Giustetto, M.; Zhu, H.; Chen, M.; Kandel,
E. R. A novel function for serotonin-mediated short-term
facilitation in aplysia: Conversion of a transient, cell-wide
homosynaptic hebbian plasticity into a persistent, protein
synthesis-independent synapse-specific enhancement. Proc.
Natl. Acad. Sci. USA 97(21):1158111586; 2000.
12. Bajd, T.; Andrews, B. J.; Kralj, A.; Katakis, J. Restoration
of walking in patients with incomplete spinal cord injuries
by use of surface electrical stimulationPreliminary results.
Prosthet. Orthot. Int. 9(2):109111; 1985.
13. Baranyi, A.; Feher, O. Conditioned changes of synaptic
transmission in the motor cortex of the cat. Exp. Brain
Res. 33(2):283298; 1978.
14. Barbeau, H.; Rossignol, S. Enhancement of locomotor
recovery following spinal cord injury. Curr. Opin. Neurol.
7(6):517524; 1994.
15. Barolat, G.; Myklebust, J. B.; Wenninger, W. Effects of
spinal cord stimulation on spasticity and spasms secondary
to myelopathy. Appl. Neurophysiol. 51(1):2944; 1988.
16. Barolat, G.; Myklebust, J. B.; Wenninger, W. Enhancement of voluntary motor function following spinal cord
stimulationCase study. Appl. Neurophysiol. 49(6):307314;
1986.
17. Barolat, G.; Singh-Sahni, K.; Staas, W. E. Jr.; Shatin, D.;
Ketcik, B.; Allen, K. Epidural spinal cord stimulation in
the management of spasms in spinal cord injury: A prospective study. Stereotact. Funct. Neurosurg. 64(3):153164;
1995.
18. Barolat-Romana, G.; Myklebust, J. B.; Hemmy, D. C.;
Myklebust, B.; Wenninger, W. Immediate effects of spinal
cord stimulation in spinal spasticity. J. Neurosurg. 62(4):
558562; 1985.
19. Behrman, A. L.; Nair, P. M.; Bowden, M. G.; Dauser,
R. C.; Herget, B. R.; Martin, J. B.; Phadke, C. P.; Reier, P. J.;
Senesac, C. R.; Thompson, F. J.; Howland, D. R. Locomotor training restores walking in a nonambulatory child with
chronic, severe, incomplete cervical spinal cord injury. Phys.
Ther. 88(5):580590; 2008.
20. Bemelmans, B. L.; Mundy, A. R.; Craggs, M. D. Neuromodulation by implant for treating lower urinary tract symptoms and dysfunction. Eur. Urol. 36(2):8191; 1999.
21. Benito, J.; Kumru, H.; Murillo, N.; Costa, U.; Medina, J.;
Tormos, J. M.; Pascual-Leone, A.; Vidal, J. Motor and gait
improvement in patients with incomplete spinal cord injury
induced by high-frequency repetitive transcranial magnetic
stimulation. Top. Spinal Cord Inj. Rehabil. 18(2):106
112; 2012.
22. Benito-Penalva, J.; Edwards, D. J.; Opisso, E.; Cortes, M.;
Lopez-Blazquez, R.; Murillo, N.; Costa, U.; Tormos, J. M.;
Vidal-Samso, J.; Valls-Sole, J.; European Multicenter
Study about Human Spinal Cord Injury Study Group;
Medina, J. Gait training in human spinal cord injury using
electromechanical systems: Effect of device type and
patient characteristics. Arch. Phys. Med. Rehabil. 93(3):
404412; 2012.
23. Betz, R.; Boden, B.; Triolo, R.; Mesgarzadeh, M.; Gardner,
E.; Fife, R. Effects of functional electrical stimulation on the

YOUNG

24.
25.

26.

27.

28.

29.

30.

31.
32.

33.

34.
35.

36.

37.
38.

39.

joints of adolescents with spinal cord injury. Paraplegia


34(3):127136; 1996.
Billian, C.; Gorman, P. H. Upper extremity applications of
functional neuromuscular stimulation. Assist. Technol. 4(1):
3139; 1992.
Blana, D.; Hincapie, J. G.; Chadwick, E. K.; Kirsch, R. F.
Selection of muscle and nerve-cuff electrodes for neuroprostheses using customizable musculoskeletal model.
J. Rehabil. Res. Dev. 50(3):395408; 2013.
Bloomfield, S. A.; Jackson, R. D.; Mysiw, W. J. Catecholamine response to exercise and training in individuals with
spinal cord injury. Med. Sci. Sports Exerc. 26(10):1213
1219; 1994.
Bosch, P. R.; Harris, J. E.; Wing, K.; American Congress
of Rehabilitation Medicine Stroke Movement Interventions
Subcommittee. Review of therapeutic electrical stimulation
for dorsiflexion assist and orthotic substitution from the
American Congress of Rehabilitation Medicine stroke movement interventions subcommittee. Arch. Phys. Med. Rehabil.
95(2):390396; 2014.
Bose, P. K.; Hou, J.; Parmer, R.; Reier, P. J.; Thompson,
F. J. Altered patterns of reflex excitability, balance, and
locomotion following spinal cord injury and locomotor
training. Front. Physiol. 3:258; 2012.
Broggi, G.; Servello, D.; Dones, I.; Carbone, G. Italian
multicentric study on pain treatment with epidural spinal
cord stimulation. Stereotact. Funct. Neurosurg. 62(14):
273278; 1994.
Brown, A. K.; Woller, S. A.; Moreno, G.; Grau, J. W.;
Hook, M. A. Exercise therapy and recovery after SCI: Evidence that shows early intervention improves recovery of
function. Spinal Cord 49(5):623628; 2011.
Brown, J. A. Motor cortex stimulation. Neurosurg. Focus
11(3):E5; 2001.
Brus-Ramer, M.; Carmel, J. B.; Chakrabarty, S.; Martin,
J. H. Electrical stimulation of spared corticospinal axons
augments connections with ipsilateral spinal motor circuits
after injury. J. Neurosci. 27(50):1379313801; 2007.
Brus-Ramer, M.; Carmel, J. B.; Martin, J. H. Motor cortex
bilateral motor representation depends on subcortical and
interhemispheric interactions. J. Neurosci. 29(19):6196
6206; 2009.
Buback, D. The use of neuromodulation for treatment of
urinary incontinence. AORN J. 73(1):176178, 181187,
189190; quiz 191196; 2001.
Bukalo, O.; Campanac, E.; Hoffman, D. A.; Fields, R. D.
Synaptic plasticity by antidromic firing during hippocampal
network oscillations. Proc. Natl. Acad. Sci. USA 110(13):
51755180; 2013.
Campos, R. J.; Dimitrijevic, M. R.; Sharkey, P. C.;
Sherwood, A. M. Epidural spinal cord stimulation in spastic
spinal cord injury patients. Appl. Neurophysiol. 50(16):
453454; 1987.
Caporale, N.; Dan, Y. Spike timing-dependent plasticity: A
Hebbian learning rule. Annu. Rev. Neurosci. 31:2546; 2008.
Caraballo, R.; Bologna, R. A.; Lukban, J.; Whitmore, K. E.
Sacral nerve stimulation as a treatment for urge incontinence
and associated pelvic floor disorders at a pelvic floor center:
A follow-up study. Urology 57(6 Suppl 1):121; 2001.
Carmel, J. B.; Berrol, L. J.; Brus-Ramer, M.; Martin, J. H.
Chronic electrical stimulation of the intact corticospinal
system after unilateral injury restores skilled locomotor
control and promotes spinal axon outgrowth. J. Neurosci.
30(32):1091810926; 2010.

ELECTRICAL STIMULATION AND MOTOR RECOVERY

40. Carmel, J. B.; Kimura, H.; Berrol, L. J.; Martin, J. H.


Motor cortex electrical stimulation promotes axon outgrowth to brain stem and spinal targets that control the
forelimb impaired by unilateral corticospinal injury. Eur. J.
Neurosci. 37(7):10901102; 2013.
41. Carmel, J. B.; Kimura, H.; Martin, J. H. Electrical stimulation of motor cortex in the uninjured hemisphere after
chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control. J. Neurosci. 34(2):
462466; 2014.
42. Carmel, J. B.; Martin, J. H. Motor cortex electrical stimulation augments sprouting of the corticospinal tract and
promotes recovery of motor function. Front. Integr. Neurosci.
8:51; 2014.
43. Cazalets, J. R.; Borde, M.; Clarac, F. Localization and
organization of the central pattern generator for hindlimb
locomotion in newborn rat. J. Neurosci. 15(7 Pt 1):4943
4951; 1995.
44. Chartier-Kastler, E. J.; Ruud Bosch, J. L.; Perrigot, M.;
Chancellor, M. B.; Richard, F.; Denys, P. Long-term
results of sacral nerve stimulation (S3) for the treatment of
neurogenic refractory urge incontinence related to detrusor
hyperreflexia. J. Urol. 164(5):14761480; 2000.
45. Chopek, J. W.; MacDonell, C. W.; Gardiner, K.; Gardiner,
P. F. Daily passive cycling attenuates the hyperexcitability
and restores the responsiveness of the extensor monosynaptic reflex to quipazine in the chronic spinally transected
rat. J. Neurotrauma 31(12):10831087; 2014.
46. Creasey, G. H.; Craggs, M. D. Functional electrical stimulation for bladder, bowel, and sexual function. Handb.
Clin.Neurol. 109:247257; 2012.
47. Crema, A.; McNaught, A.; Albisser, U.; Bolliger, M.;
Micera, S.; Curt, A.; Morari, M. A hybrid tool for reaching
and grasping rehabilitation: The ArmeoFES. Conf. Proc.
IEEE Eng. Med. Biol. Soc. 2011:30473050; 2011.
48. Crosbie, J.; Tanhoffer, A. I.; Fornusek, C. FES assisted
standing in people with incomplete spinal cord injury: A single case design series. Spinal Cord 52(3):251254; 2014.
49. Crown, E. D.; Ferguson, A. R.; Joynes, R. L.; Grau, J. W.
Instrumental learning within the spinal cord. II. Evidence for
central mediation. Physiol. Behav. 77(23):259267; 2002.
50. Darakhshan, A. A.; Williams, N. S. Recent innovations in
the management of fecal incontinence. Semin. Pediatr.
Surg. 11(2):8390; 2002.
51. Dimitrijevic, M. R.; Gerasimenko, Y.; Pinter, M. M. Evidence for a spinal central pattern generator in humans.
Ann. N. Y. Acad. Sci. 860:360376; 1998.
52. Dimitrijevic, M. R.; Halter, J. A.; Sharkey, P. C.; Sherwood,
A. M. Epidural spinal cord stimulation and carry-over effect
in chronic spinal cord injury patients. Appl. Neurophysiol.
50(16):449450; 1987.
53. Dimitrijevic, M. R.; Larsson, L. E. Neural control of gait:
Clinical neurophysiological aspects. Appl. Neurophysiol.
44(13):152159; 1981.
54. Dobkin, B.; Apple, D.; Barbeau, H.; Basso, M.; Behrman,
A.; Deforge, D.; Ditunno, J.; Dudley, G.; Elashoff, R.;
Fugate, L.; Harkema, S.; Saulino, M.; Scott, M.; Spinal
Cord Injury Locomotor Trial Group. Weight-supported
treadmill vs over-ground training for walking after acute
incomplete SCI. Neurology 66(4):484493; 2006.
55. Dobkin, B. H.; Duncan, P. W. Should body weight-supported
treadmill training and robotic-assistive steppers for locomotor
training trot back to the starting gate? Neurorehabil. Neural
Repair 26(4):308317; 2012.

439

56. Dudding, T. C. Future indications for sacral nerve stimulation. Colorectal Dis. 13(Suppl 2):2328; 2011.
57. Edgerton, V. R.; Harkema, S. Epidural stimulation of the
spinal cord in spinal cord injury: Current status and future
challenges. Expert Rev. Neurother. 11(10):13511353; 2011.
58. Edgerton, V. R.; Roy, R. R. A new age for rehabilitation.
Eur. J. Phys. Rehabil. Med. 48(1):99109; 2012.
59. Edlund, C.; Hellstrom, M.; Peeker, R.; Fall, M. First Scandinavian experience of electrical sacral nerve stimulation in
the treatment of the overactive bladder. Scand. J. Urol.
Nephrol. 34(6):366376; 2000.
60. Epstein, R.; Tauc, L. Heterosynaptic facilitation and posttetanic potentiation in Aplysia nervous system. J. Physiol.
209(1):123; 1970.
61. Esclarin-Ruz, A.; Alcobendas-Maestro, M.; Casado-Lopez,
R.; Perez-Mateos, G.; Florido-Sanchez, M. A.; GonzalezValdizan, E.; Martin, J. L. A comparison of robotic walking
therapy and conventional walking therapy in individuals
with upper versus lower motor neuron lesions: A randomized controlled trial. Arch. Phys. Med. Rehabil. 95(6):
10231031; 2014.
62. Everaert, D. G.; Thompson, A. K.; Chong, S. L.; Stein,
R. B. Does functional electrical stimulation for foot drop
strengthen corticospinal connections? Neurorehabil. Neural
Repair 24(2):168177; 2010.
63. Feraboli-Lohnherr, D.; Barthe, J. Y.; Orsal, D. Serotonininduced activation of the network for locomotion in adult
spinal rats. J. Neurosci. Res. 55(1):8798; 1999.
64. Feraboli-Lohnherr, D.; Orsal, D.; Yakovleff, A.; Gimenez
y Ribotta, M.; Privat, A. Recovery of locomotor activity in
the adult chronic spinal rat after sublesional transplantation
of embryonic nervous cells: Specific role of serotonergic
neurons. Exp. Brain Res. 113(3):443454; 1997.
65. Ferguson, A. C.; Keating, J. F.; Delargy, M. A.; Andrews,
B. J. Reduction of seating pressure using FES in patients
with spinal cord injury. A preliminary report. Paraplegia
30(7):474478; 1992.
66. Field-Fote, E.; Ness, L. L.; Ionno, M. Vibration elicits involuntary, step-like behavior in individuals with spinal cord
injury. Neurorehabil. Neural Repair 26(7):861869; 2012.
67. Forrest, G. F.; Lorenz, D. J.; Hutchinson, K.; Vanhiel,
L. R.; Basso, D. M.; Datta, S.; Sisto, S. A.; Harkema, S. J.
Ambulation and balance outcomes measure different aspects
of recovery in individuals with chronic, incomplete spinal cord
injury. Arch. Phys. Med. Rehabil. 93(9):15531564; 2012.
68. Fox, E. J.; Tester, N. J.; Phadke, C. P.; Nair, P. M.;
Senesac, C. R.; Howland, D. R.; Behrman, A. L. Ongoing
walking recovery 2 years after locomotor training in a child
with severe incomplete spinal cord injury. Phys. Ther. 90(5):
793802; 2010.
69. Fregni, F.; Boggio, P. S.; Lima, M. C.; Ferreira, M. J.;
Wagner, T.; Rigonatti, S. P.; Castro, A. W.; Souza, D. R.;
Riberto, M.; Freedman, S. D.; Nitsche, M. A.; PascualLeone, A. A sham-controlled, phase II trial of transcranial
direct current stimulation for the treatment of central pain in
traumatic spinal cord injury. Pain 122(12):197209; 2006.
70. Galea, M. P.; Dunlop, S. A.; Davis, G. M.; Nunn, A.;
Geraghty, T.; Hsueh, Y. S.; Churilov, L. Intensive exercise
program after spinal cord injury (Full-On): Study protocol for a randomized controlled trial. Trials 14:291; 2013.
71. Gallien, P.; Brissot, R.; Eyssette, M.; Tell, L.; Barat, M.;
Wiart, L.; Petit, H. Restoration of gait by functional electrical stimulation for spinal cord injured patients. Paraplegia
33(11):660664; 1995.

440

72. Ganio, E.; Luc, A. R.; Clerico, G.; Trompetto, M. Sacral


nerve stimulation for treatment of fecal incontinence: A
novel approach for intractable fecal incontinence. Dis.
Colon Rectum 44(5):619629; discussion 629631; 2001.
73. Ganio, E.; Masin, A.; Ratto, C.; Altomare, D. F.; Ripetti,
V.; Clerico, G.; Lise, M.; Doglietto, G. B.; Memeo, V.;
Landolfi, V.; Del Genio, A.; Arullani, A.; Giardiello, G.;
de Seta, F. Short-term sacral nerve stimulation for functional
anorectal and urinary disturbances: Results in 40 patients:
Evaluation of a new option for anorectal functional disorders.
Dis. Colon Rectum 44(9):12611267; 2001.
74. Ganio, E.; Ratto, C.; Masin, A.; Luc, A. R.; Doglietto, G. B.;
Dodi, G.; Ripetti, V.; Arullani, A.; Frascio, M.; BertiRiboli,
E.; Landolfi, V.; DelGenio, A.; Altomare, D. F.; Memeo, V.;
Bertapelle, P.; Carone, R.; Spinelli, M.; Zanollo, A.;
Spreafico, L.; Giardiello, G.; de Seta, F. Neuromodulation
for fecal incontinence: Outcome in 16 patients with definitive implant. The initial Italian Sacral Neurostimulation
Group (GINS) experience. Dis. Colon Rectum 44(7):965
970; 2001.
75. Gerasimenko, Y. P.; Ichiyama, R. M.; Lavrov, I. A.;
Courtine, G.; Cai, L.; Zhong, H.; Roy, R. R.; Edgerton,
V. R. Epidural spinal cord stimulation plus quipazine
administration enable stepping in complete spinal adult
rats. J. Neurophysiol. 98(5):25252536; 2007.
76. Giangregorio, L.; Craven, C.; Richards, K.; Kapadia, N.;
Hitzig, S. L.; Masani, K.; Popovic, M. R. A randomized
trial of functional electrical stimulation for walking in
incomplete spinal cord injury: Effects on body composition. J. Spinal Cord Med. 35(5):351360; 2012.
77. Giberson, C. E.; Barbosa, J.; Brooks, E. S.; McGlothlen,
G. L.; Grigsby, E. J.; Kohut, J. J.; Wolbers, L. L.; Poree,
L. R. Epidural hematomas after removal of percutaneous
spinal cord stimulator trial leads: Two case reports. Reg.
Anesth. Pain Med. 39(1):7377; 2014.
78. Godec, C.; Cass, A. S. Electrical stimulation for voiding
dysfunction after spinal cord injury. J. Urol. 121(1):73
75; 1979.
79. Gordon, T.; Mao, J. Muscle atrophy and procedures for training after spinal cord injury. Phys. Ther. 74(1):5060; 1994.
80. Graham-Brown, T. The intrinsic factors in the act of progression in the mammal. Proc. R. Soc. Lond. B Biol. Sci.
84(572):308319; 1911.
81. Granat, M.; Keating, J. F.; Smith, A. C.; Delargy, M.;
Andrews, B. J. The use of functional electrical stimulation
to assist gait in patients with incomplete spinal cord injury.
Disabil. Rehabil. 14(2):9397; 1992.
82. Granat, M. H.; Ferguson, A. C.; Andrews, B. J.; Delargy, M.
The role of functional electrical stimulation in the rehabilitation of patients with incomplete spinal cord injuryObserved
benefits during gait studies. Paraplegia 31(4):207215; 1993.
83. Grau, J. W.; Crown, E. D.; Ferguson, A. R.; Washburn, S. N.;
Hook, M. A.; Miranda, R. C. Instrumental learning within
the spinal cord: Underlying mechanisms and implications
for recovery after injury. Behav. Cogn. Neurosci. Rev.
5(4):191239; 2006.
84. Grau, J. W.; Hook, M. A. Spinal neurons exhibit a surprising capacity to learn and a hidden vulnerability when freed
from the brains control. Curr. Neurol. Neurosci. Rep.
6(3):177180; 2006.
85. Grau, J. W.; Washburn, S. N.; Hook, M. A.; Ferguson,
A. R.; Crown, E. D.; Garcia, G.; Bolding, K. A.; Miranda,
R. C. Uncontrollable stimulation undermines recovery after
spinal cord injury. J. Neurotrauma 21(12):17951817; 2004.

YOUNG

86. Graupe, D.; Kohn, K. H. Functional electrical stimulation


for ambulation by paraplegics: Twelve years of clinical observations and system studies, 1st ed. Malabar, FL: Krieger Pub.
Co.; 1994.
87. Graupe, D.; Kordylewski, H. Artificial neural network control of FES in paraplegics for patient responsive ambulation. IEEE Trans. Biomed. Eng. 42(7):699707; 1995.
88. Greve, J. M.; Muszkat, R.; Schmidt, B.; Chiovatto, J.;
Barros Filho, T. E.; Batisttella, L. R. Functional electrical
stimulation (FES): Muscle histochemical analysis. Paraplegia 31(12):764770; 1993.
89. Guertin, P. A.; Ung, R. V.; Rouleau, P. Oral administration
of a tri-therapy for central pattern generator activation in
paraplegic mice: Proof-of-concept of efficacy. Biotechnol.
J. 5(4):421426; 2010.
90. Guiraud, D.; Azevedo Coste, C.; Benoussaad, M.; Fattal,
C. Implanted functional electrical stimulation: Case report
of a paraplegic patient with complete SCI after 9 years.
J. Neuroeng. Rehabil. 11(1):15; 2014.
91. Habib, H. N. Experience and recent contributions in sacral
nerve stimulation for voiding in both human and animal.
Br. J. Urol. 39(1):7383; 1967.
92. Hajela, N.; Mummidisetty, C. K.; Smith, A. C.; Knikou,
M. Corticospinal reorganization after locomotor training in
a person with motor incomplete paraplegia. Biomed. Res.
Int. 2013:516427; 2013.
93. Hamdy, S.; Enck, P.; Aziz, Q.; Rothwell, J. C.; Uengoergil,
S.; Hobson, A.; Thompson, D. G. Spinal and pudendal
nerve modulation of human corticoanal motor pathways. Am.
J. Physiol. 274(2 Pt 1):G419423; 1998.
94. Handa, Y.; Handa, T.; Ichie, M.; Murakami, H.; Hoshimiya,
N.; Ishikawa, S.; Ohkubo, K. Functional electrical stimulation (FES) systems for restoration of motor function of paralyzed musclesVersatile systems and a portable system. Front.
Med. Biol. Eng. 4(4):241255; 1992.
95. Hangartner, T. N.; Rodgers, M. M.; Glaser, R. M.;
Barre, P. S. Tibial bone density loss in spinal cord
injured patients: Effects of FES exercise. J. Rehabil. Res.
Dev. 31(1):5061; 1994.
96. Hardin, E.; Kobetic, R.; Murray, L.; Corado-Ahmed, M.;
Pinault, G.; Sakai, J.; Bailey, S. N.; Ho, C.; Triolo, R. J.
Walking after incomplete spinal cord injury using an
implanted FES system: A case report. J. Rehabil. Res.
Dev. 44(3):333346; 2007.
97. Harkema, S.; Behrman, A.; Barbeau, H. Evidence-based
therapy for recovery of function after spinal cord injury.
Handb. Clin.Neurol. 109:259274; 2012.
98. Harkema, S.; Gerasimenko, Y.; Hodes, J.; Burdick, J.;
Angeli, C.; Chen, Y.; Ferreira, C.; Willhite, A.; Rejc, E.;
Grossman, R. G.; Edgerton, V. R. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete
paraplegia: A case study. Lancet 377(9781):19381947;
2011.
99. Harkema, S. J.; Hillyer, J.; Schmidt-Read, M.; Ardolino,
E.; Sisto, S. A.; Behrman, A. L. Locomotor training: As a
treatment of spinal cord injury and in the progression of
neurologic rehabilitation. Arch. Phys. Med. Rehabil. 93(9):
15881597; 2012.
100. Harkema, S. J.; Schmidt-Read, M.; Lorenz, D. J.;
Edgerton, V. R.; Behrman, A. L. Balance and ambulation
improvements in individuals with chronic incomplete spinal cord injury using locomotor training-based rehabilitation. Arch. Phys. Med. Rehabil. 93(9):15081517; 2012.

ELECTRICAL STIMULATION AND MOTOR RECOVERY

101. Harris-Warrick, R. M.; Cohen, A. H. Serotonin modulates


the central pattern generator for locomotion in the isolated
lamprey spinal cord. J. Exp. Biol. 116:2746; 1985.
102. Hebb, D. O. The organization of behavior: A neuropsychological theory. New York, NY: Wiley; 1949.
103. Hedlund, H.; Schultz, A.; Talseth, T.; Tonseth, K.; van der
Hagen, A. Sacral neuromodulation in Norway: Clinical
experience of the first three years. Scand. J. Urol. Nephrol.
Suppl. 36(4):8795; 2002.
104. Herman, R.; He, J.; DLuzansky, S.; Willis, W.; Dilli, S.
Spinal cord stimulation facilitates functional walking in a
chronic, incomplete spinal cord injured. Spinal Cord 40(2):
6568; 2002.
105. Hitzig, S. L.; Craven, B. C.; Panjwani, A.; Kapadia, N.;
Giangregorio, L. M.; Richards, K.; Masani, K.; Popovic,
M. R. Randomized trial of functional electrical stimulation
therapy for walking in incomplete spinal cord injury: Effects
on quality of life and community participation. Top. Spinal
Cord Inj. Rehabil. 19(4):245258; 2013.
106. Hoffman, L.; Field-Fote, E. Effects of practice combined
with somatosensory or motor stimulation on hand function
in persons with spinal cord injury. Top. Spinal Cord Inj.
Rehabil. 19(4):288299; 2013.
107. Hofstoetter, U. S.; McKay, W. B.; Tansey, K. E.; Mayr, W.;
Kern, H.; Minassian, K. Modification of spasticity by transcutaneous spinal cord stimulation in individuals with incomplete
spinal cord injury. J. Spinal Cord Med. 37(2):202211; 2014.
108. Hohenfellner, M.; Schultz-Lampel, D.; Dahms, S.; Matzel,
K.; Thuroff, J. W. Bilateral chronic sacral neuromodulation
for treatment of lower urinary tract dysfunction. J. Urol.
160(3 Pt 1):821824; 1998.
109. Hooker, S. P.; Figoni, S. F.; Rodgers, M. M.; Glaser,
R. M.; Mathews, T.; Suryaprasad, A. G.; Gupta, S. C. Physiologic effects of electrical stimulation leg cycle exercise
training in spinal cord injured persons. Arch. Phys. Med.
Rehabil. 73(5):470476; 1992.
110. Hornby, T. G.; Kinnaird, C. R.; Holleran, C. L.; Rafferty,
M. R.; Rodriguez, K. S.; Cain, J. B. Kinematic, muscular,
and metabolic responses during exoskeletal-, elliptical-, or
therapist-assisted stepping in people with incomplete spinal
cord injury. Phys. Ther. 92(10):12781291; 2012.
111. Horsch, S.; Claeys, L. Epidural spinal cord stimulation in
the treatment of severe peripheral arterial occlusive disease.
Ann. Vasc. Surg. 8(5):468474; 1994.
112. Hoshimiya, N.; Naito, A.; Yajima, M.; Handa, Y. A multichannel FES system for the restoration of motor functions
in high spinal cord injury patients: A respiration-controlled
system for multijoint upper extremity. IEEE Trans. Biomed.
Eng. 36(7):754760; 1989.
113. Hou, J.; Nelson, R.; Nissim, N.; Parmer, R.; Thompson, F. J.;
Bose, P. Effect of combined treadmill training and magnetic
stimulation on spasticity and gait impairments after cervical
spinal cord injury. J. Neurotrauma 31(12):10881106; 2014.
114. Huang, H.; He, J.; Herman, R.; Carhart, M. R. Modulation
effects of epidural spinal cord stimulation on muscle activities during walking. IEEE Trans. Neural Syst. Rehabil.
Eng. 14(1):1423; 2006.
115. Hubli, M.; Dietz, V. The physiological basis of
neurorehabilitationLocomotor training after spinal cord
injury. J. Neuroeng. Rehabil. 10:5; 2013.
116. Hunter, J. P.; Ashby, P. Segmental effects of epidural spinal
cord stimulation in humans. J. Physiol. 474(3):407419; 1994.
117. Ichiyama, R. M.; Gerasimenko, Y.; Jindrich, D. L.; Zhong,
H.; Roy, R. R.; Edgerton, V. R. Dose dependence of the

441

118.

119.

120.
121.
122.

123.

124.

125.

126.

127.
128.

129.

130.

131.
132.

5-HT agonist quipazine in facilitating spinal stepping in


the rat with epidural stimulation. Neurosci. Lett. 438(3):
281285; 2008.
Ichiyama, R. M.; Gerasimenko, Y. P.; Zhong, H.; Roy,
R. R.; Edgerton, V. R. Hindlimb stepping movements in
complete spinal rats induced by epidural spinal cord stimulation. Neurosci. Lett. 383(3):339344; 2005.
Ishigooka, M.; Suzuki, Y.; Hashimoto, T.; Sasagawa, I.;
Nakada, T.; Handa, Y. A new technique for sacral nerve
stimulation: A percutaneous method for urinary incontinence caused by spinal cord injury. Br. J. Urol. 81(2):
315318; 1998.
Ishigooka, M.; Zermann, D. H.; Doggweiler, R.; Schmidt,
R. A. Sacral nerve stimulation and diurnal urine volume.
Eur. Urol. 36(5):421426; 1999.
Jaeger, R. J. Lower extremity applications of functional neuromuscular stimulation. Assist. Technol. 4(1):1930; 1992.
Janknegt, R. A.; Hassouna, M. M.; Siegel, S. W.; Schmidt,
R. A.; Gajewski, J. B.; Rivas, D. A.; Elhilali, M. M.;
Milam, D. C.; van Kerrebroeck, P. E.; Dijkema, H. E.;
Lycklama a Nyeholt, A. A.; Fall, M.; Jonas, U.; Catanzaro,
F.; Fowler, C. J.; Oleson, K. A. Long-term effectiveness of
sacral nerve stimulation for refractory urge incontinence.
Eur. Urol. 39(1):101106; 2001.
Javidan, A. N.; Mazel, K.; Latifi, S.; Maghari, M. M.;
Saberi, H.; Nikfalah, A.; Daryasari, S. A.; Yekaninejad, M. S.
Outcomes of implementation of sacral nerve stimulation on
urination, defecation, and sexual function in patients with
spinal cord injury. Int. J. Colorectal Dis. 29(12):1577
1578; 2014.
Jayaraman, A.; Liu, M.; Ye, F.; Walter, G. A.; Vandenborne,
K. Regenerative responses in slow- and fast-twitch muscles following moderate contusion spinal cord injury and
locomotor training. Eur. J. Appl. Physiol. 113(1):191200;
2013.
Jones, M. L.; Evans, N.; Tefertiller, C.; Backus, D.;
Sweatman, M.; Tansey, K.; Morrison, S. Activity-based
therapy for recovery of walking in chronic spinal cord
injury: Results from a secondary analysis to determine
responsiveness to therapy. Arch. Phys. Med. Rehabil.
95(12):22472252; 2014.
Jordan, M. M.; Berkowitz, D.; Hannold, E.; Velozo, C. A.;
Behrman, A. L. Thinking through every step: How people
with spinal cord injuries relearn to walk. Qual. Health Res.
23(8):10271041; 2013.
Kagaya, H. [Therapeutic and functional electrical stimulation for paraplegics]. Nippon Seikeigeka Gakkai Zasshi
68(9):751762; 1994.
Kamm, M. A.; Dudding, T. C.; Melenhorst, J.; Jarrett, M.;
Wang, Z.; Buntzen, S.; Johansson, C.; Laurberg, S.; Rosen,
H.; Vaizey, C. J.; Matzel, K.; Baeten, C. Sacral nerve stimulation for intractable constipation. Gut 59(3):333340; 2010.
Kapadia, N.; Zivanovic, V.; Popovic, M. R. Restoring voluntary grasping function in individuals with incomplete
chronic spinal cord injury: Pilot study. Top. Spinal Cord
Inj. Rehabil. 19(4):279287; 2013.
Karimi, M. T. Functional walking ability of paraplegic
patients: Comparison of functional electrical stimulation
versus mechanical orthoses. Eur. J. Orthop. Surg. Traumatol.
23(6):631638; 2013.
Karimi, M. T. Robotic rehabilitation of spinal cord injury
individual. Ortop. Traumatol. Rehabil. 15(1):17; 2013.
Karoutas, G.; Karacostas, D.; Artemis, N.; Liapis, J.;
Tzotzoras, T.; Andreou, A.; Tsitsopoulos, P. Restoration of

442

133.
134.

135.

136.
137.

138.

139.
140.
141.

142.

143.

144.

145.
146.

147.
148.

YOUNG

micturition using microelectric current in experimentally


induced spastic urinary bladder in rabbits. Exp. Neurol.
102(3):333339; 1988.
Kenefick, N. J.; Nicholls, R. J.; Cohen, R. G.; Kamm,
M. A. Permanent sacral nerve stimulation for treatment of
idiopathic constipation. Br. J. Surg. 89(7):882888; 2002.
Kenefick, N. J.; Vaizey, C. J.; Cohen, C. R.; Nicholls,
R. J.; Kamm, M. A. Double-blind placebo-controlled crossover study of sacral nerve stimulation for idiopathic constipation. Br. J. Surg. 89(12):15701571; 2002.
Kinfe, T. M.; Schu, S.; Quack, F. J.; Wille, C.; Vesper, J.
Percutaneous implanted paddle lead for spinal cord stimulation: Technical considerations and long-term follow-up.
Neuromodulation 15(4):402407; 2012.
Knikou, M.; Mummidisetty, C. K. Locomotor training
improves premotoneuronal control after chronic spinal cord
injury. J. Neurophysiol. 111(11):22642275; 2014.
Koopmans, G. C.; Deumens, R.; Honig, W. M.; Hamers,
F. P.; Mey, J.; van Kleef, M.; Joosten, E. A. Functional
recovery, serotonergic sprouting, and endogenous progenitor fates in response to delayed environmental enrichment after spinal cord injury. J. Neurotrauma 29(3):514527;
2012.
Kostov, A.; Andrews, B. J.; Popovic, D. B.; Stein, R. B.;
Armstrong, W. W. Machine learning in control of functional electrical stimulation systems for locomotion. IEEE
Trans. Biomed. Eng. 42(6):541551; 1995.
Krajl, A.; Bajd, T.; Turk, R.; Benko, H. Posture switching
for prolonging functional electrical stimulation standing in
paraplegic patients. Paraplegia 24(4):221230; 1986.
Kralj, A.; Bajd, T.; Turk, R. Enhancement of gait restoration in spinal injured patients by functional electrical stimulation. Clin. Orthop. Relat. Res. 233:3443; 1988.
Kralj, A.; Bajd, T.; Turk, R.; Krajnik, J.; Benko, H. Gait
restoration in paraplegic patients: A feasibility demonstration using multichannel surface electrode FES. J. Rehabil.
R D 20(1):320; 1983.
Krauss, J. C.; Robergs, R. A.; Depaepe, J. L.; Kopriva, L. M.;
Aisenbury, J. A.; Anderson, M. A.; Lange, E. K. Effects of
electrical stimulation and upper body training after spinal cord
injury. Med. Sci. Sports Exerc. 25(9):10541061; 1993.
Kressler, J.; Nash, M. S.; Burns, P. A.; Field-Fote, E. C.
Metabolic responses to 4 different body weight-supported
locomotor training approaches in persons with incomplete
spinal cord injury. Arch. Phys. Med. Rehabil. 94(8):1436
1442; 2013.
Kuchi, P.; Iyer, V.; Hiremagalur, R.; Panchanathan, S.
Characteristics of gait of humans with incomplete spinal
cord injury. Conf. Proc. IEEE Eng. Med. Biol. Soc. 1:
586589; 2004.
Kumar, K.; Nath, R.; Wyant, G. M. Treatment of chronic
pain by epidural spinal cord stimulation: A 10-year experience. J. Neurosurg. 75(3):402407; 1991.
Kumar, K.; Toth, C.; Nath, R. K.; Laing, P. Epidural spinal cord stimulation for treatment of chronic painSome
predictors of success. A 15-year experience. Surg. Neurol.
50(2):110120; discussion 120121; 1998.
Kumar, V. P.; Lau, H. K.; Liu, J.; Pereira, B. P.; Pho,
R. W. Clinical applications of functional electrical stimulation. Ann. Acad. Med. Singapore 24(3):428435; 1995.
Labruyere, R.; van Hedel, H. J. Strength training versus
robot-assisted gait training after incomplete spinal cord
injury: A randomized pilot study in patients depending on
walking assistance. J. Neuroeng. Rehabil. 11(1):4; 2014.

149. Lang, P. The treatment of chronic pain by epidural spinal


cord stimulationA 15 year follow up; present status.
Axone 18(4):7173; 1997.
150. Leeds, E. M.; Klose, K. J.; Ganz, W.; Serafini, A.; Green,
B. A. Bone mineral density after bicycle ergometry training. Arch. Phys. Med. Rehabil. 71(3):207209; 1990.
151. Lefaucheur, J. P.; Drouot, X.; Menard-Lefaucheur, I.;
Zerah, F.; Bendib, B.; Cesaro, P.; Keravel, Y.; Nguyen, J. P.
Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain.
J. Neurol. Neurosurg. Psychiatry 75(4):612616; 2004.
152. Lefurge, T.; Goodall, E.; Horch, K.; Stensaas, L.; Schoenberg,
A. Chronically implanted intrafascicular recording electrodes.
Ann. Biomed. Eng. 19(2):197207; 1991.
153. Leroi, A. M.; Michot, F.; Grise, P.; Denis, P. Effect of
sacral nerve stimulation in patients with fecal and urinary
incontinence. Dis. Colon Rectum 44(6):779789; 2001.
154. Linder, S. H. Functional electrical stimulation to enhance
cough in quadriplegia. Chest 103(1):166169; 1993.
155. Liu, G. T.; Ferguson, A. R.; Crown, E. D.; Bopp, A. C.;
Miranda, R. C.; Grau, J. W. Instrumental learning within
the rat spinal cord: Localization of the essential neural circuit. Behav. Neurosci. 119(2):538547; 2005.
156. Liu, K.; Lu, Y.; Lee, J. K.; Samara, R.; Willenberg, R.;
Sears-Kraxberger, I.; Tedeschi, A.; Park, K. K.; Jin, D.;
Cai, B.; Xu, B.; Connolly, L.; Steward, O.; Zheng, B.; He,
Z. PTEN deletion enhances the regenerative ability of adult
corticospinal neurons. Nat. Neurosci. 13(9):10751081; 2010.
157. Lorenz, D. J.; Datta, S.; Harkema, S. J. Longitudinal patterns
of functional recovery in patients with incomplete spinal
cord injury receiving activity-based rehabilitation. Arch. Phys.
Med. Rehabil. 93(9):15411552; 2012.
158. Loubser, P. G. Adverse effects of epidural spinal cord stimulation on bladder function in a patient with chronic spinal
cord injury pain. J. Pain Symptom Manage. 13(5):251252;
1997.
159. Lu, P.; Blesch, A.; Graham, L.; Wang, Y.; Samara, R.;
Banos, K.; Haringer, V.; Havton, L.; Weishaupt, N.;
Bennett, D.; Fouad, K.; Tuszynski, M. H. Motor axonal
regeneration after partial and complete spinal cord transection. J. Neurosci. 32(24):82088218; 2012.
160. Lu, P.; Wang, Y.; Graham, L.; McHale, K.; Gao, M.; Wu,
D.; Brock, J.; Blesch, A.; Rosenzweig, E. S.; Havton, L. A.;
Zheng, B.; Conner, J. M.; Marsala, M.; Tuszynski, M. H.
Long-distance growth and connectivity of neural stem cells
after severe spinal cord injury. Cell 150(6):12641273; 2012.
161. Maeda, Y.; Lundby, L.; Buntzen, S.; Laurberg, S. Sacral
nerve stimulation for constipation: Suboptimal outcome and
adverse events. Dis. Colon Rectum 53(7):995999; 2010.
162. Maegele, M.; Muller, S.; Wernig, A.; Edgerton, V. R.;
Harkema, S. J. Recruitment of spinal motor pools during
voluntary movements versus stepping after human spinal
cord injury. J. Neurotrauma 19(10):12171229; 2002.
163. Manella, K. J.; Field-Fote, E. C. Modulatory effects of
locomotor training on extensor spasticity in individuals
with motor-incomplete spinal cord injury. Restor. Neurol.
Neurosci. 31(5):633646; 2013.
164. Martinez, M.; Delivet-Mongrain, H.; Rossignol, S. Treadmill training promotes spinal changes leading to locomotor recovery after partial spinal cord injury in cats.
J. Neurophysiol. 109(12):29092922; 2013.
165. Maruyama, Y.; Shimoji, K. [Epidural spinal cord stimulation: Its efficacy and mechanisms]. Gan No Rinsho 31(6
Suppl):729735; 1985.

ELECTRICAL STIMULATION AND MOTOR RECOVERY

166. Matzel, K. E. Defecation: Sacral nerve stimulation therapy


for defecatory disorders. Nat. Rev. Gastroenterol. Hepatol.
7(7):363364; 2010.
167. Matzel, K. E. The role of sacral nerve stimulation in treating
faecal incontinence and refractory constipation. Editorial.
Colorectal Dis. 13(Suppl 2):iiiiv; 2011.
168. Mayr, W.; Minassian, K.; Tansey, K.; Rattay, F.; Danner, S.;
Krenn, M.; Hofstoetter, U.; Dimitrijevic, M. Non-invasive
transcutaneous stimulation of the human lumbar spinal cord
facilitates locomotor output in spinal cord injury. Biomed.
Eng. 57(SI1):1024; 2012.
169. Mehrholz, J.; Kugler, J.; Pohl, M. Locomotor training for
walking after spinal cord injury. Cochrane Database Syst.
Rev. 11:CD006676; 2012.
170. Meloy, S. Neurally augmented sexual function. Acta
Neurochir. Suppl. 97(Pt 1):359363; 2007.
171. Midha, M.; Schmitt, J. K. Epidural spinal cord stimulation
for the control of spasticity in spinal cord injury patients
lacks long-term efficacy and is not cost-effective. Spinal
Cord 36(3):190192; 1998.
172. Minassian, K.; Hofstoetter, U.; Tansey, K.; Mayr, W.
Neuromodulation of lower limb motor control in restorative neurology. Clin. Neurol. Neurosurg. 114(5):489497;
2012.
173. Minassian, K.; Jilge, B.; Rattay, F.; Pinter, M. M.; Binder,
H.; Gerstenbrand, F.; Dimitrijevic, M. R. Stepping-like
movements in humans with complete spinal cord injury
induced by epidural stimulation of the lumbar cord: Electromyographic study of compound muscle action potentials.
Spinal Cord 42(7):401416; 2004.
174. Minassian, K.; Persy, I.; Rattay, F.; Pinter, M. M.; Kern,
H.; Dimitrijevic, M. R. Human lumbar cord circuitries can
be activated by extrinsic tonic input to generate locomotorlike activity. Hum. Mov. Sci. 26(2):275295; 2007.
175. Mirbagheri, M. M.; Niu, X.; Kindig, M.; Varoqui, D. The
effects of locomotor training with a robotic-gait orthosis
(Lokomat) on neuromuscular properties in persons with
chronic SCI. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2012:
38543857; 2012.
176. Morawietz, C.; Moffat, F. Effects of locomotor training
after incomplete spinal cord injury: A systematic review.
Arch. Phys. Med. Rehabil. 94(11):22972308; 2013.
177. Moreno-Duarte, I.; Morse, L. R.; Alam, M.; Bikson, M.;
Zafonte, R.; Fregni, F. Targeted therapies using electrical
and magnetic neural stimulation for the treatment of
chronic pain in spinal cord injury. Neuroimage 85 Pt 3:
10031013; 2014.
178. Morrison, S. A.; Forrest, G. F.; VanHiel, L. R.; Dave, M.;
DUrso, D. NeuroRecovery Network provides standardization of locomotor training for persons with incomplete spinal cord injury. Arch. Phys. Med. Rehabil. 93(9):15741577;
2012.
179. Morrison, S. A.; Pomeranz, J. L.; Yu, N.; Read, M. S.;
Sisto, S. A.; Behrman, A. L. Life care planning projections
for individuals with motor incomplete spinal cord injury
before and after locomotor training intervention: A case
series. J. Neurol. Phys. Ther. 36(3):144153; 2012.
180. Moshonkina, T. R.; Makarovski, A. N.; Bogacheva, I. N.;
Scherbakova, N. A.; Savohin, A. A.; Gerasimenko, Y. P.
Effects of spinal cord electrical stimulation in patients with
vertebrospinal pathology. Bull. Exp. Biol. Med. 153(1):
1620; 2012.
181. Murillo, N.; Kumru, H.; Opisso, E.; Padulles, J. M.; Medina,
J.; Vidal, J.; Kofler, M. Recovery of assisted overground

443

182.
183.

184.

185.

186.
187.
188.
189.

190.

191.

192.

193.
194.

195.
196.
197.
198.

stepping in a patient with chronic motor complete spinal


cord injury: A case report. NeuroRehabilitation 31(4):401
407; 2012.
Nanninga, J. B.; Einhorn, C.; Deppe, F. The effect of sacral
nerve stimulation for bladder control during pregnancy: A
case report. J. Urol. 139(1):121122; 1988.
Nardone, R.; Holler, Y.; Leis, S.; Holler, P.; Thon, N.;
Thomschewski, A.; Golaszewski, S.; Brigo, F.; Trinka, E.
Invasive and non-invasive brain stimulation for treatment
of neuropathic pain in patients with spinal cord injury: A
review. J. Spinal Cord Med. 37(1):1931; 2014.
Nekoukar, V.; Erfanian, A. Dynamic optimization of walkerassisted FES-activated paraplegic walking: Simulation and
experimental studies. Med. Eng. Phys. 35(11):16591668;
2013.
Niu, X.; Varoqui, D.; Kindig, M.; Mirbagheri, M. M. The
effect of robot-assisted locomotor training on walking
speed. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2012:
38583861; 2012.
OConnell, P. R. Sacral nerve stimulation for constipation.
Br. J. Surg. 100(2):174181; 2013.
ODonnell, C. M.; Harvey, A. R. An outpatient low-intensity
locomotor training programme for paediatric chronic incomplete spinal cord injury. Spinal Cord 51(8):650651; 2013.
Ohta, Y.; Akino, M.; Iwasaki, Y.; Abe, H. [Spinal epidural
stimulation for central pain caused by spinal cord lesion].
No Shinkei Geka. 20(2):147152; 1992.
Ortiz, H.; de Miguel, M.; Rinaldi, M.; Oteiza, F.; Altomare,
D. F. Functional outcome of sacral nerve stimulation in
patients with severe constipation. Dis. Colon Rectum 55(8):
876880; 2012.
Paszkiewicz, E. J.; Siegel, S. W.; Kirkpatrick, C.; Hinkel,
B.; Keeisha, J.; Kirkemo, A. Sacral nerve stimulation in
patients with chronic, intractable pelvic pain. Urology 57(6
Suppl 1):124; 2001.
Patton, B. C.; Hook, M. A.; Ferguson, A. R.; Crown,
E. D.; Grau, J. W. The behavioral deficit observed following noncontingent shock in spinalized rats is prevented
by the protein synthesis inhibitor cycloheximide. Behav.
Neurosci. 118(3):653658; 2004.
Peckham, P. H. Functional electrical stimulation: Current
status and future prospects of applications to the neuromuscular system in spinal cord injury. Paraplegia 25(3):
279288; 1987.
Peckham, P. H.; Creasey, G. H. Neural prostheses: Clinical
applications of functional electrical stimulation in spinal
cord injury. Paraplegia 30(2):96101; 1992.
Peckham, P. H.; Mortimer, J. T.; Marsolais, E. B. Controlled prehension and release in the C5 quadriplegic
elicited by functional electrical stimulation of the paralyzed
forearm musculature. Ann. Biomed. Eng. 8(46):369388;
1980.
Petrofsky, J. S. Functional electrical stimulation and the
rehabilitation of the spinal cord-injured patient. Adv. Clin.
Rehabil. 1:115136; 1987.
Petrofsky, J. S. Thermoregulatory stress during rest and
exercise in heat in patients with a spinal cord injury. Eur.
J. Appl. Physiol. Occup. Physiol. 64(6):503507; 1992.
Petrofsky, J. S.; Phillips, C. A. The use of functional electrical stimulation for rehabilitation of spinal cord injured
patients. Cent. Nerv. Syst. Trauma 1(1):5774; 1984.
Phillips, C. A. Electrical muscle stimulation in combination with a reciprocating gait orthosis for ambulation by
paraplegics. J. Biomed. Eng. 11(4):338344; 1989.

444

199. Phillips, C. A. Functional electrical stimulation and lower


extremity bracing for ambulation exercise of the spinal
cord injured individual: A medically prescribed system.
Phys. Ther. 69(10):842849; 1989.
200. Phillips, C. A. Medical criteria for active physical therapy.
Physician guidelines for patient participation in a program
of functional electrical rehabilitation. Am. J. Phys. Med.
66(5):269286; 1987.
201. Phillips, C. A.; Hendershot, D. M. A systems approach to
medically prescribed functional electrical stimulation. Ambulation after spinal cord injury. Paraplegia 29(8):505513; 1991.
202. Pinter, M. M.; Dimitrijevic, M. R. Gait after spinal cord
injury and the central pattern generator for locomotion.
Spinal Cord 37(8):531537; 1999.
203. Pinto, C. M.; Golubitsky, M. Central pattern generators for
bipedal locomotion. J. Math. Biol. 53(3):474489; 2006.
204. Possover, M. Recovery of sensory and supraspinal control
of leg movement in people with chronic paraplegia: A case
series. Arch. Phys. Med. Rehabil. 95(4):610614; 2014.
205. Ragnarsson, K. T. Functional electrical stimulation and
suppression of spasticity following spinal cord injury. Bull.
N. Y. Acad. Med. 68(2):351364; 1992.
206. Ragnarsson, K. T. Physiologic effects of functional electrical stimulation-induced exercises in spinal cord-injured
individuals. Clin. Orthop. Relat. Res. 233:5363; 1988.
207. Ragnarsson, K. T.; Pollack, S.; ODaniel, W.Jr.; Edgar, R.;
Petrofsky, J.; Nash, M. S. Clinical evaluation of computerized functional electrical stimulation after spinal cord injury:
A multicenter pilot study. Arch. Phys. Med. Rehabil. 69(9):
672677; 1988.
208. Rebesco, J. M.; Miller, L. E. Enhanced detection threshold
for in vivo cortical stimulation produced by Hebbian conditioning. J. Neural Eng. 8(1):016011; 2011.
209. Righetti, L.; Buchli, J.; Ijspeert, A. J. Dynamic Hebbian
learning in adaptive frequency oscillators. Physica D 216(2):
269281; 2006.
210. Righetti, L.; Buchli, J.; Ijspeert, A. J. From dynamic
Hebbian learning for oscillators to adaptive central pattern
generators. Proceedings of 3rd International Symposium
on Adaptive Motion in Animals and Machines, AMAM
2005. Ilmenau: Verlage ISLE.
211. Robergs, R. A.; Appenzeller, O.; Qualls, C.; Aisenbrey, J.;
Krauss, J.; Kopriva, L.; DePaepe, J. Increased endothelin
and creatine kinase after electrical stimulation of paraplegic
muscle. J. Appl. Physiol. 75(6):24002405; 1993.
212. Roche, N.; Lackmy, A.; Achache, V.; Bussel, B.; Katz, R.
Effects of anodal tDCS on lumbar propriospinal system
in healthy subjects. Clin. Neurophysiol. 123(5):10271034;
2012.
213. Roy, F. D.; Gibson, G.; Stein, R. B. Effect of percutaneous
stimulation at different spinal levels on the activation of
sensory and motor roots. Exp. Brain Res. 223(2):281
289; 2012.
214. Roy, R. R.; Harkema, S. J.; Edgerton, V. R. Basic
concepts of activity-based interventions for improved
recovery of motor function after spinal cord injury. Arch.
Phys. Med. Rehabil. 93(9):14871497; 2012.
215. Rushton, D. N. Functional electrical stimulation and
rehabilitationAn hypothesis. Med. Eng. Phys. 25(1):
7578; 2003.
216. Sadowsky, C. L.; Hammond, E. R.; Strohl, A. B.; Commean,
P. K.; Eby, S. A.; Damiano, D. L.; Wingert, J. R.; Bae, K. T.;
McDonald, J. W.3rd. Lower extremity functional electrical
stimulation cycling promotes physical and functional recovery

YOUNG

217.

218.

219.
220.

221.

222.

223.
224.

225.
226.

227.

228.

229.

230.

in chronic spinal cord injury. J. Spinal Cord Med. 36(6):


623631; 2013.
Salisbury, L.; Shiels, J.; Todd, I.; Dennis, M. A feasibility
study to investigate the clinical application of functional
electrical stimulation (FES), for dropped foot, during the
sub-acute phase of stroke - A randomized controlled trial.
Physiother. Theory Pract. 29(1):3140; 2013.
Sato, K. L.; Johanek, L. M.; Sanada, L. S.; Sluka, K. A.
Spinal cord stimulation reduces mechanical hyperalgesia
and glial cell activation in animals with neuropathic pain.
Anesth. Analg. 118(2):464472; 2014.
Saxena, S.; Nikolic, S.; Popovic, D. An EMG-controlled
grasping system for tetraplegics. J. Rehabil. Res. Dev.
32(1):1724; 1995.
Sayenko, D. G.; Angeli, C.; Harkema, S. J.; Edgerton,
V. R.; Gerasimenko, Y. P. Neuromodulation of evoked
muscle potentials induced by epidural spinal-cord stimulation in paralyzed individuals. J. Neurophysiol. 111(5):1088
1099; 2014.
Schmidt, R. A.; Jonas, U.; Oleson, K. A.; Janknegt, R. A.;
Hassouna, M. M.; Siegel, S. W.; van Kerrebroeck, P. E.
Sacral nerve stimulation for treatment of refractory urinary
urge incontinence. Sacral Nerve Stimulation Study Group.
J. Urol. 162(2):352357; 1999.
Schwartz, I.; Meiner, Z. [The influence of locomotor treatment using robotic body-weight-supported treadmill training
on rehabilitation outcome of patients suffering from neurological disorders]. Harefuah 152(3):166171, 182; 2013.
Schwartzkroin, P. A.; Wester, K. Long-lasting facilitation
of a synaptic potential following tetanization in the in vitro
hippocampal slice. Brain Res. 89(1):107119; 1975.
Sheldon, R.; Kiff, E. S.; Clarke, A.; Harris, M. L.; Hamdy,
S. Sacral nerve stimulation reduces corticoanal excitability
in patients with faecal incontinence. Br. J. Surg. 92(11):
14231431; 2005.
Sherrington, C. S. Flexion-reflex of the limb, crossed extensionreflex, and reflex stepping and standing. J. Physiol. 40(12):
28121; 1910.
Sherwood, A. M.; Sharkey, P. C.; Dimitrijevic, M. R. Biomedical engineering specifications for epidural spinal cord
stimulation to augment motor performance. Int. Rehabil.
Med. 2(2):6267; 1980.
Shimoji, K.; Hokari, T.; Kano, T.; Tomita, M.; Kimura,
R.; Watanabe, S.; Endoh, H.; Fukuda, S.; Fujiwara, N.;
Aida, S. Management of intractable pain with percutaneous
epidural spinal cord stimulation: Differences in pain-relieving
effects among diseases and sites of pain. Anesth. Analg.
77(1):110116; 1993.
Shin, H. Y.; Kim, H.; Kwon, M. J.; Hwang, D. H.; Lee,
K.; Kim, B. G. Molecular and cellular changes in the lumbar spinal cord following thoracic injury: Regulation by
treadmill locomotor training. PLoS One 9(2):
e88215; 2014.
Siegel, S. W.; Catanzaro, F.; Dijkema, H. E.; Elhilali, M. M.;
Fowler, C. J.; Gajewski, J. B.; Hassouna, M. M.; Janknegt,
R. A.; Jonas, U.; van Kerrebroeck, P. E.; Lycklama a
Nijeholt, A. A.; Oleson, K. A.; Schmidt, R. A. Long-term
results of a multicenter study on sacral nerve stimulation for
treatment of urinary urge incontinence, urgency-frequency,
and retention. Urology 56(6 Suppl 1):8791; 2000.
Simpson, R. K.Jr.; Robertson, C. S.; Goodman, J. C. Segmental recovery of amino acid neurotransmitters during
posterior epidural stimulation after spinal cord injury. J. Am.
Paraplegia Soc. 16(1):3441; 1993.

ELECTRICAL STIMULATION AND MOTOR RECOVERY

231. Slawinska, U.; Miazga, K.; Jordan, L. M. The role of serotonin in the control of locomotor movements and strategies
for restoring locomotion after spinal cord injury. Acta
Neurobiol. Exp. 74(2):172187; 2014.
232. Solopova, I. A.; Selionov, V. A.; Kazennikov, O. V.;
Ivanenko, Y. P. Effects of transcranial magnetic stimulation
during voluntary and non-voluntary stepping movements
in humans. Neurosci. Lett. 579C:6469; 2014.
233. Soto, F.; Ma, X.; Cecil, J. L.; Vo, B. Q.; Culican, S. M.;
Kerschensteiner, D. Spontaneous activity promotes synapse
formation in a cell-type-dependent manner in the developing retina. J. Neurosci. 32(16):54265439; 2012.
234. Spiess, M. R.; Jaramillo, J. P.; Behrman, A. L.; Teraoka,
J. K.; Patten, C. Unexpected recovery after robotic locomotor training at physiologic stepping speed: A single-case
design. Arch. Phys. Med. Rehabil. 93(8):14761484; 2012.
235. Sqalli-Houssaini, Y.; Cazalets, J. R.; Clarac, F. Oscillatory
properties of the central pattern generator for locomotion in
neonatal rats. J. Neurophysiol. 70(2):803813; 1993.
236. Stein, R. B.; Everaert, D. G.; Roy, F. D.; Chong, S.;
Soleimani, M. Facilitation of corticospinal connections in
able-bodied people and people with central nervous system
disorders using eight interventions. J. Clin. Neurophysiol.
30(1):6678; 2013.
237. Subbarao, J. V. Walking after spinal cord injury. Goal or
wish? West. J. Med. 154(5):612614; 1991.
238. Sykes, L.; Campbell, I. G.; Powell, E. S.; Ross, E. R.;
Edwards, J. Energy expenditure of walking for adult patients
with spinal cord lesions using the reciprocating gait orthosis
and functional electrical stimulation. Spinal Cord 34(11):
659665; 1996.
239. Sykes, L.; Ross, E. R.; Powell, E. S.; Edwards, J. Objective measurement of use of the reciprocating gait orthosis
(RGO) and the electrically augmented RGO in adult patients
with spinal cord lesions. Prosthet. Orthot. Int. 20(3):182
190; 1996.
240. Takakusaki, K.; Kohyama, J.; Matsuyama, K.; Mori, S.
Synaptic mechanisms acting on lumbar motoneurons during postural augmentation induced by serotonin injection
into the rostral pontine reticular formation in decerebrate
cats. Exp. Brain Res. 93(3):471482; 1993.
241. Talalla, A.; Bloom, J. W.; Nguyen, Q. Successful intraspinal
extradural sacral nerve stimulation for bladder emptying in
a victim of traumatic spinal cord transection. Neurosurgery
19(6):955961; 1986.
242. Tan, Z.; Liu, H.; Yan, T.; Jin, D.; He, X.; Zheng, X.; Xu,
S.; Tan, C. The effectiveness of functional electrical stimulation based on a normal gait pattern on subjects with early
stroke: A randomized controlled trial. Biomed. Res. Int.
2014:545408; 2014.
243. Tani, N.; Saitoh, Y.; Hirata, M.; Kato, A.; Yoshimine, T.
Bilateral cortical stimulation for deafferentation pain after
spinal cord injury. Case report. J. Neurosurg. 101(4):687
689; 2004.
244. Tator, C. H.; Minassian, K.; Mushahwar, V. K. Spinal
cord stimulation: Therapeutic benefits and movement generation after spinal cord injury. Handb. Clin. Neurol. 109:
283296; 2012.
245. Taylor, P.; Humphreys, L.; Swain, I. The long-term costeffectiveness of the use of Functional Electrical Stimulation for the correction of dropped foot due to upper motor
neuron lesion. J. Rehabil. Med. 45(2):154160; 2013.
246. Taylor, P. N.; Ewins, D. J.; Fox, B.; Grundy, D.; Swain,
I. D. Limb blood flow, cardiac output and quadriceps muscle

445

247.

248.
249.

250.

251.

252.

253.

254.
255.

256.

257.

258.
259.

260.

bulk following spinal cord injury and the effect of training


for the Odstock functional electrical stimulation standing
system. Paraplegia 31(5):303310; 1993.
Terson de Paleville, D.; McKay, W.; Aslan, S.; Folz, R.;
Sayenko, D.; Ovechkin, A. Locomotor step training with
body weight support improves respiratory motor function
in individuals with chronic spinal cord injury. Respir.
Physiol. Neurobiol. 189(3):491497; 2013.
Thomas, G. P.; Dudding, T. C.; Rahbour, G.; Nicholls,
R. J.; Vaizey, C. J. Sacral nerve stimulation for constipation. Br. J. Surg. 100(2):174181; 2013.
Thorsen, R.; Dalla Costa, D.; Chiaramonte, S.; Binda, L.;
Beghi, E.; Redaelli, T.; Occhi, E.; Ferrarin, M. A noninvasive neuroprosthesis augments hand grasp force in individuals with cervical spinal cord injury: The functional and
therapeutic effects. Scientific World Journal 2013:836959;
2013.
Tillakaratne, N. J.; Guu, J. J.; de Leon, R. D.; Bigbee,
A. J.; London, N. J.; Zhong, H.; Ziegler, M. D.; Joynes,
R. L.; Roy, R. R.; Edgerton, V. R. Functional recovery of
stepping in rats after a complete neonatal spinal cord transection is not due to regrowth across the lesion site. Neuroscience 166(1):2333; 2010.
Twist, D. J.; Culpepper-Morgan, J. A.; Ragnarsson, K. T.;
Petrillo, C. R.; Kreek, M. J. Neuroendocrine changes during functional electrical stimulation. Am. J. Phys. Med.
Rehabil. 71(3):156163; 1992.
van Wunnik, B. P.; Baeten, C. G.; Southwell, B. R.
Neuromodulation for constipation: Sacral and transcutaneous stimulation. Best Pract. Res. Clin. Gastroenterol. 25(1):
181191; 2011.
Varoqueaux, F.; Sigler, A.; Rhee, J. S.; Brose, N.; Enk, C.;
Reim, K.; Rosenmund, C. Total arrest of spontaneous and
evoked synaptic transmission but normal synaptogenesis in
the absence of Munc13-mediated vesicle priming. Proc.
Natl. Acad. Sci. USA 99(13):90379042; 2002.
Veale, J. L.; Rees, S. Renshaw cell activity in man. J. Neurol.
Neurosurg. Psychiatry 36(4):674683; 1973.
Verhage, M.; Maia, A. S.; Plomp, J. J.; Brussaard, A. B.;
Heeroma, J. H.; Vermeer, H.; Toonen, R. F.; Hammer,
R. E.; van den Berg, T. K.; Missler, M.; Geuze, H. J.;
Sudhof, T. C. Synaptic assembly of the brain in the
absence of neurotransmitter secretion. Science 287(5454):
864869; 2000.
Wang, Y.; Chen, Y.; Chen, L.; Wolpaw, J. R.; Chen, X. Y.
Cortical stimulation causes long-term changes in H-reflexes
and spinal motoneuron GABA receptors. J. Neurophysiol.
108(10):26682678; 2012.
Ward, P. J.; Herrity, A. N.; Smith, R. R.; Willhite, A.;
Harrison, B. J.; Petruska, J. C.; Harkema, S. J.; Hubscher,
C. H. Novel multi-system functional gains via task specific
training in spinal cord injured male rats. J. Neurotrauma
31(9):819833; 2014.
Wernig, A. Locomotor programs versus conventional
physical therapy? Locomotor training. Spinal Cord 50(8):
641; author reply 642; 2012.
Wernig, A. Long-term body-weight supported treadmill
training and subsequent follow-up in persons with chronic
SCI: Effects on functional walking ability and measures of
subjective well-being. Spinal Cord 44(4):265266; author
reply 267268; 2006.
Wernig, A. Treadmill training after spinal cord injury:
Good but not better. Neurology 67(10):1901; author reply
19011902; 2006.

446

261. Wernig, A. Weight-supported treadmill vs over-ground


training for walking after acute incomplete SCI. Neurology
67(10):1900; author reply 1900; 2006.
262. Wernig, A.; Muller, S. Laufband locomotion with body
weight support improved walking in persons with severe
spinal cord injuries. Paraplegia 30(4):229238; 1992.
263. Wernig, A.; Muller, S.; Nanassy, A.; Cagol, E. Laufband
therapy based on rules of spinal locomotion is effective
in spinal cord injured persons. Eur. J. Neurosci. 7(4):823
829; 1995.
264. Wernig, A.; Nanassy, A.; Muller, S. Laufband (LB) therapy in spinal cord lesioned persons. Prog. Brain Res. 128:
8997; 2000.
265. Wernig, A.; Nanassy, A.; Muller, S. Maintenance of locomotor abilities following Laufband (treadmill) therapy in
para- and tetraplegic persons: Follow-up studies. Spinal
Cord 36(11):744749; 1998.
266. Wernig, A.; Wernig, S. Step training with severely damaged
spinal cord. Brain 132(Pt 7):e117; author reply e118; 2009.
267. Westerveld, A. J.; Kuck, A.; Schouten, A. C.; Veltink,
P. H.; van der Kooij, H. Grasp and release with surface
functional electrical stimulation using a Model Predictive
Control approach. Conf. Proc. IEEE Eng. Med. Biol. Soc.
2012:333336; 2012.
268. Whitehurst, T. K.; McGivern, J. P. Spinal cord stimulation
as a therapy for sexual dysfunction. US006862479B1.
United States. U.S. Patent Office; 2005.
269. Wilson, V. J. Recurrent facilitation of spinal reflexes. J. Gen.
Physiol. 42(4):703713; 1959.
270. Wirz, M.; Bastiaenen, C.; de Bie, R.; Dietz, V. Effectiveness of automated locomotor training in patients with acute
incomplete spinal cord injury: A randomized controlled
multicenter trial. BMC Neurol. 11:60; 2011.
271. Woolf, C. J.; Wall, P. D. Relative effectiveness of C primary
afferent fibers of different origins in evoking a prolonged
facilitation of the flexor reflex in the rat. J. Neurosci. 6(5):
14331442; 1986.
272. Worsoe, J.; Rasmussen, M.; Christensen, P.; Krogh, K.
Neurostimulation for neurogenic bowel dysfunction.
Gastroenterol. Res. Pract. 2013:563294; 2013.

YOUNG

273. Wrigley, P. J.; Gustin, S. M.; McIndoe, L. N.; Chakiath,


R. J.; Henderson, L. A.; Siddall, P. J. Longstanding neuropathic pain after spinal cord injury is refractory to transcranial
direct current stimulation: A randomized controlled trial.
Pain 154(10):21782184; 2013.
274. Wu, M.; Hornby, T. G.; Landry, J. M.; Roth, H.; Schmit,
B. D. A cable-driven locomotor training system for restoration of gait in human SCI. Gait Posture 33(2):256260;
2011.
275. Wu, M.; Landry, J. M.; Schmit, B. D.; Hornby, T. G.;
Yen, S. C. Robotic resistance treadmill training improves
locomotor function in human spinal cord injury: A pilot
study. Arch. Phys. Med. Rehabil. 93(5):782789; 2012.
276. Young, E. E.; Baumbauer, K. M.; Elliot, A.; Joynes, R. L.
Neonatal hind-paw injury disrupts acquisition of an instrumental response in adult spinal rats. Behav. Neurosci.
121(5):10951100; 2007.
277. Young, W. Spinal cord regeneration. Cell Transplant. 23(45):
573611; 2014.
278. Zabihi, N.; Mourtzinos, A.; Maher, M. G.; Raz, S.;
Rodriguez, L. V. The effects of bilateral caudal epidural S2-4
neuromodulation on female sexual function. Int. Urogynecol.
J. Pelvic Floor Dysfunct. 19(5):697700; 2008.
279. Zermann, D. H.; Weirich, T.; Wunderlich, H.; Reichelt,
O.; Schubert, J. Sacral nerve stimulation for pain relief in
interstitial cystitis. Urol. Int. 65(2):120121; 2000.
280. Zhang, S. X.; Huang, F.; Gates, M.; White, J.; Holmberg,
E. G. Tail nerve electrical stimulation induces body
weight-supported stepping in rats with spinal cord injury.
J. Neurosci. Methods 187(2):183189; 2010.
281. Zhu, H.; Feng, Y. P.; Young, W.; You, S. W.; Shen,
X. F.; Liu, Y. S.; Ju, G. Early neurosurgical intervention
of spinal cord contusion: An analysis of 30 cases. Chin.
Med. J. 121(24):24732478; 2008.
282. Zukor, K.; Belin, S.; Wang, C.; Keelan, N.; Wang, X.; He,
Z. Short hairpin RNA against PTEN enhances regenerative
growth of corticospinal tract axons after spinal cord injury.
J. Neurosci. 33(39):1535015361; 2013.