Eur Spine J (2008) 17:1256–1269
DOI 10.1007/s00586-008-0729-3

ORIGINAL ARTICLE

Role of electrical stimulation for rehabilitation and regeneration
after spinal cord injury: an overview
Samar Hamid Æ Ray Hayek

Received: 12 February 2008 / Accepted: 15 July 2008 / Published online: 2 August 2008
Ó Springer-Verlag 2008

Abstract Structural discontinuity in the spinal cord after
injury results in a disruption in the impulse conduction
resulting in loss of various bodily functions depending
upon the level of injury. This article presents a summary of
the scientific research employing electrical stimulation as ameans for anatomical or functional recovery for patients
suffering from spinal cord injury. Electrical stimulation in
the form of functional electrical stimulation (FES) can help
facilitate and improve upper/lower limb mobility alongwith other body functions lost due to injury e.g. respiratory,
sexual, bladder or bowel functions by applying a controlled
electrical stimulus to generate contractions and functional
movement in the paralysed muscles. The available rehabilitative techniques based on FES technology and various
Food and Drug Administration, USA approved neuroprosthetic devices that are in use are discussed. The second
part of the article summarises the experimental work donein the past 2 decades to study the effects of weakly applied
direct current fields in promoting regeneration of neurites
towards the cathode and the new emerging technique ofoscillating field stimulation which has shown to promotebidirectional regeneration in the injured nerve fibres. The
present article is not intended to be an exhaustive review
but rather a summary aiming to highlight these two
applications of electrical stimulation and the degree ofanatomical/functional recovery associated with these in thefield of spinal cord injury research.
Keywords Spinal cord injury  Oscillating fieldstimulation  Functional electrical stimulation 
S. Hamid (&)  R. Hayek
Environmental and Life Sciences, Macquarie University,
Sydney, NSW, Australia
e-mail: shamid@els.mq.edu.au123

Axonal regeneration  Advances in spinal
cord research

Introduction
Spinal cord injury (SCI) is one of the most catastrophic
injuries of the nervous system resulting in permanentneurological deficits. Typically SCI occurs in young,
otherwise healthy adults as a result of trauma. Nearly 50%
of SCI occurs in the age bracket of 16–30 years (Fig. 1)[18, 25]. The number of people suffering from SCI is quite
significant. There are approximately 11,000 new cases eachyear in the United States [25]. The number of people livingwith SCI in June 2006 was approximately 253,000 [25].
The average yearly health care and living expenses are
directly proportional to the level of injury and have been
estimated to be between USD 1.0 and 2.9 million perperson [25]. Each year in Australia, about 300–400 new
cases of SCI are added to an estimated prevalent SCI
population of about 10,000 cases [18] (Figs. 2, 3).
A few decades ago, most of the people with SCI usuallydied in a fairly short period of time due to limited emergency care available at the time of injury. Their life
expectancy today is becoming close to that of the normal
population [25], yet for the rest of their lives they remain
dependent on others for managing their day to day living.
Those surviving the initial brunt would suffer from manyother associated medical conditions like respiratory infections, urinary tract infections, decubitus ulcers,
cardiovascular diseases, etc. Recent advances in emergency and rehabilitative medical care have greatly reduced
the premature mortality and morbidity in these patients.
Spinal cord injury is classified as acute or chronic,
although there is no clear demarcation as to when an acuteEur Spine J (2008) 17:1256–1269

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Fig. 1 SCI statistics (National
Spinal Cord Injury StatisticalCentre, University of Alabama
at Birmingham)

Fig. 2 Neurocontrol Freehand (Neurocontrol Corporation)

injury converts into a chronic one. Generally, the time
elapsed between initial hours and a few weeks after the
injury is considered as acute phase, whereas months toyears after injury is characterised as chronic phase. Thisclinical classification is necessary as the biology of thesetwo phases is significantly different from each other anddifferent strategies are needed while developing experimental therapies for functional recovery. Hence an in depth
understanding of the pathophysiology of SCI is vital fordeveloping new strategies to target the cellular mechanisms
involved in the development and perpetuation of acute or
chronic injury. SCI can be described as a disconnection
syndrome [33] that disrupts the descending motor fibres
from the motor cortex to the spinal motoneurons, and theascending somato-sensory fibres from the spinal cord to thebrain. The functional loss seen in SCI is due to interruptionof electrical impulse conduction through the lesioned axons. Intrinsic circuits below the level of injury remain
intact but disconnected from the descending controls of thecerebral cortex. Anywhere else in the body this physiological conduction blockade is tackled with regrowth,
regeneration and sometimes functional re-connectivity of
the axons to the designated end-organ resulting in variable

Fig. 3 Finetech-Brindley Bladdersystem (Finetech Medical) (previously marketed as Vocare bladder system by Neurocontrol
Corporation in US). a Schematic diagram showing the working
mechanics of the system, b implantable portion, c external controller

levels of functional recovery [26]. In the event of a central
nervous system (CNS) injury, regrowth of axons is notpossible because CNS has multiple additional factors (atthe cellular as well as molecular level) which act as barriers
towards regeneration and make the environment hostile toinherent regenerative ability [77, 88].
The initial mechanical injury to the spinal cord results inlocalised oedema and haemorrhage in the central grey
matter along with vasospasm of arteries supplying the
spinal cord. This leads to severe ischaemia of the cord

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triggering a secondary injury from within due to the releaseof various inflammatory biochemical mediators such asarachidonic acid metabolites, free radicals and many otherapoptotic molecules. Further injury occurs due to the disruption of the ionic homeostasis in the cells such as
accumulation of Ca++ ions intracellularly and of K+ ions
extracellularly [28, 95]. This ionic disruption in concert
with ischaemic, inflammatory, haemorrhagic and biochemical reactions induces a secondary axonal dieback andretraction that contributes towards the self-destruction of
the spinal cord leading to loss of structural integrity andsevere functional loss. At present, there are no known
definitive treatment strategies that can alter the pathophysiology and bring a significant change to the conditionof patients suffering from this injury.
Although complete recovery of function in an injured
spinal cord is still not possible in clinical setting, numerous
research efforts are being conducted to promote regeneration and repair the interruption of nerve impulses as seen in
SCI. Currently there are three main research avenues underprogress (see Table 1). The first approach aims to minimise
the extent of initial and secondary injury in the spinal cord
and attempts to limit or even reverse the physiologicalconduction blockade by preserving the surviving viable
non-functioning white matter with the help of various
pharmacological compounds such as Methylprednisolone[44, 68, 83], Polyethylglycol [14, 22, 80, 81] and 4-aminopyridine [21, 38, 62].
The second approach concentrates on ways to regenerate and reconnect the injured axons within the spinal
cord by modifying the various factors responsible for the
antagonistic CNS environment and make it more receptive towards regeneration. Various kinds of cellulartransplants such as foetal neuronal cells, stem cells,
peripheral nerves, Schwann cells and olfactory glial cells
have been employed in an effort to bridge the gap inexperimental models [52, 54]. Antibodies are currently
being designed to neutralise the endogenous inhibitors ofnerve regeneration such as Nogo, Oligodendrocyte myelin
glycoprotein and other apoptotic factors associated withthe glial scar that forms at the site of injury [35, 49, 77,84]. Other neural repair strategies are aiming to supplement the endogenous neurotrophic factors like brainderived neurotrophic factor (BDNF) or Neurotrophin-3(NT-3) etc., to achieve greater sprouting and elongation ofdamaged axons [51–53, 77]. Another rather new regenerative strategy is application of weak electrical fields
around the lesion to induce a regeneration permissive
environment at the injury site in the CNS [5]. This will be
discussed in detail in the second part of this review. Allof these neuro-regenerative strategies are looking quite
promising at this stage and some have even enteredclinical trials but we do not know to what extent theresults will be mirrored in human patients.
The third approach is directed towards regaining thefunctional recovery, regardless of the anatomical connections within the spinal cord. This involves the use ofelectrical stimulation through neural prosthetic devices forpartially restoring the lost functions. Several Food andDrug Administration (FDA) approved devices are commercially available at present. These are also discussed indetail in this review.
The basic goal of these experimental therapeutic interventions is to re-create a regenerative environment forstructural re-connectivity and to bring functional recovery
in an injured spinal cord. This paper summarises theapplications of electrical stimulation in spinal cord injury
for rehabilitation purposes, and for the regeneration of thesevered axons and the degree of functional/ anatomical
recovery associated with these.

Restoration of function through electrical stimulation
Nearly half a century has been dedicated to the research
involving use of electric currents for stimulating theTable 1 Summary of current research approaches in SCI
Current research approaches in SCINeural transplantation

Neural stem cells, foetal neural cells
Olfactory ensheathing cells
Peripheral neural bridges, Schwann cells

Modification of CNS environment

Antibodies to various endogenous inhibitory factors
Promotion of neurotrophic factors
Pharmacological interventions

Electrical stimulation

Functional electrical stimulation (FES)

Therapeutic applications
Functional application

Axonal regeneration

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Direct current stimulation
Oscillating field stimulation

Uni-directional growth
Bi-directional growthEur Spine J (2008) 17:1256–1269

paralysed muscles with intact peripheral motor nerves.
Electrical stimulation can overcome the deficit produced by
the lesion in the spinal cord and maintain the integrity ofvarious bodily functions through direct neuromuscular
stimulation.

Functional electrical stimulation
Functional electrical stimulation (FES) is the technique of
applying safe levels of electric current to activate thedamaged or disabled neuromuscular system in a coordinated manner in order to achieve the lost function. Neuroprosthesis is a device that uses electrical stimulation toactivate the nervous system. These initiate a physiologicallike stimulation in the intact peripheral nerves, providing
functional restoration of various body organs in the neurologically impaired individuals.
External neuromuscular excitation has been attempted
since the eighteenth century, when Luigi Galvani discovered that external electric current can cause the severed
nerves to generate an action potential leading to muscular
contractions [30]. However, achieving functionally useful
movements remained a challenge till the development of
the first functional electrical stimulator (FES) to prevent
foot-drop in hemiplegic patients by Liberson et al. in 1961[50]. Functional electrical stimulator was first defined as
the technique used to artificially stimulate the muscles
deprived of nervous control by appropriate sequencing
bursts of electrical pulses with a view to generate muscular
contractions and produce a functionally useful movement.
The efforts to develop a suitable human functional stimulator which can achieve synergistic activity of various
muscles accelerated in the late 1980s and early 1990s. In
1987, Davis proposed the development of a FES system
based on multi-cochlear implant technology to restore
function in paraplegic patients [19]. Kralj, Bajd and Turk in
1988 applied FES to SCI patients with lesions between T4
and T12 in an effort to restore standing and walking [46].
Other parallel studies at that time also concluded that FES
assisted walking is feasible in patients with incomplete SCI
even with severe motor loss [37, 48].
The initial goal of FES technology was to provide
greater mobility to the patients after SCI. However, withthe advances in biomedical engineering within the last
2 decades, FES is no more limited to locomotion alone.
Therefore, the definition of FES has changed considerably
and is now considered to be the technique of applying safe
levels of electric current to stimulate various organs of the
body rendered disabled due to SCI. Examples include
assistance with respiration, bowel/bladder activity or somereturn of upper or lower limb function.

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Mechanism of FES operation
Both nerves and muscle fibres respond to electric current. However, for practical purposes FES is used todirectly stimulate nerve fibres only, as a much lower
amount of current is required to generate an action
potential in a nerve than the one required for musculardepolarisation.
The main component of a FES system is the microprocessor-based electronic stimulator which determines
when and how the stimulation is provided, with channels
for delivery of individual pulses through a set of electrodes connected to the neuromuscular system. The
microprocessor contains programs for sitting, standing,walking, hand grasp etc. It serves to generate a train of
impulses that grossly imitate the neural triggers thatwould have normally passed through the spinal cord to
the appropriate peripheral nerves below spinal cord lesion
for these different programs. These stimuli thus trigger
action potentials in the peripheral nerves which inturn
activate muscle contractions in the associated muscles
fibres [72]. The pulse amplitude (magnitude of current),
duration, frequency, waveform (a display of a signal onan oscilloscope that shows the magnitude of current or
voltage with respect to time) and duty cycle (the total
time to complete one on/off cycle) regulate the stimulation parameters. The numbers of channels, which canrange from one to several, govern the sophistication
required for complex outputs like FES assisted standing.
The programmable microprocessor activates the various
channels sequentially or in unison to synchronize thecomplex output of the stimulator. Electrodes provide theinterface between the electrical stimulator and the nervous system. Various types of electrodes have beendeveloped and are available ranging from non-invasive
surface electrodes to invasive implantable ones. Implantable electrodes provide more specific and selective
stimulation to the desired muscle group than the surface
electrodes. The feedback control of the FES system canbe either open-looped or closed-looped. Open-looped
control is used for simple tasks such as for muscle
strengthening alone, and requires a constant electrical
output from the stimulator. In a closed-looped system, theparameters for electrical stimulation are constantly modified by a computer via feedback information on muscle
force and joint position thus stimulating various muscle
groups simultaneously leading to a combination of muscular contraction needed for a complex sophisticatedfunctional activity such as walking [34]. Paraplegicpatients using FES for ambulation still require the use ofwalker or other orthotic devices for stabilising the ankle,
knees and hips.

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Implantable
Breathing assistance
MEDIMPLANT

MedImplant Biotechnisches Labor. Functional
Austria

Commercial

Not approved

Implantable
Breathing assistanceCommercial
Functional

IDE not
approved

Approved 1998
Implantable
Breathing assistanceCommercial
Functional

Avery Biomedical devices Inc.
USA
IDE: ATROSTIM PHRENIC NERVE STIMULATOR Atrotech Ltd. Finland
V1.0 & V2.0
MARKIV BREATHING PACEMAKER SYSTEM

Not approved

Approved 1998

External
Hand grasping Tenodesis

Current scope, applications and limitations of FES

Bladder & bowel function Implantable
Commercial

Experimental

FINETECH-BRINDLEY SYSTEM (previously
VOCARE)

Functional
Neuromotion Inc. Canada

Finetech medical Ltd. UK

BIONIC GLOVE

Functional

Not approved
Hand grasping Palmer and Implantable
lateralNEC Inc. JapanNEC FESS MATE

Functional

Commercial

Approved 2001
Hand grasping Palmer and ExternallateralCommercial
NESS Co. Israel
HANDMASTER NMS I

Functional

Not approved
External
Exercise/ cardiac
conditioning
Therapeutic Technologies Inc.
USA
ERGYS 2 CLINICAL REHABILITATION SYSTEM

Therapeutic Commercial

External
Ambulation
Sigmedics Inc. USA
PARASTEP-I

Functional

Commercial

Implantable /external
Type of system
Manufacturing
statusFES
category
Name of manufacturer
Name of system

Table 2 Various available FES systems

Approved 1994

Eur Spine J (2008) 17:1256–1269

FDA approval
status1260

There are clinically two applications of FES devices whichhave been designed to help SCI patients according to theirneed. Therapeutic applications include cardiovascularconditioning and the prevention of muscular atrophy
through exercise. Functional applications assist with vital
body functions lost due to SCI. Examples include ambulation and locomotive support in cases of paraplegia,
assistance with respiration or hand grasp in case of quadriplegia, in addition to electro ejaculation, bowel or bladdervoiding. Several commercial as well as research based FES
devices have been developed in different centres aroundthe world for various therapeutic and functional applications. For commercially available system (see Table 2).
Functional applications
The FES devices were initially designed in an attempt toprovide assistance with standing or walking, provided theparaplegic patient had adequate upper body motor control
and strength. There are more than 24 centres in the worldthat are actively assessing the role of FES induced walking
or standing and many systems are under development [34].
However, the only FDA approved FES system for shortdistance ambulation is Parastep I that uses a walker support
for balance. [36]. It is a transcutaneous, micro-computerised, electrical stimulation system built into a small unit
powered by batteries and is controlled by a finger touch
button located on a walker’s handbars for manual selectionof stimulation menus. The system provides stimulation
output to 12 surface electrodes that are attached to the skinat appropriate placements. These stimulation pulses trigger
action potentials in the intact peripheral nerves to generatemuscle contraction. It is the only system which is widely
available and has been evaluated for its ambulation performance and medical/psychological effects [16, 31, 34,36]. To be a candidate for FES induced ambulation
patients need to be selected after a thorough evaluation
conducted by a physician and physical therapist. Factors
considered include the presence of neurologically stable
and complete SCI, level of injury (preferably between T4
and T12), patient motivation, degree of spasticity, muscle
contractile response to electrical stimulation, cardiorespiratory capacity, and musculoskeletal integrity [36].
The use of these FES devices designed to permit or
improve ambulation is not simple or without risks. Paraplegic patients require extensive training to build muscle
strength in the upper body in order to achieve FES assisted
ambulation. The amount of energy spent with FES walking
is almost twice than that for normal walking, although theachievable speed is slower than that of normal walking [16,45]. The risk of injury with FES assisted ambulation isEur Spine J (2008) 17:1256–1269

more likely to be higher due to fatigue of the stimulated
muscle causing an increase incidence of fall and fractures.
These factors limit the true functional utilisation of thissystem. Another major practical problem associated withthe current FES locomotive models is mainly related tofeedback control. There is a need for more sensors tomeasure the muscular force, muscular fatigue, joint position, angular velocity and trunk position, which are to beconstantly analysed by the microprocessor. In response to
all these sensory inputs, the FES system should be able toredefine the stimulation parameters according to the feedback it receives thus delivering more natural responses,
smoother transitions and making ambulation on roughsurfaces a possibility as well. In spite of these associatedlimitations for everyday mobility in daily life, there arepotential functional, medical and psychological benefits of
FES assisted standing and walking. These devices can help
increase their level of independence by providing someassistance with standing while transferring from thewheelchair to a car, climbing a few steps or reaching for ahigher object. The medical advantages of short distanceambulation include increased blood flow to lower limbs,
increase in lower limb muscle mass, reduced spasticity,
lower heart rate at sub peak work intensities and beneficial
effects on digestion, bowel and bladder function [34, 36].
Psychological benefits achieved through FES assisted
walking such as the associated increase in self esteem andreduction in depression are all well documented [16, 31,
34, 36].
Most of the studies conducted which have evaluated therole of FES assisted walking have a very small sample size
and a short follow up time. Thus, the limited amount ofdata is currently insufficient to demonstrate a viable role
for this technology in the management of SCI. FES assisted
walking is likely to be accepted clinically as a form of
locomotion for SCI patients only if it can be proven to be amore reliable, convenient, safer and faster system than an
average wheelchair.
FES devices for quadriplegic patients mainly focuses on
restoring the grasp and pinch function. Presently there arequite a few FES devices available for restoration of handfunction out of which only two have been approved by
FDA: Freehand system and HandMaster [67]. These
devices enable the restoration of palmer grasp for holding
bigger/heavier objects and lateral grasp for smaller andthinner ones. These can also stimulate the triceps brachii
muscle to generate elbow extension for reaching as well.
The Freehand system was the first to be granted the FDA
approval. It is a surgically implantable, 8 channel stimulator, with an external control unit that can be programmed
to synthesize the movement of muscles through subcutaneously implanted electrodes to provide smooth grasp.
Patients control the device through a joystick placed on the1261

shoulder or wrist. Auditory or sensory feedback provide theuser with information regarding the system state. Patientscan choose between lateral and palmer grasp in order toassist with handling large or small objects. The main disadvantage of the Freehand system is that in case of failed
hardware components, additional surgery is required to fix
the problem. This is the only system that has been extensively evaluated and several multicentre studies support theFreehand system’s safety and efficacy along with user’s
satisfaction [41, 59, 89]. Unfortunately the company previously marketing the Freehand system in United States
has recently decided to stop manufacturing new devices but
still provides maintenance to previously implanted systems[63].
Another device for restoration of hand function thatreceived FDA approval in 2001 is called HandMaster. At
present this is the only FDA approved system that iscommercially available. It comprises a hinged shell withthree built in surface electrodes to stimulate the finger
flexors and extensors and the thenar musculature and has aspiral splint to stabilise the wrist. A separate control unit isused by the user to start the stimulation pattern and choose
between different programs for muscle activation. Traditionally it has been used as an exercise tool for stroke
patients. A literature search for its role in the SCI population showed that it has only been evaluated in a handfulof these patients [3, 86]. The advantages of HandMaster arethat it is non-invasive and has ease of application. However; it does not allow the user to fully supinate the arm
due to the splint that fixes the wrist joint angle and is lesscustomisable than the Freehand system. Both these devices
are designed for patients with C5-C6 injury with adequate
motor innervation of the forearm and hand muscles, good
passive range of motion, good upper trunk support, intact
vision and controlled spasticity. Both these devices––byrestoring grasp, hold and release function of the hand––increase the level of independence in the tetraplegicpatients. There is a time delay of 1–2 s between the command generation and execution of grasp function thatinterferes with the speed with which the patient can grasp
and release objects. Future designs should focus on
increasing the stimulation channels and sensors technology
in order to provide increased flexibility in controlling themuscle movement and providing a feedback about the wrist
joint movement.
Electrical stimulation of the phrenic nerve in order toachieve effective diaphragmatic contraction is used in highcervical tetraplegics (usually C3 or above) as an alternative
to long term mechanical ventilation. Three companies arecommercially manufacturing these stimulators, although
only Avery’s Mark IV breathing pacemaker system has
been successful in achieving FDA approval [34]. This is asurgically implanted phrenic nerve stimulator which

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delivers electrical impulses to the diaphragm in order torestore breathing function. Small electrodes are sutured tothe phrenic nerves either in the neck or by a trans-thoracic
approach through the second intercostal space, connectedby leads to receivers implanted subcutaneously. Radiosignals from an external transmitter and antenna activate
the receivers, and the stimulating pulses delivered to thephrenic nerve cause the diaphragm to contract, producing
inhalation [34]. Post operative care requires 4–6 weeks ofmostly in patient training. Candidates for phrenic nerve
pacing must have the phrenic nerve intact, as well as
normal lung function and normal chest wall compliance. It
is more suitable for C1/C2 injuries than those at C3-C5
injuries where anterior horn cells might have been damaged. Therefore pre-implantation screening includes
verification of phrenic nerve function by either a nerve
conduction study or visualising diaphragmatic movements
under fluoroscopy [34, 74]. To avoid the risk of nerve
damage implantation is done at one year post SCI. It has anumber of advantages over the traditional ventilator
assisted respiration. It improves the patient’s ability to
speak, reduces the amount of respiratory secretions,improves the level of comfort in the patient and reduces thelevel of required nursing care as needed with ventilator
dependent respiration [34, 74]. The possible complications
include infection, intraoperative mechanical damage to thephrenic nerve, reduction in ventilation and technical malfunctions leading to failure, with a need to retain atracheostomy stoma. The future work investigates thediaphragmatic stimulation through laparoscopic implantation of intramuscular electrodes in order to avoid thechances of per operative damage to phrenic nerves [23].
Other functional applications of FES which help to restore
useful functions and thus improve the quality of life include
bladder and bowel voiding and electro-ejaculation. Voluntary control of bowel and bladder function is either lost or
considerably impaired depending upon the level and severityof SCI and can lead to multiple complications. The Vocare
bladder system (currently available as Finetech-Brindley
bladder system) is a surgically implantable sacral anteriorroot stimulator that allows individuals with complete spinal
cord injury to urinate on demand [74]. Secondary use of thedevice is to aid in bowel evacuation. It was approved by FDA
in 1998. It consists of an external controller and transmitterand an implantable receiver-stimulator and electrodes. Thissystem is operated by radio frequency signals transmitted toelectrodes placed on the sacral spinal nerves (S2-S4) andleads to bladder/large bowel and urethral/ anal sphincter
contraction [34]. At the time of implantation, a posterior
rhizotomy through laminectomy at sacral level is performed
to abolish the uninhibited reflex bladder contractions. Thiseliminates the reflex incontinence caused by the activation of
the sensory reflex pathway [24]. However it also causes a loss

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of perineal sensations and reflex erection and ejaculation if
present. Patient selection criteria for Vocare implantation
include neurologically stable and clinically complete suprasacral SCI and intact parasympathetic innervation to detrusor
musculature. The major disadvantage of this system is theneed for major surgery for implantation and posterior rhizotomy. However, this device offers an improved quality oflife, social ease, as well as a reduction and prevention ofurinary tract infections and their associated complications[15, 17, 34]. Another added benefit of this system is enhanced
bowel evacuation with most patients reporting a reduction in
the time required for bowel evacuation along with a reduction in constipation and faecal impaction [17]. A slower
stimulation time sequence is required for defeacation thanfor micturation. Approximately 60% of men can also produce penile erection using this device [15].
Electroejaculation is one of the several techniques now
available to harvest viable sperm for the purposes of artificial
insemination or in vitro fertilization [34]. An electric probe isinserted into the rectum near the prostate to stimulate thenerves and contract the pelvis muscles, causing ejaculation[39]. The ejaculate is collected from the urethra and preparedfor use in artificial insemination. Caution need to be taken inmen with SCI who have a history of autonomic dysreflexia aselectroejaculation can cause a significant increase in bloodpressure and heart rate. This system was also previously
manufactured and supplied by a US based company which is
no longer functioning [63] however it is still available inEurope through a new manufacturer (see Table 2).
Therapeutic applications
In SCI the problem is not confined to spine alone rather thewhole body is affected. Depending upon the level of injury,
unused paralysed muscles undergo disuse atrophy with
reduced peripheral circulation and demineralisation in thebones leading to osteoporosis. The paralysis forces thepatients towards a more sedentary life style. The autonomic
nervous system impairment coupled with the lack of
exercise and mobility leads to various cardiovascular
problems thus increasing the morbidity in SCI sufferers. A
significant rehabilitative application of FES is in improving
muscle bulk and strength and prevention of denervation
muscular atrophy. It also facilitates cardiovascular conditioning and improvement in peripheral circulation throughthe use of stationary exercise devices. The most common
system for lower extremity FES exercise is the bicycle
ergometer. Two commercial systems which are approved
under Class II devices are currently available: StimMasterand ERGYS 2 clinical rehabilitation system, which is a
FDA approved, commercially available ergometer. These
are computer controlled closed-looped systems that bilaterally activate the gluteals, quadriceps and hamstrings

Eur Spine J (2008) 17:1256–1269

through surface electrodes in a sequential and alternating
pattern. Both these systems are fully portable thus allowing
the user to use these at home as well. Patients with partiallypreserved sensations in their lower limbs are usually unable
to tolerate stimulation since the intensity of electric current
applied is quite high [74].
The neurological benefits of exercise after SCI have beenstudied in animal models. Gazula et al. [32] demonstrated
the effects of lower limb exercise on spinal motor neurons
in animal models. They compared the effect of lower limb
exercise in three groups of animals; a group with intact
spinal cords, animals with complete spinal cord transection(SCT) and a third group of animals with complete spinal
cord transaction who underwent a daily exercise program.
They were able to show that the group with daily exercise
had none of the atrophic/ regressive changes in the motor
neurons that the group with SCT exhibited.
The clinical benefits that can be achieved through theexercises conducted via the FES systems include cardiac
conditioning when training for at least 30 min a day for 3–
5 days/week [69, 74]. However in individuals with injury
above T5, the increase in heart rate, stroke volume andcardiac output is limited due to the loss of supra-spinal
sympathetic control [70]. Other benefits include improvement of venous return from lower limbs thus reducing theincidence of deep venous thrombosis; increase in muscle
bulk, strength and endurance and an improvement in bowel
functions [34, 74]. The ability to regulate the body functions through FES also leads to additional psychologicalbenefits [34, 74]. However, there is no conclusive data on
whether these FES induced exercises can retard osteoporosis, increase insulin resistance and improve carbohydrate
metabolism as well or not.
All of the above mentioned FES strategies for various
SCI related complications have had a varied uptake into
clinical trials. It is largely to a variety of factors such asavailability and affordability of these devices, regional
ethical requirements, and technical difficulties in transforming a theoretical model into a viable clinical tool.
The other issues that need to be addressed are the inadequate system reliability, inappropriate cosmetics andportability of the system. These issues can be resolved bychanges in the design specifications to miniaturise thesystem, a better manufacturing processes and a stricter
safety and reliability analysis so that the freedom ofmobility and other bodily functions is not restricted to thelaboratory environment.

Future scope
Although the current development and advances in thedesign of FES system have made it possible to provide

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some mobility and functions to the SCI patients, at present,
FES alone has multiple inherent limitations. To restore thelost function safely, completely and efficaciously, further
research is needed. There are multiple challenges that need
to be met before it can be utilised by the SCI population ona regular basis.
Many centres around the world are engaged in further
development of FES prototypes with lesser limitations andmore control. FES promises a new era in rehabilitation andoffers great hope for patients who are wheelchair bound or
suffering from ambulatory difficulties as a result of a CNS
dysfunction. However, ultimate freedom of motion andfunction is not likely to be seen in the near future. Experimental models of FES systems with implantable electricalstimulators and portable microprocessors are under development [20, 85]. Another emerging paradigm is intraspinal
micro-stimulation (ISMS), where the spinal-cord-locomotor-circuits called Central Pattern Generators (CPG) aredirectly tapped for stimulation and restoration of limb
movements [75]. Future work on these neural prosthetic
devices is also focusing on decoding the intended motion
trajectories from the cerebral motor cortex and using thissignal to control the FES devices. Hybrid Neuro-prosthetics
are being investigated and may lead to the development of a
cognitive link through cerebral motor cortex to these neural
prosthetic devices [61, 65]. Recently, Muller-Putz [60]reported a case study where an implanted FES device Freehand system was connected with an electroencephalogram(EEG) based-Brain-Computer Interface (BCI). The patient
was given a short training course in order to be able to generate distinct EEG patterns by imagining the movement of
his paralysed hand. The patterns were further classified by
the BCI and output signals generated by BCI emulated thoseof the shoulder joystick for different grasp phases that theFreehand system provides. With consecutive imaginations,the patient was able to move a simple object from one place
to another. These and other further improvements in the FES
technology would help augment its role as a valuable therapeutic and rehabilitative technique.

Axonal regeneration through electrical stimulation
Contrary to the long held clinical belief that adult CNS,
once injured, does not posses any regenerative ability,
advances in neuroscience have shown that a mature CNS
has a limited ability to regenerate after injury. If thedamaged spinal cord has got the potential to grow in aneffort to bridge the gap, then why is it unable to do so?
Spanish neurologist Ramón Y Cajal concluded some
100 years ago that the failure of CNS regeneration was infact due to the absence of certain growth promoting factors
in the CNS environment, rather than an intrinsic neuronal

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deficit for regeneration [71]. Therefore, it is necessary todefine ways to facilitate regeneration that spontaneously
begins after injury to the CNS, but stops prematurely due toits non-permissive environment. It is now well understoodthat neurotrophic (growth stimulating) and neurotropic(growth guiding) factors are essential for any degree ofneuronal regrowth. The majority of work on finding a curefor SCI is focussed on developing ways to induce andsupport axonal sprouting and elongation in the desired
direction.
Axonal regeneration is the ability to extend the tip of theproximal portion of an amputated/ severed axon. This tip of
the growing axon, called the growth cone, has got theability to sense cues from the environment and steer theaxon to grow in one direction or another. For successful
regeneration to happen, a series of biological events isrequired. Most importantly, the neurons with lesioned axons must survive the initial injury. Second, the lesioned
axons must be able to sprout and grow towards the target
area. Finally, the axons must form functional synaptic
connections with their target areas in order to conduct theaxoplasmic flow. Several research studies conducted oncomparative SCI regeneration in other species, haveestablished that a variable degree of functional recovery is
possible even without the accurate point to point connectivity of the axonal synapses [73, 93, 94]. Anatomicallyinappropriate synaptic connections can still serve to provide some behavioural recovery after spinal cord trauma.
Today, many researchers in different countries are
striving to regenerate and repair the damage produced by
the spinal cord after injury and the pace of their researchcontinues to accelerate. Recent progress in cellular andmolecular biology and transplantation techniques has madeit possible to induce axonal growth. This has involved
manipulating the intrinsic processes that limit the CNS
regeneration via neutralisation of growth inhibitory factors
and promotion of endogenous neurotrophic factors.
Another concept in neural regeneration is of axonal guidance or neurotropic factors which help the regenerating
axons to grow in the desired direction. Regenerative studies
done in the peripheral nervous system (PNS) have demonstrated that for successful regeneration the growing
axons need a guidance channel to follow so that growth canhappen in the appropriate direction [90, 94]. In case of the
PNS, this guidance is provided by the Schwann cells which
are missing in the CNS. In the absence of such guidance,
the axonal growth in the CNS results in a haphazard
sprouting. Various researchers studying the effects of
weakly applied electric fields on the innately regenerating
axons have suggested that exogenously applied weakelectric fields around the lesioned axons have a role to playin facilitating axonal regeneration, possibly by providing
neurotropic guidance to the growing axons [6, 56, 57, 64].

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Applied electrical fields for axonal regeneration
Steady, polarized extracellular voltage gradients are anormal environmental component in the early developing
nervous system and are required for cranial-to-caudal
development [4, 42, 82]. Interfering with these endogenous
electrical fields interferes with the morphogenic fields inthe embryo, thus certifying their role in normal development [42]. These currents have also been found during
normal wound healing when tissue regeneration is required[8], suggesting that endogenous currents play some causal
role in morphogenesis.
Invitro experiments conducted by Lionel Jaffe and Mooming Poo established the relationship between extracellularapplied electric fields and the neurite regeneration [46]. It
was demonstrated that the single nerve processes react
within minutes of exposure to an applied DC electric field.
The growing nerve fibres respond immediately to thevoltage gradient and tend to orient themselves parallel withthe long axis of this gradient. Another important phenomenon observed was the directional response of thegrowing nerve fibres within the imposed electrical field.
The position of the electrodes determines the direction ofneurite growth. Neurites tend to grow three times fastertowards the cathode electrode in DC field between 70 and
140 mV/mm. However, after a lag period of 30 min following the exposure to voltage gradient, the neurites facing
the anode start to regress as if being repelled by the anodal
electrode. Further clarification on the response of applied
Direct Current (DC) voltages on single nerve fibres wasshown by Hinkle et al. [40] and Patel & Poo [64]. Theyobserved that the neurites that were parallel to the fieldgrow towards the cathode, while the ones that were perpendicular to the electric field turned in order to growtowards the cathode. The cathode-directed reorientation
was dependent on the strength of the electric field, and thethreshold level for this directional growth was 7 mV/mm.
Borgens et al. [7] studied axonal regeneration withapplied DC fields in living animals. He applied a weak
voltage gradient to the severed spinal cord of sea lamprey
larvae. The applied weak DC field was able to enhance therate of regeneration in the severed axons towards theimplanted cathode. These regenerated axons were also able
to make functional synaptic connections with the caudal
end of the injured spinal cord. The placement of cathoderostral or caudal to the site of an SCI determined the
direction of regeneration. Proliferation and faster growthrate was seen towards the cathode (negative pole). In
experiments where the cathode electrode was placed rostral
to the injury functionally only sensory recovery (ascending
fibres) was established [9, 11]. In other experiments, Borgens et al. created specific lesions in the spinal cords ofguinea pigs, which permanently eliminated a specific spinal

Eur Spine J (2008) 17:1256–1269

reflex in the dorsal column. Application of steady voltage
gradients induced both anatomical and functional recoveryof the reflex in a significant proportion of animals [10–12].
Wallace, Tator and Piper studied the effects of DC fieldpolarity in axons after severe compressive injuries in rats.
This type of injury closely resembles the injury sustainedby humans after spinal cord trauma. Stimulating electrodes
were positioned with anodes proximal and cathodes distal
to the injury site and the response of axons to the weak DC
electric fields was studied for a period of 15 weeks [92].
These electrodes were attached to a subcutaneously
implanted stimulator. Results of these experimental studies
also indicated that electrical stimulation can lead to significant functional recovery as compared to the control
animals. However, they were unable to elicit any histological difference in the Schwann cell or ependymal cells
proliferation and in the new myelin formation in the spinal
cords of the two groups. The functional recovery seen canbe explained by the development of alternate synaptic
pathways which could be picked up by the anterograde andretrograde tracer techniques in the studied histologicalregion of spinal cord. Fehlings et al. [27, 29] conductedsimilar in vivo experiments in animal models of SCI tostudy the effect of applied DC fields on regeneration ofaxons and associated functional recovery. In all of theseexperiments significant functional recovery was observedin the cathode caudal groups. They were also able todemonstrate that motor evoked potentials, counts of neurons retrogradely labelled by horse radish peroxidise (HRP)and the axons count at the injury site were greater in thegroup treated with DC field with cathode caudal to injury
as compared to the sham and cathode rostral groups.
In another set of experiments Wallace studied the effectof alternating current (AC) with square pulse wave. After
15 weeks of continuous spinal cord stimulation, no significant difference in functional recovery was observed
among the experimental group and the control group [91].
In most of these studies conducted to evaluate theeffects of electrical stimulation on nerve growth, electricalfields were applied immediately after SCI. Politis andZanakis [66] investigated whether similar recovery could
be established after a delay in the initiation of treatment.
They contused spinal cords of rats and allowed untreatedrecovery for 10 days. DC fields were then applied to thedorsal region of the cord. The results indicated that applied
electric fields facilitate behavioural recovery and regeneration even after a delay in the treatment.
Recently, Shen et al. [79] showed that if the concurrently occurring spinal oedema is reduced via the use oflarge dose methylprednisolone, the efficacy of DC field
improves and results in earlier recovery of nerve function.
In summary, various experiments conducted in the last
2 decades revealed that a weakly imposed electrical field

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affects orientation and regeneration of axons invitro andinvivo, and also leads to functional recovery after spinal
cord injury. Applied DC electrical fields give directionalcues to the regenerating axons. The position of the cathodeelectrode either rostral or caudal to the injury site facilitates
regeneration in one direction only. After a lag period
regression is seen in nerve fibres facing the anodal electrode. Symmetric AC fields do not provide directional cues
unless it is converted into an asymmetric AC field. The rateof growth of axons in an applied electric field is dependent
on the magnitude of the imposed electric field [55].

Mechanism for electrical stimulation
The exact mechanisms responsible for enhancing axonal
regeneration in response to applied voltage gradients are
not yet fully known. The axonal growth seen with theapplication of electrical field has been proposed to be
mediated via membrane bound receptors and some secondary messengers like adenyl cyclase and interaction withother physiological neurotrophins present in the CNS [56,57]. The cathode is believed to lead to a reduction of thecyto-destructive effects of the endogenous calcium currentof injury into damaged axons, which in turn brings marked
reduction in the degeneration of the axonal growth tip
facing the cathode [55, 56, 87]. Other possible mechanisms
include reduction in the number of astrocytes within the
injury site [55, 58] and changes to post-traumatic spinal
cord blood flow [92]. Electrical stimulation has also shownto enhance the expression of regeneration-associated genes(RAGs) and accelerate regeneration in peripheral nervous
system [1, 2]. There are no studies to comment whether
such an effect exists in CNS regeneration as well.

Recent advances and future scope in electricalstimulation
The observation that neurites grow faster towards thecathode and are repelled by the anode after the impositionof a DC electric field has led to the development of a
special stimulatory technique referred to as oscillating fieldstimulation (OFS). This implantable device reverses thepolarity of the applied field being exposed to the injured
axons every 15 min. Thus facilitates the cathodal growth
before the anodal regression sets in, and leads to a bidirectional axonal growth. Two randomised double-blindedclinical trials were conducted to evaluate the efficacy andbiocompatibility of the implantable OFS in canines withnaturally occurring SCI [12, 13]. The OFS was implanted
for a period of 14 weeks. The dogs were evaluated for
behavioural recovery at 1 week, 6 week and 6 month after

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injury. Significantly greater neurological improvement wasobserved in the OFS treated group. The dogs regained theability to walk although not perfectly. The ascending anddescending axons projected to the plane of transection,
whereas degeneration of ascending and descending axons
was seen in sham-treated control animals. The device also
proved to be safe. The FDA approval for the ‘human use
OFS device’ was attained in late 2000 and the first Phase I
human clinical trial began in 2001. In this trial, OFS was
surgically implanted in 10 patients with acute neurologically complete SCI between C5 and T-10 [78]. Patients
also underwent intravenous methylprednisolone therapy
according to the NASCIS III protocol prior to the entry into
the trial. OFS was implanted within 18 days of sustaining
the SCI and left in place for 15 weeks. At the end of thisperiod it was explanted and studied for bio-compatibility.
Patients were observed for functional recovery at 6 weeks,
6 and 12 months. The net gain in neurological improvement was assessed. Significant neurological improvementfrom baseline in motor and sensory function was observedin all the patients except for one patient who was lost tofollow-up. The outcome measures included behaviouralassessment of recovery and electrophysiological studies.
All patients reported improvement in proprioceptive andexteroceptive sensations. The application of the device wassafe and well tolerated by all the patients. Based on thepositive data from this phase I trial, FDA has given
approval for ten additional patients to be enrolled in the
study [78].
Research on the application of electrical stimulation inan effort to enhance axonal regeneration has existed formore than 2 decades, but significantly increased therapeutic ratios have not been demonstrated. Borgens’ work
represents a new success in electrical stimulation technology. Oscillating field stimulation seems to be safe andeffective in enhancing neurological outcome after SCI.
However, OFS is an invasive intervention and multiple
risks (surgical technique, wound infection, breakage ofwires, battery life, and control device) are associated withthis kind of experimental therapy. Second, in the first phase
I trial, all ten patients also underwent the methylprednisolone therapy and decompression procedure before theimplantation of the OFS device. Thus the true nature andextent of neurological recovery directly associated with theTable 3 Criteria for evaluating
spinal cord regeneration
experiments (National Instituteof Neurological andCommunicative Disorders andStroke Guidelines)

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OFS alone cannot be assessed. The full therapeuticpotential of OFS technology can only be discussed after the
OFS technique goes to test by a multicentre randomised
double-blind controlled clinical trial.
Future studies need to explore the effects of various
neuro-regenerative approaches when combined with electrical stimulation (for example NT3, Nogo, BDNF or OEC
transplantation etc.), in conjunction with a DC field
application. The applied DC field would in these cases
provide the essentially needed directional cue to thealready sprouting axons.

Conclusion
The long standing belief that the central nervous system––once injured––could never be repaired, still lingers on tosome extent in the clinical world. However, recent
advances in experimental regenerative research have created optimism that the spinal cord is not a rigid andunrepairable structure. Researchers in this field believe that
it is merely a matter of time before a therapy is developed
to change the quality of life of individuals suffering fromthis devastating condition. However there are a certain
standard criteria to be satisfied before any success for realaxonal regeneration can be claimed (see Table 3).
Studies on the pathophysiology of SCI have identified
multiple factors believed to be involved in the generationof the final outcome of the injury and the associated neurological deficit. All the factors that lead to secondary
injury e.g. blood flow changes at the injury site, excitotoxicity, inflammation and the free radical injury, need to
be dealt with before any potential for recovery or curative
treatment is seen. Neural regeneration after SCI is likely to
become a clinical reality and a major contributor towards
recovery and re-connectivity of the damaged site. The
question remains however, as to the level of functional
recovery that can be attained with the neural re-connectivity. Assistive neuroprosthetic devices will therefore
continue to play an important role in rehabilitation. FES is
more likely to provide functional recovery for people withlongstanding SCI, whereas the research on axonal regeneration with applied electric field is expected to benefit
those with acute SCI.

Key criteria to assess axonal regeneration after experimental SCI
1.

The experimental lesion must cause disconnection of nerve processes

2.

Processes of CNS neurons must bridge the level of injury

3.

The regenerated fibres must make Synaptic contacts

4.

The regenerated fibres must generate post-synaptic responses

5.

Functional responses must derive from regenerated connections

Eur Spine J (2008) 17:1256–1269

A combination of interventions would be significantly
more effective than either alone, suggesting a synergistic
action between biological, pharmacological and electricalstimulation. SCI research represents an exciting new
evolving field, with more promising results demonstrated
in the last few years than in the past 2 decades. Overall,insights arising from the result of all these experimental
strategies will eventually lead to better therapeutic interventions that can lessen the functional disability andenhance the quality of life in patients with SCI.
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