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Functional Electric = Stimulation=20 for sensory and motor functions: Progress and Problems

Dimiter = Prodanov1,2, Enrico Marani1,2, Jan=20 Holsheimer1

1 Biomedical = Signals=20 & Systems Group, Faculty of Electrical Engineering, Twente = University,=20 Enschede, The Netherlands

2Neuroregulation Group,=20 Department of Neurosurgery, Leiden University Medical Center, Leiden, = The=20 Netherlands

Address for = correspondence:=20 E. Marani,=20 Neuroregulation Group, PO Box 9604, 2300 RC Leiden, The Netherlands, = e-mail: e.marani@lumc.nl

Published in Biomedical Reviews, 2003, 14:23-50.=20

Copyright - pre-acceptance version =A9 2003 by the authors. = However,=20 permission to reprint or republish this material for advertising or = promotional=20 purposes or for creating new collective works for resale or = redistribution to=20 servers or lists, or to reuse any copyrighted component of this work in = other=20 works, must be obtained from the copyright holder.

To avoid copyright issues, here follows the pre-acceptance = version=20 of the manuscript.

 

Abstract

Functional Electrical Stimulation = (FES)=20 tries to restore the lost functions of the nervous system by means of = electrical=20 stimulation. FES is recapitulated in this review.  An overview is = given of=20 the relevant moments in history. The principal notions behind FES are = outlined,=20 in which special attention is dedicated to the electrodes for selective=20 stimulation. FES applications encounter specific research problems, = which are=20 extensively covered. The major clinical applications are overviewed: = pacing of=20 the heart, respiratory pacing of the diaphragm, the rehabilitation and=20 restoration of locomotion and hand functions, and the restoration of = bladder and=20 bowel functions. An analysis of the current applications based on the=20 evidence-based clinical approach is performed. 

FES for restoration of = the lost=20 locomotor functions is a rapidly developing area that is on the verge of = broadening its applications. Evidence for this is the increasing number = of=20 various neuroprosthetic devices that have been developed recently. Some = of them=20 are already beyond the prototype stage. The present FES treatments = combined with=20 conventional occupational and physical therapy still remain the most = promising=20 approach in rehabilitating Spinal Cord Injury patients and stroke = patients. FES=20 in combination with neuromodulation becomes a viable option in the = treatment of=20 various urological disorders, however it is still in a rather empirical = state of=20 operation.

The=20 presented overview of the FES applications shows that despite the = substantial=20 amount of research performed in the field which led to successful = development of=20 cardiac and phrenic pacemakers and cochlear prostheses, a number of = fundamental=20 scientific problem still remains to be solved before one will see a = comparable=20 degree of effectiveness and penetration in common medical practice for = the=20 locomotion neuroprostheses and urological FES appliances. The major = up-to-date=20 directions of research in clinical and theoretical aspects are = summarized.=20

History=20 of electrical stimulation
<Figure=20 1 Galvani>
<Figure=20 2 Friction machine>

Principal=20 notions in FES
Electrochemical=20 processes at the tissue-electrode interface
Voltage-controlled=20 and current-controlled stimulation
Monopolar,=20 bipolar and tripolar stimulation
Cable=20 properties of the nerve fibers
Active=20 properties of the nerve fibers
<Table=20 1>
<Figure=20 3 McNeal Model>

Stimulation=20 Electrodes
Surface=20 electrodes
Intramuscular=20 and epimysial electrodes
Cuff=20 electrodes
<Figure=20 4 cuff electrode >
<Figure=20 5 3D MEA>
Intraneural=20 electrodes
Intraneural=20 wire electrodes
Intraneural=20 multi-electrode arrays (MEAs)

Research=20 Problems
Biocompatibility=20 of the implantable devices: general considerations
Chemical=20 biocompatibility
Mechanical=20 biocompatibility
Implantation=20 and the Nerve damage
Tissue=20 reaction to implantation
Nervous=20 Tissue reaction to electrical stimulation
Selectivity=20 concepts
Surface=20 stimulation vs. Implantation

Contemporary=20 Clinical applications of FES
The=20 cochlear implant 20 Drop-foot=20 stimulator
<Figure=20 6 Peroneal Drop-foot stimulator>
Restoration=20 of Lower limb Function
Hand=20 disabilities =96 reaching and grasping
Phrenic=20 stimulation

Clinical=20 trials / Evidence based medicine for FES
Efficacy=20 of FES after stroke
Efficacy=20 of FES in urological conditions
Detrusor=20 sphincter dysynergia
Overactive=20 bladder
Experimental=20 and theoretical research
Experimental=20 research
Visual=20 prosthesis: blind eye vs. normal brain
Spinal=20 Cord Stimulation in motor disorders

Theoretical=20 Modeling studies
Research=20 on spatially-selective nerve stimulation
<Figure=20 7>
Research=20 on fiber size selective stimulation

Conclusions

References

History of=20 electrical stimulation

Functional Electrical = Stimulation=20 (FES) is a part of the broader field of electrotherapy. The term was = introduced=20 relatively late in the history of FES by Moe and Post (1)=20 . In general, history of electrical stimulation follows the = theoretical and=20 technological breakthroughs in electricity and magnetism and it is based = on the=20 developments in Neuroanatomy and Neurophysiology, since electrical = stimulation=20 is mainly an application of electro-magnetic theory in the nervous = system.=20 Nevertheless, the history of electrical stimulation has its own = particular=20 subjects of which the major ones, related to the nervous system, are = given in=20 this review.

In the field of = Neuroanatomy the=20 application of ethanol to fix brain tissue (Felix Vicq d=92Azyr, = 1748-1794) opened=20 the microscopic approach for the study of the brain, ending up with the=20 detection of the sub cellular protrusions of the neuron and its = supporting=20 cells. One should notice that the detection of the micro-architecture of = peripheral nerves (Van Leeuwenhoek, 1719) was remarkably accurate but = forgotten=20 for nearly a century. The descriptions of Dutrochet in 1824 (2) and=20 Remak in 1838 (3) once=20 again depicted the tubular structure of the entities in the nerve, = together with=20 the detection of myelinated and non-myelinated fibers.

Albrecht Haller = (1708-1777)=20 described, the =93irritation phenomenon of muscles=94: in fact the = contraction and=20 relaxation of a muscle. In his notion, it was a =94force=94 that passed = along the=20 nerves that could induce this excitation of the muscles. In addition, = Haller=20 made the first concept on sensibility. He found that tissues by = themselves lack=20 sensations, but they were noticed and relayed by nerves and their=20 endings.

Luigi Galvani = (1737-1798), who=20 developed the so-called =93galvanic=94 element, by means of which nerves = could be=20 stimulated, studied the muscle contractions. Later on in 1792, = Allesandro Volta=20 (1745-1827) could demonstrate that the galvanic element used = electricity. So,=20 the nerves were since considered to be the electric cabling of the body. =

Figure 1. Galvanic experiments on human muscles. = From G.=20 Aldini, Essai théorique en experimental sur le Galvanisme, avec = série=20 d=92experiences=85 Paris, Fournier fils, 1804 Courtesy: Prof. H. = Beukers, Leiden=20 University

 

In = the mean=20 time, friction electricity was in use and the first capacitor, =93de = Leidse fles=94=20 (1746), was developed by Muschenbroeck. From 1784 till 1791 the biggest=20 friction-electrical machine was build by John Cuthbertson. Two men had = to move=20 two enormous glass discs. Each disc was frictioned by four cushions. The = electricity on the glass discs had to be induced into the conductors, a = series=20 of Leiden jars. The potential difference reached nearly 330 kV. Van = Marum=20 (1750-1837), biologist, physician and botanist used this machine to do=20 electrophysiological research for ten years. This shows that around the=20 beginning of the XIX century systematic application of electricity in = research=20 and medicine had already started.

Figure 2. The enormous friction electrical = machine=20 together with the Leiden jars built by J. Cuthbertson. Courtesy: Teylers = Museum

 

By = the middle of=20 the XIX century with the discovery of static electricity, capacitance = and=20 electromagnetic inductance, physiologists could study muscle = contractions, nerve=20 conduction and cell excitation.

In = the=20 nineteenth century J. Müller (1801-1858) introduced the law of = Specific Nerve=20 Energies: =93the kind of sensation, following the stimulation of a = sensory nerve,=20 depends not on the mode of stimulation but on the nature of the sense = organ with=20 which the nerve is linked=94. His own disciple Helmholtz (1821-1894) = measured the=20 velocity of the nervous impulse and Emil DuBois-Reymond (1818-1896), = also a=20 disciple of Müller, proved the existence of the resting membrane = potential in=20 the nerve fibers and also proved that each impulse is directly related = to a=20 change in potentials.

Sir = Charles Bell=20 (1774-1842) and Francois Magendie (1783-1855) established the neuronal = basis for=20 the reflex. The dorsal root contains afferent, sensory information, = while the=20 ventral root relays the motor function.

The = final idea=20 that the central nervous system is the controller of the organism was = brought=20 forward by T. H. Huxley (1825-1895) in his Manual of the Anatomy of = the=20 Invertebrate Animals (1817) and became generally accepted. This = concept=20 became the fundament for the effective application of electrical = stimulation. In=20 this period medical applications were numerous but short lived and = poorly=20 understood. Electricity was reported to cure rheumatism, neuralgia, = insomnia and=20 even cold feet (4)=20 .

In XX=20 century, the major technological advances in electronics and computing=20 (discovery of the diode, triode, transistor and integrated circuits) = lead to the=20 development of contemporary FES appliances. The main push in the = applications of=20 FES was the successful development and clinical applications of the = heart=20 pacemakers.

Literature shows = controversy over=20 who was the first inventor of the artificial heart pacemaker (5) . In=20 1932 Dr. Albert Hyman described an =93artificial pacemaker=94 that he = had used with=20 experimental animals to resuscitate the =93arrested=94 heart. About that = time, the=20 Australian physician Mark C. Lidwill, along with the physicist Major = Edgar=20 Booth, built a portable pacemaking unit. It was demonstrated in 1931, = while=20 Hyman developed his device in 1930-31. Lidwill's apparatus had one pole = applied=20 to the skin and another into the appropriate cardiac chamber (6) .=20 Later on, the Hyman device was successfully used in patients

The application of = cardiac=20 pacemakers to stimulate the human heart dates as far back as 1954. = However, it=20 was not until the 60s when pacemakers were adopted on a great scale in = clinical=20 practice. Their potential for different applications in the beginning = was not=20 recognized both by the medical profession and by the industry. The other = reason=20 was the immaturity of the technology and the implantation techniques.=20 Stimulation was carried out by skin electrodes, which left uncomfortable = burns=20 when used for a couple of days or more. Later, electrode wires leading = through=20 the skin were tried, but infections along the wires were an unsolvable = problem=20 (6) .=20 Its solution was the implantation of the entire pacemaker. Dr. Rune = Elmqvist=20 designed the world's first implantable pacemaker. The first 10 patients = for the=20 implantable pacemaker were operated in 1960 (7) . In=20 the 1970=92s, heart pacemakers demonstrated the reliability of implanted = electronic devices and showed the benefits in terms of improved quality = of=20 life.

In parallel went the = attempts to=20 apply stimulation of the diaphragm for respiratory pacing. For = some 200=20 years, electricity has been applied to the phrenic nerves to activate = the=20 diaphragm. However, the actual therapeutic opportunity arose in = the=20 1950s, at the same time the heart pacemakers were developed. The first = attempts=20 to pace the diaphragm with implanted electrodes were carried out between = 1948=20 and 1950 by Sarnoff and co-workers (8) . One=20 of the most important prerequisites of the routine clinical applications = was the=20 introduction of the long-term electrical stimulation by the radio = frequency=20 inductive method introduced around the end of the 1950s (9)=20 . In 1966, Dr William Glenn at Yale University performed the first = clinical=20 application to patients with hypoventilation of central origin. The = ventilation=20 support was made by radio frequency pacing of the diaphragm. Pacing for = total=20 ventilatory support in patients with respiratory paralysis was applied = in 1971.=20 In the early 1980=92s the first commercial phrenic nerve pacers were=20 introduced.

As a result of the = successful=20 application of the pacing of the heart, the technological advances = achieved=20 during the development of the pacemakers were also successfully applied = in other=20 neural prostheses. Restoration of hearing to the profoundly deaf was an = early=20 target.

A report by Gersuni and = Volokhov=20 in 1936 (10= )=20 indicated that hearing could be produced over a normal frequency range, = and that=20 it persisted following the surgical removal of the tympanic membrane and = ossicles. One of the first recorded attempts to stimulate the auditory = nerve was=20 made by Lundberg in 1950, who employed sinusoidal currents during a=20 neurosurgical operation. The patient could only hear noise.

However, a milestone for = the=20 development of the auditory prosthesis was the electrical = stimulation of=20 the acoustic nerve of a deaf man by an implanted electrode achieved by = Djourno=20 and Eyries (11= ) .=20 They used an implanted induction coil connected with one end to the = inner ear=20 electrode and with the other to an indifferent electrode at the = temporalis=20 muscle. Another coil, outside the body was held over the implanted coil = to=20 inductively transmit the signal from a microphone. The usefulness of the = device=20 was very limited since the patient could recognize only few words from = the=20 transmitted signal ('papa', 'maman', and 'allo'). This operation, = however,=20 opened the doors for further attempts to interface the sense organs. =

The early investigators = were=20 subjected to severe criticism by both neuroscientists and clinical = professionals=20 for the insufficient safety studies and unsatisfactory design of the = implants=20 used. The safety of the cochlear implantation improved in the late 1950s = with=20 the evolution and developments of microsurgical techniques and stapes = surgery.=20 The indications and contraindications for this implantation were = elaborated in a=20 broad debate between the clinicians and the promoters of the cochlear=20 prostheses. Questions were also raised about which device should be used = and=20 about the safety of the electrical stimulation. The seventies could be=20 considered as a decade of controversy concerning the implant itself and = its use.=20 Finally after more than twenty years of on-going experimentation, in = 1984, the=20 cochlear implant received FDA approval for use in adults in USA. = Nowadays the=20 cochlear implant is a historical example of how a neural prosthesis can=20 revolutionize treatment.

In 1929, Foerster = described the=20 effects of electrical stimulation of the human visual cortex (12= ) .=20 The subjects reported for =93perception=94 of a small point of light = during=20 stimulation, which was later called a phosphene This result was = reproduced many=20 times in both sighted subjects and blind subjects. The idea that = concurrent=20 stimulation of many sites in the brain could produce a single coherent = image was=20 postulated by Krieg (13= ) ,=20 based on the retinotopy in the visual cortex.

As a second milestone = for the=20 development of neural prostheses can be accounted the implantation of = prosthesis=20 in the visual cortex of a blind woman in 1968 by Lewin and Brindley (14= ) .=20 The prosthesis did not benefit the patient much (she reported only about = occasional phosphenes in her visual field), but demonstrated that it is = possible=20 to transfer large amount of information in the visual system. Giles = Brindley,=20 one of the greatest protagonists in the FES field, attained recognition = and=20 acceptance of the applications of neural prostheses in the clinical = field.=20

The results obtained by = the=20 Brindley implant and the early cochlear stimulator showed the need to = stimulate=20 selectively small groups of neurons or fibers in order to transmit = meaningful=20 information into the central nervous system.

Attempts to=20 restore the lost functions of the paralyzed leg muscles were performed = for the=20 first time in 1961 by Liberson and colleagues (15= ) .=20 The system was developed to compensate for the =93drop foot=94 problem = in hemiplegic=20 stroke patients. By stimulating the peroneal nerve, the prosthesis = triggered=20 ankle dorsiflexion, eversion and inversion. Since 1961, a number of=20 neuroprostheses for restoration of walking, hand and arm functions have = been=20 designed and tested with various patients and with different levels of = success.=20

Apart from these = well-endorsed=20 success stories, other applications of FES still suffer from major = difficulties=20 regarding the clinical acceptance and patient compliance. Two examples = are given=20 here:

Long = and=20 Masciarelli introduced prosthesis for the hand that could not meet the=20 expectations of the patients and it was later on abandoned.

In = the 70s,=20 attempts to treat refractory epilepsy were also carried out by means of=20 stimulation of the cerebellar cortex. Later on, the performed double = blind=20 clinical trials did not confirm the claimed effects (16= )=20 .

In=20 conclusion: History of FES shows that pacing of the heart emerged at = different places and its success stimulated pacing of the = diaphragm.

The = criticism of=20 the early cochlear prostheses could be surmounted because of tenacious = research.=20 However, one might consider these first successful applications as = =93lucky=20 shots=94, based on the simple reactions of the involved = organs:

For = the cardiac=20 muscle and the diaphragm =96 simple contraction, and since the = tonotopically=20 organized inner ear can easily decode the transmitted signal, the = success of the=20 cochlear implant was understandable.

Neuroprostheses=20 for locomotion as well as those for reaching and grasping, on the other = hand,=20 require selective stimulation of the fibers in the nerves, which = innervate the=20 muscles making the movements. Therefore, in the case of selective nerve=20 stimulation, the research should be directed towards localization of the = types=20 of (myelinated) axons and their spatial organization.

FES tries to restore the = lost=20 functions of the nervous system by means of electrical = stimulation. This=20 can be achieved by either rehabilitation thus improving recovery or by=20 prosthesis (artificial substitution of a dysfunctional part) of = the lost=20 function or orthosis (device around organs in the case of = impairment) of=20 the diminished function. Example of the latter is the peroneal = stimulator=20 for foot-drop and of the former the stimulators of the phrenic nerve. = FES is=20 also sometimes referred to as Functional Neuromuscular Stimulation or = FNS. This=20 approach is limited only to the sensory and the motor functions. The = initiation=20 of reflex activity is, though, not the aim of FES but may be a secondary = and an=20 useful collateral effect.

Apart from the = clinically=20 recognized =93success stories=94 of electrical stimulation FES for = restoration of=20 the lost locomotor functions is a rapidly developing area that is on the = verge=20 of broadening its applications. Evidence for this is the increasing = number of=20 various neuroprosthetic devices that have been developed recently. Some = of them=20 are already beyond the prototype stage. That is why this paper will deal = further=20 on primarily with the electrical stimulation of the motor system. =

Principal=20 notions in FES

Electrochemical processes at the tissue-electrode=20 interface

Electrical stimulation = of=20 biological tissues with metal electrodes requires the flow of ionic = charge in=20 the biological tissue. This flow is induced by both capacitive and = faradic=20 mechanisms. The capacitive mechanism involves periodic charge and = discharge of=20 the electrode double layer. There is no charge transfer across the=20 electrode/electrolyte interface. This is an ideal mechanism for charge=20 injection, but it is limited by the maximal amount of charge that can be = transferred before the dielectric breaks down. This is approximately 20=20 mC/cm2. Because the charge required for physiological = stimulation=20 exceeds this limit, all electrical stimulation is performed by faradic = charge=20 injection. The faradic mechanism involves charge transfer across the=20 electrode/tissue interface and, therefore, electrochemical = reduction/oxidation=20 processes. These reactions can be either reversible or irreversible. All = irreversible electrochemical reactions are undesirable since they alter = the=20 chemical composition of the extracellular fluid, producing cytotoxic = products or=20 bringing about large changes in pH. For every material used in the = production of=20 electrodes, there is a charge limit for the reversibility of the = electrochemical=20 process. This charge limit depends on the particular properties of the = material,=20 the shape of the electrode, and its size, and the stimulation waveform. = The=20 temporal shape of the stimulation wave is the most important according = to=20 Robelle and Rose (1990) (17= )=20 .

In order to diminish the = oxidation=20 and dissolution of the electrodes generally a noble metal like=20 Pt, Ir or Au is used = as=20 material for the anode. Of the non noble metals 316L stainless steel is = also=20 used for intramuscular electrodes (18= ) .=20 At the cathode, however, O2 molecules are reduced to=20 O2-, which in turn react to produce free radicals. = The=20 free radicals are known to damage the cell membranes and DNA molecules. = During a=20 typical neurostimulation pulse, a substantial amount of the = O2=20 molecules is reduced to anions (19= ) .=20

Part of the free = radicals=20 generated near the cathode can be neutralized by oxidation when an = anodic pulse=20 follows the cathodic pulse. Morton et al. (1994) (19= )=20 concluded that the reduction of oxygen, and thus the generation of free = radicals=20 are restricted most when the cathodic pulse has a small width and when = an anodic=20 pulse with the same charge immediately follows the cathodic pulse. This=20 principle is known as biphasic charge-balanced stimulation (20= ) .=20 The continuous stimulation with biphasic, charge-balanced pulses without = delay=20 between the pulses are more beneficial with regard to nerve degeneration = than=20 those with delays (21= ) .=20

The continuous = stimulation with=20 biphasic, charge-balanced pulses was shown not to have harmful effects = to=20 sciatic nerves (22= )=20 .

Voltage-controlled and current-controlled=20 stimulation

Historically the = implantable FES=20 systems in clinical applications have generally been voltage-controlled, = as for=20 example are cardiac pacemakers. In contrast, the current-controlled = devices=20 dominate in experimental set-ups. In the voltage-controlled devices, the = output=20 voltage V of the pulse generator is regulated. Generally V = is kept=20 constant, thus creating a rectangular voltage pulse, the related current = obeying=20 Ohm=92s Law. In contrast, in the current-controlled devices the current = I=20 is kept constant, whereas V is automatically adapted according to = the=20 value of the impedance Z, which may vary over time due to the = reaction of=20 the surrounding tissue to the implant. The current needed for = stimulation does=20 not change chronically and thus no corrections are needed. In the=20 voltage-controlled systems, however, the voltage needed for stimulation = is=20 influenced by the changing value of Z over time and thus the = amplitude of=20 stimulation has to be adapted at least in the first two months after=20 implantation when the fibrous encapsulation layer develops.

Since the current = consumption=20 determines battery life of an implanted pulse generator, it is important = that=20 the stimulation current is determined in the first place. This is, = however, not=20 possible when a voltage- controlled pulse generator is used, since I = depends on=20 the unknown value of Z. Therefore, the battery life cannot be = accurately=20 predicted from V. Nevertheless, it is often erroneously assumed = that a=20 reduction of V reflects a reduction of I and vise-versa.=20

Monopolar,=20 bipolar and tripolar stimulation

Since the cathodic = threshold for=20 nerve fibers is 3-7 times lower than the anodic threshold current, = cathodic=20 stimulation is by far the most efficient way (23= ) .=20 In monopolar stimulation, the active electrode (in or near the neuronal = target)=20 is therefore the cathode and the distant, indifferent electrode, is an = anode. In=20 that situation, the current injected by the cathode is distributed more = or less=20 evenly in all directions.

Activation of nerve = fibers always=20 happens near a cathode in bi-, tri- and multipolar stimulation. For the = optimal=20 stimulation, in bi-, tri- and multipolar stimulation, the position of = the=20 cathode is more important then the position of the anode. In the = clinical=20 applications of FES phenomena such as cathodic block, anodic excitation = and=20 anodic block are not likely to occur (24= ) ,=20 (25= )=20 . The threshold current for stimulation of a nerve fiber increases = with the=20 distance between the cathode and the fiber and is inversely related to = the fiber=20 diameter. The preferential stimulation of large fibers is favored most = when=20 short pulses (~ 60 ms) are applied. Smaller fibers can be activated more = easily=20 when pulses are wider. The current consumption is minimized when = stimulation is=20 given with a =93guarded=94 cathode parallel to the fiber bundle as in = peripheral=20 nerve stimulation and Spinal Cord Stimulation (SCS).

Cable=20 properties of the nerve fibers

The theory of the = current flow in=20 electric cables was developed for submarine cables by lord Kelvin = (1855). It was=20 first applied in studies on excitable cells towards the end of XIX=20 century.

Cable theory opens the = possibility=20 to derive equations for current flow in cylindrical nerve and muscle = fibers=20 subjected to voltage changes which are small enough for the membrane = properties=20 to be linear; or equations that describe finite cables, since in most=20 experiments the length of the preparation is not large enough, compared = to the=20 space constant l for the cable to be regarded as infinite.

This means that the = behavior of=20 the impulse in an axon can be predicted.

Active=20 properties of the nerve fibers

The nerve fibers conduct = information by means of action potentials. The action potentials = propagate at a=20 velocity proportional to the fiber diameter.

Table=20 1. Morphology and electrophysiology of the fibers in Peripheral = nervous=20 system

Fiber type =

class

MCV1=20 (m/s)

Diameter = (μm)

Function

Aα

myelinated

70-120

12-20

motor somatic = muscle fibre;=20 proprioception; muscle spindle annulospiral; proprioception; Golgi = tendon=20 organ

Aβ

myelinated

70-120

5-12

proprioception; = muscle=20 spindle flower spray; exteroception; touch & = pressure

Aγ =

myelinated

30-70

3-6

motor somatic = muscle=20 spindle

Aδ

myelinated

12-30

2-5

exteroception; = pain=20 temperature (some ) touch

B

thin myelinated=20

3-14

<3

motor autonomic=20 preganglionic

C

unmyelinated

.5-2.5

0.4-1.2 =

exteroception; = pain reflex=20 responses

C

unmyelinated

.5-2.5

0.3-1.3 =

motor autonomic=20 postganglionic sympathetic

1Mean = Conduction=20 Velocity

Moreover, the threshold = of=20 excitations also depends of the fiber type.

In the myelinated = fibers, the=20 conduction is saltatory, with the active involvement of the nodes of = Ranvier.=20 For the first time the action potential of the non-myelinated fibers = were=20 mathematically described by Hodgkin and Huxley in 1952 (26= ) .=20

The electrical behavior = of the=20 myelinated nerve fiber can be represented by a simple cable network. = McNeal was=20 the first to introduce this model (27= ) in=20 order to calculate how a stimulation-induced extracellular field affects = nodal=20 transmembrane voltages. According to this model, the node of Ranvier = that is=20 closest to the cathode will be excited first when the stimulus current = is=20 sufficiently high. The results of this theoretical approach are in = accordance=20 with the general observation that the threshold stimulus of nerve fiber=20 excitation is smallest near the cathode and rises with the increase of = the=20 distance (23= ) .=20 As a result, cathodic stimulation gives rise to a depolarization of = several=20 nodes, whereas a larger number on both sides of the cathode are = hyperpolarized=20 to a lesser extent, thus creating a virtual anode.

Figure=20 3. The McNeal cable model for the axon. Each node of Ranivier is = represented=20 by an equivalent electric scheme. Vi =96 intramembrane potential, Ve =96 = extamembrane potential, Ra =96intraaxonal resistance, R =96 variable = membrane=20 resistance, C- membrane capacity, V =96 resting membrane=20 potential

In anodic stimulation = the opposite=20 effects occur. The virtual anode and virtual cathode = effects=20 underlay phenomena such as cathodic block and anodic excitation. Anodic=20 excitation is possible when the anodic current is so large that the = virtual=20 cathodic depolarization on either side of the hyperpolarized membrane = generates=20 action potential. In cathodic block, the opposite is true =96 if the = cathodic=20 current is large enough the induced virtual anodic hyperpolarizations = can block=20 the propagating action potential.

The McNeal model is the = basis of=20 all the theoretical research performed in the area of FES.

Stimulation=20 Electrodes

Spatially selective = stimulation of=20 the nerve fibers within a given nerve bundle is important, because = different=20 muscles are innervated by fibers possessing a specific localization = within a=20 nerve bundle, and moreover often a mixture of efferent and afferent = fibers is=20 present in the nerve. Such mixed populations may lead to undesirable = sensations=20 during stimulation. In the case of several nerve fibers innervating = different=20 muscle fibers of one muscle, cyclic stimulation can be performed which=20 guarantees an overall stimulation frequency, while stimulation frequency = and=20 thus fatigue of a single muscle fiber can be kept low (28) .

Many different designs = of=20 electrodes exist. They employ different materials and geometries of the=20 contacts. Most of them are used only in animal experiments, and only few = are=20 employed in clinical FES applications as well.

Several types of = stimulation=20 electrodes for FES have been developed. A simple subdivision = is

  1. Surface (skin)=20 electrodes
  2. Intramuscular=20 and epimysial electrodes
  3. Extraneural=20 electrodes (cuff or helical electrode around a peripheral = nerve)
  4. Intraneural=20 wire electrodes
  5. Intraneural linear, = 2D and 3D=20 multi-electrode arrays

An = extensive=20 account on the cuff, intrafascicular and sieve electrodes designs and=20 fabrication technology can be found in (29= ) and=20 (30= )=20 .

Surface=20 electrodes

Transcutaneous stimulation is = performed=20 with self-adhesive or non-adhesive electrodes that are placed on the = subject=92s=20 skin, above the peripheral nerve (respectively the motor fibers). The = metal=20 electrode is connected to the skin with a saline bridge.

Criteria=20 for surface electrodes are low impedance with even current spread, = flexibility,=20 ease of application and removal and lack of skin irritation (31= ) .=20 The application is simple. Damage of the skin only can occur by the = diffusion of=20 soluble electrochemical products. The large distances to the stimulation = targets=20 and the insulation of the skin and the fat tissue demand high = stimulation=20 strengths, which in turn results in low selectivity. Complications are = rare and=20 include burns, skin irritation, erythema and local pain.

Intramuscular and epimysial = electrodes

Muscle electrodes have = their=20 stimulating surfaces onto or inside a striated muscle. In the former = case, they=20 are sutured to the epimysium of the muscle and, therefore, are called = epimysial.=20 If terminal motor branches are present, the electrodes exert their = action by=20 stimulating the nerve endings. Therefore, it is correct to consider them = also as=20 nerve electrodes. In comparison with the transcutaneal electrodes they = produce=20 contractions with lower currents and with greater selectively. For these = reasons, muscle-based electrodes are preferable for situations that = require=20 independent control of several isolated muscles.

Depending on their = intended=20 application, intramuscular electrodes can be introduced either = percutaneously=20 (see for example (32= ) )=20 or in an open surgical procedure (33= ) .=20 However, intramuscular electrodes can also activate neural structures = near their=20 stimulating tips other than those intended, thus recruiting muscles in = addition=20 to the ones targeted (34= ) .=20 Nevertheless, intramuscular electrodes are considered safe and effective = means=20 to produce strong and isolated contractions of single muscles. =

Complications include = infections=20 and wire breakdowns. In an effort to avoid the use of percuataneous = leads for=20 muscle electrodes, Loeb (2001) (35= ) and=20 Cameron et al. (1997) (36= )=20 developed implantable muscle stimulators that can be controlled = telemetrically,=20 and are inductively powered from external magnetic devices in order to = overcome=20 infections. According to the promoters of such an approach, this would=20 ultimately alleviate the burdens involved with maintenance of the = awkward=20 external electronic equipment.

Cuff=20 electrodes

Cuff electrodes = circumscribe the=20 nerve. They were introduced in the 1970s. The first cuff electrodes had = a very=20 simple cylindrical rigid design. Modern cuff electrodes use flexible = materials=20 and adaptable geometries.

They are=20 implanted by a simple surgical procedure, and their size can be adapted = to the=20 diameter of the nerve of interest. If needed, they can be surgically = fixed to=20 adjacent tissues.

Various designs have = been=20 developed and applied such as the helix-shaped electrode (37) , the = spiral-cuff=20 (38= )=20 , and the so-called "half-cuff" electrode of (39= ) .=20 Another particular design is the arrangement of flexible interdigitating = sub-units with microelectrodes along a backbone-like carrier (40= )=20 .

The main push for their = continuing=20 development was the inadequate spatial and fiber selectivity they = provided at=20 first. The first cuff electrodes could stimulate only the most = superficial=20 fibers of the nerves (29= )=20 .

With a sufficient number = of=20 electrodes within the cuff, high spatial selectivity of stimulation can = be=20 achieved by combinations of longitudinal and transversal currents = produced by=20 appropriately switched electrodes (41= ) .=20 Longitudinally aligned tripolar dot electrodes on the surface of a nerve = trunk=20 restrict excitation to superficial nerve trunk regions more successfully = than=20 will monopolar dot electrodes do (42= ) .=20 Selectivity was dependent on the relative location of the electrode = contacts and=20 the nerve fascicles, as well as the size and relative spacing of = neighboring=20 fascicles of a 12 contact spiral nerve cuff electrode (43= ) .=20 On the basis of computer modeling results Deurloo et al. (2003) (44= )=20 concluded that transverse steering provides more selective stimulation = than=20 longitudinal steering. However, the problem of different fiber = diameters, which=20 leads to different activation thresholds of the fibers, is not solved by = these=20 methods. Goodall et al. (1996) found that large fibers were activated = before=20 smaller with a cuff electrode containing 12 electrodes arranged in four=20 longitudinal tripoles, irrespective of the fiber position (45= ) .=20 Transverse current from an anode positioned opposite to the stimulating = cathode=20 was found to improve spatial selectivity, and position selectivity was = enhanced=20 when the ratio of transverse current to longitudinal current was = increased.=20

The use of silicone and = helical=20 designs in cuff electrodes has improved surgical access and reduced = nerve damage=20 (46= )=20 , (47= ) and=20 (41= )=20 .

Figure 4. A schematic view of a cuff electrode. = Courtesy:=20 K Deurloo, from (96) p.=20 66

Figure 5. (a) Scheme of the University of Twente = 128-electrode 3-D glass-silicon array (UT-128 array), mounted on a CMOS = , mixed=20 mode, processing chip with dimensions 4x4 mm. Needle length is 600, 425 = or 250=20 μm, width at tip is 15 μm, needle spacing is 120 μm. (b) = Details of the=20 dimensions and materials used for the UT-128 array. (c) A =91sea=92 of = sawn and=20 etched silicon needles of three different lengths, embedded in a glass = matrix.=20 Courtesy: W. Rutten, from (30= ).=20

Intraneural=20 electrodes

In an attempt to = overcome the=20 selectivity problems with stimulation cuff electrodes intraneural = electrodes=20 were developed. They are another type of electrodes directly contacting = nerve=20 fibers within a given nerve bundle.

Intraneural=20 wire electrodes

The first penetrating = electrodes=20 were simply thin metal wires or needles, which were inserted into the = nervous=20 tissue. They are used for both recording and stimulation. An = interesting,=20 non-silicon approach for intrafascicular stimulation is the use of = tethered=20 platinum microwires. Nannini and Horch (1991) (48= )=20 tested the performance of Pt-Ir intrafasicular = electrodes (25=20 mm diameter) implanted in nerves innervating the gastrocnemius and = soleus=20 muscles. The electrodes were originally developed for recording = purposes. They=20 concluded that intrafascicular recording electrodes are also a = potentially=20 suitable technology for FES. Yoshida and Horch (1993) (49= )=20 used dual intrafascicular electrodes to study activation of nerve fibers = by=20 pairs of Pt-Ir wire electrodes implanted within single=20 fascicles of the nerve innervating the gastrocnemius muscle in cats, in = order to=20 determine whether intrafascicular electrodes can activate nerve fibers = in=20 different fascicles independently of each other and if they can be used = to=20 activate separate subsets of axonal populations within a single = fascicle.=20

Intraneural=20 multi-electrode arrays (MEAs)

A simple classification = consist=20 of

a) Linear=20 multielectrodes:

Wedge-shaped microprobes = carry a=20 line of electrode sites for recording and stimulation, the so-called=20 "one-dimensional" (1D-) arrays (50= )=20 .

b) Two- and = three-dimensional=20 multielectrodes

The 2D-array consists of = electrodes with tips ending in the same plane. The tips are configured = either as=20 a bundle of wires or galvanically grown needles. The substrate carrying = the=20 electrodes is either needle- or wedge-shaped to allow penetration of the = nervous=20 tissue which makes recording from and stimulation of axons possible not = only on=20 the surface but also in a well-defined depth within the tissue, e.g. = within the=20 fiber bundle. When the array is slanted or the needles have = otherwise=20 variable lengths the electrode is named a 3D-array. Implantation of any = such a=20 device is always associated with some damage of the nervous tissue, cell = death=20 of neurons and disruption of axons. Moreover, stiffness of many models = may also=20 lead to mechanical damage of nervous tissue. Thus, the efforts are = directed to=20 miniaturize the penetrating parts of the implant and to use materials = that are=20 more flexible.

Rutten et al. produced a = 3D needle=20 array with 128 recording sites on one electrode placed on the tip of a = needle=20 (51) . The needles are made of silicon and are embedded into a glass = substrate.=20 They vary in height from 250 to 600 um and have a distance of 120 um, = with a tip=20 size of 15×15 um. The array is intended to serve as an interface = between a=20 stimulator and a peripheral nerve. The different length of the needles = allows=20 stimulation in the volume of the nervous tissue. The dimensions of the = array=20 were based on calculations for optimal stimulation, based on random = uniform=20 distribution of the nodes of Ranvier in the peripheral myelinated=20 axons.

For signal recording and = stimulation over a larger area, e.g. areas of the cortex, = two-dimensional MEAs=20 are necessary. An example of such a 2D array is the Utah Electrode Array = initially developed by Nordhausen and colleagues (52= ) .=20 It is designed for implantation in the human visual cortex and is = intended as=20 prototype in development of visual prostheses (53= ) .=20 It provides a multichannel interface to the visual cortex using a large = number=20 of 1.5mm long electrodes (typically 100 in a 10 x 10 square grid) = projecting out=20 from a very thin (200 um) substrate and are separated from each other by = 400 um.=20

With the technological = advance in=20 the field of constructing flexible polymeric substrates, so-called = "flexible=20 nerve plates" came into development (54= ) .=20 They consist of a flexible substrate, which carries a Micro Electrode = Array and=20 it is possible to add other elements of a microelectronic=20 circuitry. 

In general the silicon=20 microtechnology based fabrication leads to improvement of recording = structures,=20 which made it possible to create not only planar two-dimensional Micro = Electrode=20 Arrays but also intraneural electrode structures for in vivo=20 measurements.  Alike the cuff electrodes, geometry and arrangement = of the=20 intraneural electrode arrays are currently optimised to fit with = geometrical=20 nerve fiber characteristics (fiber position in a bundle, diameter of the = fibres=20 and their orientation). While Smit (1996) argues for intrafascicular=20 stimulation, the proposed approach could be employed only in acute = experiments,=20 thus limiting the use of the obtained knowledge for clinical = applications (55= )=20 .

In theory intraneural = electrodes=20 should give better spatial selectivity than the cuff electrodes (56= , 49= ),=20 but the distribution of the nodes of Ranvier in the peripheral nerves = makes the=20 stimulation a probabilistic process. The implanted intraneural electrode = may=20 simply miss the target fiber population when the topography of the nerve = fibers=20 is unknown.

Also since during = implantation=20 these intraneural electrodes must penetrate the relatively tough = epineurium and=20 the perineurium of the nerve, they can cause short- and long-term nerve = damage=20 during the electrode insertion procedure (57= , 58= , 59= , 60= ).=20 Nevertheless, histological results suggest that intraneural electrodes = can be=20 used chronically in peripheral nerves (61= , 62= , 63= ).

The main prerequisite = for=20 successful application of the modern sophisticated electrode designs and = stimulation protocols is detailed knowledge of the topography of the = nerve=20 fibers within the nerve bundle and their function. Moreover, a really = reliable=20 fixation of the cuff must be achieved because otherwise the cuff may = rotate=20 around the nerve or shift along the nerve, both leading to a serious = loss of=20 selectivity.

In conclusion: The = implantable=20 electrodes are surgically set in: around, within or adjacent to a nerve = trunk or=20 root. By means of transcutaneous electrodes it is difficult or = impossible to=20 selectively activate individual muscles, especially deep muscles such as = hip=20 flexors (64= , 65= ).=20 Large currents may be required to drive sufficient charge through the = skin and=20 intervening tissues between the electrode and the peripheral nerve. In = many=20 cases, cutaneous pain receptors are excited, and patients with preserved = or=20 heightened sensation may find it difficult to tolerate surface = stimulation at=20 the levels required to produce a functional motor response.

Advantages of the = implantable=20 electrodes over the superficial, epimysial and intramuscular = include:

  • The current needed to = excite an=20 action potential in the target fibers is smaller in at least an order = of=20 magnitude over the current required for the latter designs.=20
  • Muscle length and = limb position=20 are expected to have substantially less effect on the recruitment=20 characteristics in the case of an implantable electrode. =

Cuff-electrodes are easy = to=20 implant and are generally less invasive to the nerve than intraneural = electrodes=20 are.

Despite all new = developments in=20 electrodes, the robustness of stimulation is hampered by the structure = of the=20 nerve:

An ideal peripheral = nerve=20 electrode array would have the neural selectivity of the intraneural = electrode=20 and the ease of implantation, stability, and biocompatibility of the = extraneural=20 electrode.

Research=20 Problems

The = major issues=20 in the development of a neural prosthesis from the point of view of the=20 neuroscientist are:

Biocompatibility of the implantable devices: general = considerations

Implantable devices = should be able=20 to survive in the rather aggressive internal milieu of the body without = causing=20 significant tissue reaction. The major prerequisite for the application = of=20 implants is that the organism accepts the implant, i.e. that the implant = is=20 biocompatible. This also holds for objects that come in close contact = with the=20 skin or mucose. An accepted definition of biocompatibility is "the = ability of a=20 material to perform with an appropriate host response in a specific = application"=20 (66= )=20 . The selection and evaluation of materials and devices intended for use = in=20 humans requires a structured program of assessment to establish = biocompatibility=20 and safety.

Current regulations, = whether in=20 accordance with the U.S. Food and Drug Administration (FDA) (ISO = 10993-1/EN=20 30993 standard, since 1995), the International Organization for = Standardization=20 (ISO), or E.U. regulation bodies (The EU council directive - 93/42/EEC, = since=20 1993), as part of the regulatory clearance process require conduction of = adequate safety testing of the finished devices through pre-clinical and = clinical phases (67= )=20 . An extensive account on the biocompatibility may be found in the = standard=20 ISO 10993-1/EN 30993.

In brief, the notion of=20 biocompatibility encloses non-toxicity, non-immunogenity, non- = carcinogenicity,=20 non-mutagenity and haemocompatibility. An implant can be considered=20 biocompatible if it gives negative results on the following=20 tests:

  1. Cytotoxicity=20
  2. Sensitisation=20
  3. Genotoxicity=20
  4. Implantation=20
  5. Chronic=20 Toxicity
  6. Carcinogenicity=20
  7. Irritation=20 Intracutaneous
  8. Acute Systemic=20 Toxicity
  9. Subchronic=20 Toxicity

In other words, it = includes the=20 whole behaviour of the implant in its biological environment. =

According to Heiduschka = and Thanos=20 (1998), the "biosafety" and the "biofunctionality" also have to be = considered=20 (29) . Biosafety means that the implant does not harm its host in any = way, and=20 biofunctionality means that the implant acts in the body as it was = intended. In=20 addition, "biostability" is important which means that the implant must = not be=20 susceptible to attack of biological fluids, proteases, macrophages or = any=20 metabolic substances. For example, implants may be subject to continuous = attack=20 by hydrolytic enzymes (68= ) or=20 free radicals produced by monocytes and/or cell lysis. Stability of = implanted=20 material is important not only for a stable function, but also because=20 degradation products may be harmful to the host organism. Overview about = biological reactions to implanted materials can be found in Ratner et = al. (1996)=20 (69= )=20 .

Chemical=20 biocompatibility

Chemically appropriate = implant=20 materials are designed to be as inert as possible. If chemical reactions = are to=20 be expected they should be minimal and all resulting products should be = inert.=20 Candidate materials for neuroprothesis pass especially rigorous testing = since=20 they must remain inert not only passively but also when subjected to = electrical=20 stimulation. Typical materials for nerve electrode arrays include=20 platinum-iridium alloys or stainless steel for the conducting parts and = epoxy=20 resins, polytetrafluoroethylene (PTFE, Teflon=AE), silicone = rubbers and=20 polyimide for insulators (70= , 29= ) .=20 These polymers are biocompatible, electrically insulating and = stable.

The amount of platinum = ions=20 released into the surrounding tissue may be neglected even after = long-term=20 stimulation. During the last years, iridium has been of increasing = importance=20 because a stable oxide film can be formed on the surface of iridium = electrodes.=20 This oxide film has a big charge delivery capacity and is, for this = reason, well=20 suited for stimulating electrodes. Platinum and iridium are established=20 materials in microelectronics, and carbon can be deposited onto = microelectronic=20 structures. Glassy carbon or carbon fibers are also used as electrode = materials,=20 and they are biocompatible and stable, though they have a higher = roughness than=20 metals.

The bulk properties of = polymers as=20 backbones for electrodes can be modified to a certain degree and also = surface=20 modification procedures are performed in order to improve = biocompatibility.=20 However, certain surface modifications like autologous protein coatings = also=20 enhance the adhesion of pathogenic bacteria to the implant surface (71= , 72= ).=20 For a review on the chemical modifications employed in the production = for neural=20 prostheses, see (29= )=20 .

Mechanical=20 biocompatibility

The mechanical = biocompatibility of=20 an implant depends on the basic mechanical properties of the tissue and = the=20 implant. Ideally, the implantable device should have mechanical = properties=20 similar to the tissue in which it is implanted. This includes = flexibility,=20 strength and durability. It is also important to consider the tissue = motion=20 within the implantation site. For example, flexibility is important in = the=20 peroneal foot-drop stimulator and not in the devices for spinal cord = stimulation=20 and anterior lumbo-sacral root stimulator.

For any implant, the = allowable=20 size must be defined relative to its function. It is not necessarily = true that=20 increased function is associated with larger size. The geometrical=20 characteristics of an implant are of great importance too. For example, = sharp=20 edges and blunt corners should be avoided.

The primary goal for a = cuff=20 electrode design is to minimize the size, however any constriction = injury in the=20 implanted site should be avoided. Such designs have been associated with = incidence of morphological changes in neural tissue like axonal = degeneration,=20 demyelinization and fibrosis (37= ) .=20 Thus, the recommendation had been to implant cuffs with an internal = diameter=20 equal to 150% of the nerve diameter (73= ) .=20 This recommendation was criticized as to be actually more likely to = create=20 neuronal trauma (37= ) .=20 It also limits the degree of selectivity that is obtained during = extraneural=20 stimulation (41= , 31) = .

Implantation=20 and the Nerve damage

The key factor = determining the=20 damage of electrode implantation is the disruption of the = microcirculation of=20 the nerve, which results in edema. This holds especially for = intrafascicular=20 electrodes. Another factor is the damage to the endoneurium and the = disruption=20 of the homeostasis, maintained by the blood-nerve barrier. The = mechanisms of the=20 damage during implantation are still debatable. According to Agnew and = McCreery=20 (1990) on the first place stands direct mechanical interaction between = the=20 electrode and the nerve (70= ) .=20 Other mechanisms that may play a role during implantation = are:

  1. Surgical trauma to = either the=20 neural microvasculature or the nerve itself.=20
  2. Pressure caused by=20 post-surgical edema, seroma formation, or excessive fibrous = encapsulation of=20 the implant.=20
  3. Reduced mobilization = of the=20 nerve caused by excessive scar tissue formation, which could fuse the = nerve to=20 the surrounding tissues.=20
  4. Undue tension in the = electrode=20 leads.=20
  5. The transmission of = forces from=20 muscles to the electrode array and the nerve.=20
  6. Obstruction of the=20 microstimulation

For epineural and = intraneural=20 designs, though, the most important factors are the implant procedure = itself and=20 transmission of tension via the leads.

Tissue=20 reaction to implantation

Implantation usually = causes=20 foreign body reaction involving the natural inflammatory defensive = response of=20 the body. The acute response starts with protein adsorption onto = the=20 surface of the implant. Therefore, the surface properties like roughness = and=20 surface chemical composition, which depend on the production process, = are=20 important for the grade of the subsequent response (74= ) .=20 The late response produces the typical cellular and humoral = reaction=20 including tissue edema, cytokines secretion, neutrophil, lymphocyte and=20 macrophage migration and adhesion. This is a complex process mediated by = the=20 secreted cytokines.

Chronically a = fibrotic=20 capsule around the foreign body is formed, consisting of collagen fibers = and=20 fibroblasts. The thickness and the structure of the capsule is generally = a=20 measure of the severity of the response. The severity of the reactions = can be=20 determined by the amount of the giant Langerhans cells and=20 macrophages.

The electrical = properties of this=20 fibrotic capsule were studied by Grill and Mortimer (1994) (75= ).=20 They found that resistivity of the encapsulating tissue had a frequency=20 dependency between 10 Hz and 1kHz and decreased from 454 =B1 123 to 193 = =B1 98=20 Ohm.cm and was frequency -independent between 1 kHz and 100 kHz with a = mean=20 value of 195 =B1 88 Ohm.cm. Moreover, the fibrotic capsule may lead to=20 displacement of the electrode positions and changes in the tissue = impedance (75= )=20 .

The results from early = experiments=20 (37= ,=20 76= )=20 , indicated that nerves implanted with snuggly fitting spiral cuffs = showed signs=20 of sustained trauma. The typical pattern was a crescent-shaped = region=20 containing thinly myelinated axons, proliferation of subperineurial = connective=20 tissue, and a reduced axon density. In a more extensive study of the = tissue=20 reaction to the spiral cuff, 4 of 44 nerves exhibited peripheral = crescent-shaped=20 areas which contained thinly myelinated fibers with an apparent = reduction in=20 axon density, but there was no correlation between the cuff-to-nerve = diameter=20 ratio and the presence of morphological abnormalities. Similar results = have been=20 found in cuff electrode studies conducted by researchers at the = Huntington=20 Medical Research Institutes (77= )=20 .

Recently Grill and = Mortimer (2000)=20 (78= )=20 reported focal areas of abnormal neural morphology including perineurial = thickening, endoneurial fibrosis, thinly myelinated axons, and focal = reduction=20 in the density of myelinated axons in chronic implantation experiments = with cuff=20 electrodes.

Intrafascicular = electrodes can=20 also produce morphological changes in neural tissue (63= ) .=20 Chronic implantations of intraneural coiled-wire electrodes showed = endoneurial=20 fibrosis and edema, loss of nerve fibers with the large myelinated = fibers being=20 the most susceptible, and variable shifts in the excitation threshold. = However,=20 there were no changes in conduction velocities indicating that no = significant=20 damage occurred due to implantation (61= ) .=20 The bulbous enlargement formed at the point where the electrode = penetrated the=20 perineurium was associated with focal nerve fiber compression, = demyelination,=20 edema, and fibrosis (61= , 79= ) .=20 Electrodes sutured to the epineurium have also led to neural damage = including=20 endoneurial edema, endoneurial fibrosis, loss of axons, and reduction of = myelin=20 (80= ,=20 81= )=20 . In general, intraneural electrodes are associated with greater risk of = trauma=20 than the cuff-electrodes (82= )=20 .

Nervous=20 tissue reaction to electrical stimulation

Brief stimulation of the = peripheral (83= ) or=20 the cranial nerves results in increased expression of Immediate Early = Genes=20 (IEG) in the related neuronal cell bodies (for example c-Fos (84= ) ).=20 The family of the Immediate Early Genes consists of approx. 30 genes, = with=20 related proteins acting as transcription factors (85= ) .=20 Members of the IEG family in general are activated shortly after cell=20 stimulation and without the requirement for de novo protein=20 synthesis.

Brief unilateral = electrical=20 stimulation of the cochlear nerve (120=96250 mA, 5 Hz, 30 min) in = anaesthetized=20 rats with a biphasic current resulted in increased expression of c-Fos = in the=20 ipsilateral ventral and bilateral dorsal cochlear nucleus (84= ) .=20 Intracochlear electrical stimulation with a cochlear implant in rats = lead to=20 changes in the phosphorylation state of the cAMP response element = binding=20 protein (CREB) and the expression of the IEG family members c-fos = and=20 egr-1 in a tonotopically precise pattern in the central auditory = neurons=20 (86= )=20 . These neurons resided nearly in all auditory brainstem nuclei. = Moreover,=20 effects of electrical stimulation were identified in the medial = vestibular=20 nucleus and the lateral parabrachial nucleus. Regionally, CREB was=20 dephosphorylated, wherever immediate-early gene expression went up. = These=20 massive stimulation-dependent modulations of transcription factors in = the=20 ascending auditory system indicate ongoing plastic changes as a = consequence of=20 the stimulation of the inner ear.

In the spinal cord, = Molander et=20 al. (1992) (87= )=20 showed that in chronically axotomized nerves, c-fos is expressed after=20 electrical stimulation of the fibers. Stimulation of the normal sciatic = nerve at=20 C-fiber intensity resulted in c-fos protein-positive cells within the = sciatic=20 projection territory in the ipsilateral dorsal horn (lamina I and outer = lamina=20 II) and stimulation of A/B fibers had little effect. The expression was=20 delimited to the projection areas of the sensory A/B-fibers (ipsilateral = laminae=20 II, III and IV and in the gracile nucleus) in young animals. This = suggests that=20 the excitability of these neurons is increased by nerve = injury.

The role of the IEGs is = implied in=20 the structural plasticity of the nervous systems (88= , 89= ).=20 One may speculate that the continuous improvement of the responses of = the=20 individuals after early rehabilitation, in contrast with late = rehabilitation, is=20 due to FES being able to guide the plastic phenomena occurring after = injury in a=20 direction towards restoration of function. This line of thought is = supported=20 also in the review on animal experimentation (90= )=20 showing accumulation of physiological and behavioral data that adaptive=20 (plastic) processes also occur within spinal circuits. The potential = ability of=20 the spinal cord to =93learn=94 has obvious implications for altering and = improving=20 locomotor function after injury.

Recent studies in man = indicate=20 that a significant population of stroke and Spinal Cord Injury (SCI) = patients=20 could also benefit from FES rehabilitation (91= , 92= ). In=20 particular, it was found that stroke patients as well as incomplete SCI = patients=20 subjected to intensive FES treatment were able to recover grasping or = walking=20 function faster and better compared to patients who did not participate = in the=20 FES treatment post injury.

In the peripheral = nervous system,=20 prolonged high-frequency (f> 20-50 Hz) electrical stimulation of = a=20 peripheral nerve induces a typical type of neural injury, called early = axonal=20 degeneration (EAD), with a characteristic =93salt-and-pepper=94 like = mixture of=20 =93normal=94 and damaged fibers. The primary damage is observed as = collapse of the=20 myelin into the axoplasm and is restricted primarily to the large = caliber axons=20 (Aa, Ab type). It is followed by degradation and phagocytosis of the = axon. (77= , 93= , 82= ) .=20 The neuronal injury originating from electrical stimulation has two = mechanisms=20 of occurrence:

a)     =20 Direct injury resulting from the electrochemical process near = the=20 electrodes. Brummmer and Turner (1972) (94= )=20 have shown that the rate of production of compounds by electrochemical = reactions and the type of compounds produced are directly related to = the=20 charge density (charge transferred per unit area of the electrode = surface).=20 The charge density near the surface of an electrode determines the = extent of=20 depolarization and hyperpolarization induced in the neurons close to = the=20 electrodes. If such depolarization is abundant and going on for a long = time=20 the second mechanism of injury comes into play.

b)      The=20 excitotoxic neuronal injury, which is caused by the excitatory=20 neurotransmitter glutamate through its NMDA receptors. This = view is=20 supported also by the finding that MK-801, a potent NMDA receptor = antagonist,=20 is a neuroprotective factor during prolonged electrical stimulation = (95= ).=20 The mechanism of the induced neuronal cell death is necrotic. Such = damage=20 occurs when the stimulus charge density or the charge per phase is=20 large.

Selectivity=20 concepts

In the paradigm of the = implantable=20 devices, selective stimulation of individual components of = multifascicular=20 nerves would allow control of several muscles with less hardware (43= ) .=20 Different aspects of selectivity may be distinguished depending on the=20 structures being stimulated. Here we propose modification of the = classification=20 of Smit (55= )=20 .

 Surface stimulation vs. Implantation

An important advantage = of the=20 surface FES systems is that they do not require surgical intervention, = with its=20 inherent risks. They also can be removed at any time if = contraindications arise.=20 Another advantage is that the transcutaneous electrode can be placed = directly=20 above the target muscle, and thus muscle-selective stimulation can be = achieved=20 (96= )=20 . A typical example where surface stimulation can be used is restoration = of hand=20 function. Surface FES can be applied at a very early stage of the=20 rehabilitation, during the recovery and reorganization period of the = central and=20 peripheral nervous systems (plasticity), allowing early benefit for the = patient.=20 FES training during recovery may help a subject to restore a function to = the=20 point that he/she no longer needs a neuroprosthesis.

Popovic et al. advocate = an early=20 start of FES as part of the rehabilitation in stroke patients. This = benefits the=20 use of surface FES systems since the objective of the treatment is to = help=20 patients to relearn the grasping task rather than to provide them with a = permanent assisting system (91= ) .=20 In SCI subjects there are two possibilities: implantation and surface=20 stimulation. For the implantation, the patient should have reached = stable=20 neurological status.Surface FES is also preferred in treatment of = spasticity in=20 order to strengthen the antagonistic muscles and in recovery of simple=20 movements, which requires stimulation by few electrodes with easy = positioning=20 (4)=20 .

A disadvantage is that = only a=20 small part of a muscle can be stimulated, causing a rapid development of = muscle=20 fatigue. Furthermore, the reproducibility of muscle force is = insufficient due to=20 changes in the muscle geometry during contraction. Another issue is the=20 displacement of the electrodes, which may occur during use of the FES = device=20 (96) .

The advantages of the = implantable=20 FES systems are that the stimulation does not depend on the geometry of = the=20 muscle and a single electrode can stimulate several muscles with low = energy=20 consumption. Therefore, implantable stimulation is preferred in the = following=20 cases (4)=20 :

  1. When deep=20 muscles that are difficult to stimulate by surface electrodes have to = be=20 recruited
  2. For = complex=20 movements which require a large number of electrodes in a limited=20 space
  3. To = avoid pain=20 and burns, caused by stimulation of the pain receptors and the=20 skin.

The disadvantages are = that the=20 existing implantable FES systems still do not provide enough selectivity = of=20 stimulation, the surgical trauma associated with the implantation and = some=20 unresolved issues in the geometry of the electrodes (97= )=20 .

In conclusion: = Implantation of a=20 FES device induces acute, late and chronic inflammatory response. The = least=20 effect is caused by the chemical reaction due to the inert device = materials=20 used. The biggest damage comes from mechanical stress or is due to=20 surgery.

Contemporary=20 Clinical applications of FES

The cochlear=20 implant

The cochlear implant = relies on the=20 assumption that there are enough auditory nerve fibers left for = stimulation near=20 the electrodes. Although the first fully implantable cochlear prostheses = preceded the fully implantable heart pacemakers, in the 1970=92s, heart = pacemakers=20 achieved high reliability and improved quality of life of the = patients. In=20 the USA, FDA nevertheless approved the first cochlear implant device for = clinical use not earlier than 1984. Over the past 20 years of clinical=20 experience more than 20.000 people worldwide have received cochlear = implants.=20

Cochlear implantation = has a=20 profound impact on hearing and speech perception in postlingually = deafened=20 adults. Most individuals demonstrate significantly enhanced speech = reading=20 capabilities, attaining scores of 90 -100% correct on everyday sentence=20 materials (98) .=20 Moreover, according to the NIH Consensus Statement the cochlear implant = is the=20 first, and still the only, neural prosthesis that is aiding a = significant=20 portion of a disabled population. In recapitulation - while the cochlear = implant=20 has reached wide acceptance and maturity as device, most of the other=20 neuroprosthetic applications are still in childhood.

Drop-foot=20 stimulator

The first = neuroprosthesis for=20 walking was developed in 1961 by Liberson and colleagues (15) . This = system was=20 developed to compensate for the =93drop-foot=94 problem. The drop-foot = is a=20 pathological condition, caused by diminished ability to use the muscles = that=20 lift the foot. It may be caused by stroke, cerebral palsy, multiple = sclerosis,=20 or neurological trauma. By stimulating the peroneal nerve, the = prosthesis=20 elicited ankle dorsiflexion, eversion and/or inversion thus allowing the = subject=20 to make a step with the disabled leg. Since then a multitude of devices = has been=20 developed, mostly in former Yugoslavia. The Fepa system was proposed by = Vodovnik=20 and colleagues (1978) (99) . = Currently there=20 are several commercial systems all based on surface stimulation - = MikroFES=20 (Jozef Stefan Institute of Science, Slovenia), Odstock 2 (Salisbury = District=20 Hospital, UK) (1= 00)=20 and WalkAide (Neuromotion, Canada) (1= 01) .=20 The drop-foot stimulators are commonly controlled by a foot switch. A = recent=20 overview on the different FES systems can be found in Popovic et al. = (2001a) (97= )=20 .

So = far, most=20 systems are external with a surface electrode over the peroneal nerve = just below=20 the head of the fibula.

More = recently,=20 radio-frequency transmitter enabled implants have been developed: for = example,=20 the new implantable two-channel system (Finetech, UK) (1= 02)=20 with subepineural electrodes in the n. peroneus profundus and n. = peroneus=20 superficalis. It has been tested in 10 patients. This dual channel = implant will=20 soon be registered with CE-mark. It has the ability to stimulate = independently=20 the deep and superficial branch of the peroneal nerve, thus allowing the = correction for excessive eversion and inversion.

Odstock 2 is a = surface=20 stimulation system that has been used mostly in the clinical = environment. It is=20 based on the stimulator proposed by Liberson. The device can be used as = an=20 assisting aid or as a training device to strengthen muscles and improve=20 voluntary control. Additionally, the device has a role in physiotherapy = in gait=20 re-education allowing isolated components of the gait cycle to be = practiced=20 under therapist control. (1= 03,=20 1= 04)=20 The Odstock 2 was perceived by the users to be of considerable benefit. = A=20 comprehensive clinical follow-up service is essential to achieve the = maximum=20 continuing benefit from FES-based orthoses. A recent review on the = subject can=20 be found in Lyons et al. (2002) (1= 05)=20 and (97= ).=20 Odstock 2 and the MikroFES, have been fitted to more than 500 subjects. = Thus=20 far, only the WalkAid has been FDA approved.

Figure 6. The peroneal stimulator (Finetech, UK) = (see=20 text) Courtesy: J. Holsheimer, G. Bulstra and H.E. van der = Aa

Restoration=20 of Lower limb Function

In 1963, Kantrowitz = reported the=20 first application of FES to a T-3 paraplegic patient who achieved = standing by=20 surface stimulation of the gluteus and the quadriceps for brief periods. = The=20 first systems were external devices enabling walking and were developed = by Bajd=20 and Kralj in the 1970s through 1980s in Lublijana, Slovenia (1= 06) .=20 The initial devices only used two surface stimulation channels for each = leg to=20 produce standing and walking. The stimulation was delivered to both knee = extensors. Devices with 4 channels have been proposed later (1= 07) .=20 Systems used by patients included stationary bikes for exercise, = transfer=20 systems to enable the patient to move between a wheelchair and a bed, = transfer=20 systems between standing and sitting, and walking aids (1= 06) .=20 The targeted patient group was paraplegics after SCI. Patients used a = rolling=20 walker frame or crutches for support. About 50 patients successfully = used the=20 system (1= 08) .=20 One of the first implantable multichannel stimulators was developed by = Brindley=20 with electrodes applied on the femoral and the gluteal nerves (1= 09) .=20 An overview of the contemporary devices can be found in (97= ) .=20 In brief they are Parastep, LARSI (1= 10) ;=20 FESmate, HAS, RGO, Praxis24 and the implanted FES system proposed in (1= 11)=20 .

The only commercialized = system,=20 developed initially by Graupe and colleagues (1= 12,=20 1= 13) ,=20 is Parastep (Sigmedics Inc., USA). It is based on the earlier work of = Kralj (1= 06) .=20 The target patient group consists of the complete or almost complete = T4-T12 SCI=20 patients. The system uses surface electrodes and no orthotic aids. The = Parastep=20 system was applied to more than 400 subjects and was the first = FDA-approved FES=20 system.

Although FES of = locomotion gains=20 clinical acceptance, it is still in its experimental phase of = development. =20 At this stage, FES of locomotion is so far incapable to deliver a = complete=20 treatment for the target groups of patients. Only in several cases, it = may=20 provide pathogenetic treatment. The main impediment of its development = is the=20 insufficient selectivity of stimulation and the small number of = applications in=20 patients, which hinders assessment of any beneficial clinical=20 outcome.

Hand=20 disabilities =96 reaching and grasping

In tetraplegic and = stroke=20 patients, the most important target for achieving a high level of = independence=20 in active daily life is the restoration of the hand function. Thus, the = main=20 objective in applying FES in such patients is to improve the hand = function by=20 creating a reliable and long lasting power grasp, or a smooth pulp-pinch = grasp=20 that is needed to manipulate small objects. Neuroprostheses for grasping = are=20 used to restore or improve grasping function in tetraplegic and stroke = subjects.=20 The patients that would benefit most from such a neuroprosthesis would = be C5-7=20 quadriplegics. The available neuroprostheses for grasping enable the = restoration=20 of the two most frequently used grasping styles, the palmar and the = lateral=20 grasp (1= 14) .=20 The best known grasping neuroprostheses are the Freehand system (1= 15) ,=20 Handmaster NMS (1= 16) ,=20 Bionic Glove (1= 17) ,=20 NEC FESMate system (1= 18) ,=20 ETHZ-ParaCare neuroprosthesis (1= 14) ,=20 the systems developed by Rebersek and Vodovnik  (1= 19)=20 and the Belgrade Grasping system (1= 20) .=20 A recent overview can be found in (91= )=20 .

In 1997, FDA approved = for clinical=20 use the Freehand system (NeuroControl Corp., Cleveland) for = restoration=20 of the hand grasp in quadriplegics. The research and development process = took 25=20 years, mostly carried out by the researchers at the Case Western Reserve = University. The device consists of a stimulator and electrodes implanted = in=20 wrist and forearm muscles, a "joystick" controller implanted in the = opposite=20 shoulder, and an external processing unit (1= 15) .=20 The joystick-like sensor placed on the chest relaxes and tightens the = hand as=20 the shoulder moves back and forth. A detailed description of the = prosthesis can=20 be found in (1= 21) .=20 This prosthesis has been experimentally implanted in more than 130 = people. With=20 training, most patients with this device can open and close their hand = in two=20 different grasping movements and lock the grasp in place by moving their = shoulder in different ways. A recent small clinical study with 6 = patients (1= 22)=20 is a sign of increasing acceptance and application of the Freehand = system=20 outside USA. Researchers reported that all subjects were able to grasp, = move and=20 release more objects within the 30-s test period with the = neuroprosthesis than=20 without it. In 85% of the occasions, the six subjects expressed a = preference for=20 using the neuroprosthesis to perform these activities in daily living. = Twelve=20 months after rehabilitation, five of the six subjects still used the=20 neuroprosthesis regularly. One of the main advantages of the Freehand = system is=20 that the time needed to put on (donning) and to take of (doffing) the = system is=20 significantly shorter compared to most surface stimulation FES systems. = On the=20 other hand, the Freehand system can be applied only 18-24 months after = the=20 injury and is only suitable for SCI subjects and not individuals = suffering from=20 stroke (1= 14)=20 .

The Bionic Glove = is a=20 hybrid system that utilizes a glove with FES electrodes. The detection = of wrist=20 extension stimulates finger flexion; therefore, the control of the = device is=20 directly related to the normal grasping sequence. Only patients who have = sufficient wrist extension strength can use this type of device. The = controls of=20 the Freehand system and the Handmaster are not related to the normal = movements=20 included in the motor function, whereas the Bionic Glove uses mechanical = sensors=20 to detect wrist extension and the control is therefore directly = coordinated by=20 the grasping sequence. Bionic Glove can significantly improve = independence in=20 patients with C5-C7 spinal cord injury if their initial Functional = Independence=20 Measure and Quadriplegia Index of Function scores are 20% to 50% of the = maximum=20 values. The study is part of a multicenter clinical trial (1= 23)=20 .

The Handmaster = is an=20 orthosis for grasping with three pairs of surface stimulation = electrodes. This=20 system can be used to generate a grasping function in tetraplegic and = stroke=20 patients. Originally, this system was envisioned as an exercise and=20 rehabilitation tool, but it is also used as a permanent prosthetic = system.=20

One of = the=20 advantages of the Handmaster is that it is easy to put on and to take = off. The=20 Handmaster is predominately used as an exercise tool for stroke subjects = and is=20 commercially available in a limited number of countries.

An interesting attempt = is the=20 MeCFES system (myoelectrical controlled functional electrical = stimulator)=20 where the residual myoelectric signals from the paretic wrist extensor = (m.=20 extensor carpi radialis) are used to control stimulation of either the = wrist=20 extension (i.e., the same muscle) or thumb flexion. Initial results of = six=20 spinal cord lesion patients and one stroke patient show improvement of = the wrist=20 extension (1= 24)=20 .

With the exception of = the Freehand=20 and NEC-FES systems, all other neuroprostheses for grasping are FES = systems with=20 surface stimulation technology. Only the Freehand and Handmaster systems = are=20 currently available on the market while the other neuroprostheses are = produced=20 in laboratory environments.

All of the discussed=20 neuroprostheses for grasping have demonstrated, in clinical trials in = stroke=20 and/or SCI subjects, improvement of the grasping function. These systems = confirmed that the FES technology in principle could facilitate = comfortable and=20 secure grasp. However, the grasp strategies that can be provided = with the=20 existing neuroprostheses for grasping are very limited and can only be = used for=20 a restricted set of grasping and holding tasks.

In conclusion, it is too = early to=20 consider any of the existing systems, including Freehand and Handmaster, = as=20 success because of the small number of patients using the systems (about = 150 for=20 Freehand and a comparable amount for Handmaster).

Phrenic=20 stimulation

Of those people who = sustain a high=20 cervical spinal cord injury, a substantial number initially require some = form of=20 mechanical ventilation of their lungs. Most of them will be able to = breathe=20 spontaneously with recovery, but 25% will remain dependent upon some = form of=20 ventilation support for the remainder of their lives. Most of these = injuries=20 occur in young, otherwise healthy people with a life expectancy of 20 = years or=20 more, assuming they have access to appropriate medical care. In patients = with=20 cervical lesions of the spinal cord, direct stimulation of the phrenic = nerve can=20 be applied for respiratory pacing. This is one of the earliest clinical=20 applications of FES.

Diaphragm pacing is = useful for=20 conditions in which the brain stem respiratory centers provide little or = no=20 activation of the respiratory muscles, i.e. central hypoventilation = syndrome,=20 Arnold-Chiari malformation/brain stem dysfunction and high quadriplegia. = Suitable patients are those with an intact phrenic nerve motor neuron = pool in=20 their cervical spinal cord on both sides. This can be checked by = measuring the=20 phrenic nerve conduction velocity and the diaphragm electromyogram = (EMG). To do=20 this phrenic nerves are stimulated by needle or surface electrodes in = the neck=20 and the diaphragm muscle EMG is recorded from electrodes placed low on = the chest=20 at the front. The patient wears an external radio-frequency (RF) = transmitter=20 over an implanted receiver, and a stimulating current is induced without = the=20 need for any percutaneous wires. The introduction of phrenic nerve = pacing more=20 than two decades ago by Dr William Glenn and associates at = Yale=20 University has provided many ventilator-dependent tetraplegic=20 patients with freedom from mechanical ventilation (9, 1= 25,=20 1= 26)=20 .

More than 1.200 phrenic = nerve=20 stimulator implantations have been performed throughout the world since = 1968.=20 Patients from several months of age to over 80 years of age have been=20 successfully implanted and paced for long periods. Many patients have = been=20 successfully helped for more than 10 years; the longest period of pacing = in a=20 patient has been more than 20 years. In patients with = ventilator-dependent=20 quadriplegia, phrenic nerve pacing provides significant clinical = advantages=20 compared with mechanical ventilation. This technique, however, generally = requires a thoracotomy with its associated risks; in-patient hospital = stay and=20 it carries some risk of phrenic nerve injury.

During the past decade, = diaphragm=20 pacing has also been attempted in small infants. The appropriate = stimulation=20 parameters are low stimulus frequency, short inspiration time and = moderate=20 respiratory rate. In a clinical trial in 33 pediatric patients, the mean = time to=20 failure was 56 months, which is acceptable for limited application of = the=20 pacemakers (1= 27) .=20 Among the benefits of the phrenic nerve pacing can be = outlined:

 To recapitulate: = one may=20 consider the phrenic stimulator as a major improvement of the quality of = life of=20 the patient, which also reduces the overall costs for nursing of the=20 patient.

Clinical=20 trials / Evidence based medicine for FES

Efficacy of=20 FES after stroke

Meta analysis showed = that in=20 post-stroke hemiparetic patients FES promotes recovery of muscle = strength if=20 included as part of the rehabilitation (based on the paretic muscle = force=20 measurements). The study was based on the results of clinical trials = dating=20 between 1978 and 1992 (1= 28) .=20 There is, however, more evidence for improvement of the motor control of = the=20 upper extremity after stroke (129) . The = meta=20 analysis was based on six randomized controlled trials on the = therapeutic=20 electrical stimulation on motor control and functional abilities. After = stroke,=20 up to 81% of the individuals develop shoulder subluxation, a condition=20 frequently associated with poor upper limb function. FES on the shoulder = muscles=20 has been used in treatment of this condition. The results of seven (four = early=20 and three late) trials indicate when added to conventional therapy FES = is=20 beneficial early after stroke for prevention of shoulder subluxation (1= 30).=20 Burridge et al. in a randomized controlled trial in subacute = single=20 stroke patients measured the effect of the Odstock Dropped Foot = Stimulator as a=20 supplement to physiotherapy (100). The = results of=20 32 subjects showed increase in walking speed and beneficial = Physiological Cost=20 Index, if the stimulator had been used. 

 

Efficacy of=20 FES in urological conditions

Stimulation of the = sacral spinal=20 nerves or the sacral spinal roots or the pelvic nerves can be used to = restore=20 bladder function in patients with voiding disorders. Several therapeutic = techniques have become established in clinical urology as part of = therapy at an=20 increasing number of specialized centers.

As part of the treatment = of=20 different kinds of lower urinary tract dysfunctions, refractory to = conservative=20 treatment, Tanagho and Schmidt introduced sacral nerve = neuromodulation in=20 the 80s (1= 31) .=20 Neuromodulation is now carried out by stimulation of the S3 sacral = nerve. In=20 brief, an electrode is placed in S3 foramen. The electrode has to be = brought=20 into the ventral side of the opening in front of the S3 ventral ramus. = This=20 procedure is minimally invasive, as compared to sacral neurostimulation. = The=20 patient is sent home with an external pulse generator for a few days as = part of=20 an evaluation test. Responders are then implanted with a permanent = sacral=20 foramen implant and an implantable pulse generator (1= 32)=20 .

Since its early = applications,=20 neuromodulation has grown in popularity and the indications for this = procedure=20 are multiplying. Among them are now urge incontinence and sensory = urgency,=20 idiopathic chronic urinary retention, pelvic pain and interstitial = cystitis=20 (1= 33).=20 Complications in general are minimal and included electrode migration, = electrode=20 failure and pain at the implantable pulse generator site (1= 34).

The sacral = neurostimulation=20 approach proposed in the 1980s by Brindley (1= 35)=20 consists of intradural implantation of a so-called book electrode to = stimulate=20 S2-S3 ventral roots, together with posterior S2-S4 rhizotomy. The = primary=20 purpose of the Brindley bladder stimulator is to improve bladder = emptying,=20 thereby eliminating urinary infection and preserving kidney function in=20 suprasacral SCI patients. It also assists in defecation = and=20 enables male patients to have a sustained full erection. Nowadays the = Brindley=20 bladder stimulator is being developed by the company Finetech in = UK.

Detrusor=20 sphincter dysynergia

The suprasacral SCI = patients=20 develop detrusor sphincter dyssinergia, which imposes serious health = risk. The=20 results from the first 500 patients implanted with the Brindley = stimulator show=20 usage in 424 after a mean follow up of 4 years. (1= 36) .=20 Another study reported 38 patients with a complete spinal cord lesion = (1= 37) .=20 During the follow-up period, ranging up to 12 years all patients had = increased=20 bladder capacity and reduced residual urine volumes; 31 patients were = continent;=20 29 males could achieve a sustained full erection; 27 patients used the = implant=20 for bowel function. The long long-term favorable effects of the = stimulator were=20 also confirmed in follow-up studies on urodynamics (1= 38)=20 and cost-effectiveness (1= 39)=20 in 52 patients.

Overactive=20 bladder

The overactive bladder = comprises a=20 spectrum of conditions ranging from urgency-frequency syndrome to urge=20 incontinence. The incidence of the overactive bladder increases with = age, with a=20 prevalence exceeding 4% to 5.5% of the population. The efficacy of the=20 neuromodulation therapy was evaluated in a prospective 12-center study = in=20 Europe, Canada, and the United States conducted form 1993 to 1999 with = the=20 InterStim system (Medtronic, Inc., Minneapolis, Minnesota). The study = enrolled=20 184 patients for urinary urge incontinence, 220 for urgency-frequency, = and 177=20 for retention for a total of 581 patients (1= 40) .=20

Urge Incontinence and = Sensory=20 Instability

Neuromodulation is used = in=20 patients with urge incontinence and with therapy-resistant idiopathic = detrusor=20 instability, where in a follow-up trial results showed clinically = significant=20 improvement of the quality of life (1= 33) .=20 In patients with detrusor hyperactivity implantable neuroprosthetic = devices also=20 lead to improvement in the urodynamic parameters (1= 41) .=20 Out of 20 patients with urge urinary incontinence, presented by Thon and = colleagues (2003) (1= 42) ,=20 17 showed an improvement of more than 50% compared to the baseline, = which=20 persisted for more than a year of follow-up. Elabbady and colleagues = (1994) (1= 43)=20 presented their results in 9 patients with urgency frequency and/or urge = incontinence: frequency improved by 73%, urgency by 42% and incontinence = by 50%.=20 However, the number of patients is small to derive statistically valid=20 conclusions for the success rate of the operation.

On the other hand, the = outcome of=20 the multi-center trial is promising. Results demonstrate that after 3 = years, 59%=20 of 41 urinary urge incontinent patients showed greater than 50% = reduction in=20 leaking episodes per day with 46% of patients being completely dry. = After 2=20 years, 56% of the urgency-frequency patients showed greater than 50% = reduction=20 in voids per day (1= 40)=20 . 

Idiopathic = Non-Obstructive=20 Chronic Urinary Retention

The results for the = idiopathic=20 urinary retention of the multi-center trial were also separately = reported in (1= 44) .=20 A total of 177 patients with urinary retention refractory to standard = therapy=20 were enrolled in the study. Compared to the control group, patients = implanted=20 with the InterStim system had statistically and clinically significant=20 reductions in the catheter volume per catheterization. Successful = results were=20 achieved in 83% of the implant group with retention compared to 9% of = the=20 control group at 6 months. Temporary inactivation of sacral nerve = stimulation=20 therapy resulted in a significant increase in residual volumes but = effectiveness=20 of sacral nerve stimulation was sustained through 18 months after=20 implant. In another study, Thon and colleagues (2003) (1= 42)=20 reported that from 33 patients with chronic urinary retention implanted=20 permanently with neuroprosthesis 23 showed a long-lasting significant=20 improvement, but in the remaining 10 the improvement did not reach 50% = compared=20 to baseline. In 7 patients with chronic retention, Vapnek and Schmidt = (2003)=20 reported for success in 5 cases (1= 45)=20 and Elabbady and colleagues (1994) (1= 43)=20 presented success in 8 of 8 cases. Results of all the presented studies=20 demonstrate that sacral nerve stimulation is effective for restoring = voiding in=20 patients with retention who are refractory to other forms of=20 treatment.

Pelvic pain and=20 discomfort

Pelvic pain or = discomfort is a=20 very common symptom associated with other storage or voiding = dysfunctions. In=20 the available literature on sacral root neuromodulation, associated = pelvic pain=20 has improved from 85% to 90% when postimplant status was compared to = baseline=20 (1= 34,=20 1= 42).

In conclusion: The = correlation=20 between the clinical outcome and the urodynamic test results is poor. = The=20 results of the presented studies on neuromodulation show that 40% of the = selected patients do not qualify for the procedure and the effect of = treatment=20 is not enduring: voiding dysfunctions return as soon as the = neuroprosthesis is=20 switched off. It is thought that the effect is based on antidromic=20 stimulation of the inhibitory neurons in the spinal cord. Due to the = fact that=20 the stimulators are voltage-controlled so far, the amount of injected = current=20 into the tissues is unknown and the fibers which are stimulated are also = not=20 known (may be both myelinated or non-myelinated) and also the direction = of=20 stimulation (ortho- antidromic). More basic and clinical research needs = to be=20 performed before this treatment can be introduced as a routine procedure = in=20 patients with serious voiding dysfunction refractory to conservative = measures=20 (1= 46)=20 .

 =20

Experimental and = theoretical=20 research

Experimental=20 research

Visual=20 prosthesis: blind eye vs. normal brain

Blindness can=20 result when any step of the optical pathway=97the optics, the retina, = the optic=20 nerve, visual cortex, or other cortical areas involved in the processing = of=20 vision =97 sustains damage. In Germany, 17.000 patients become blind = every year=20 for whom there is no effective treatment or cure (1).

Public discussion of = electricity's=20 effect on vision dates to 1751, when it was addressed by Benjamin = Franklin=20 following his celebrated kite-and-key experiment. Despite some = advocates, the=20 idea of treating blindness through electrical stimulation did not catch = on. In=20 the last 30 years extensive experimental research for development of = visual=20 prostheses has been performed. In 1967-68 the experiments of Brindley = and Lewin=20 (14= )=20 showed the feasibility of the long-term interface with the visual = system. The=20 approach of the cortical prostheses has its foundations in the = observations of=20 the visuotopic organization of electrically evoked phosphenes in the = occipital=20 cortex. This have led a number of investigators to propose that = electrical=20 stimulation of visual cortex via arrays of electrodes might provide the=20 profoundly blind with a limited form of functional vision. Several = groups=20 investigated the stimulation with cortical surface electrodes =96 the so = called=20 =93cortical prostheses=94 of Brindley, Dobelle (1974) (1= 47) ;=20 cortical penetrating electrodes of Bartlett and Doty (1980) (1= 48)=20 and of Schmidt and Hambrecht (1996) (1= 49) .=20 However influential it is, so far this idea has very little practical = progress.=20 The neurons in the cortex represent textures, depth (displacements), = angles and=20 brightness /colors of the object. The perception of images is not based = on=20 pixelation; therefore, all the bitmap-based stimulation approaches are = doomed to=20 fail. On the other hand, the cortical stimulation approach may provide = the only=20 therapeutic approach for individuals with non-functional retinas and/or = optic=20 nerves.

Recently Dobelle (2000) = (1= 50)=20 reported for the development of a visual prosthesis providing a sort of=20 "artificial vision" to a blind volunteer by connecting a digital video = camera,=20 computer and associated electronics to the visual cortex of his brain. = As an=20 alternative to the cortical stimulation, two other approaches have been = also=20 investigated. 

The idea to realize a = visual=20 prosthesis by stimulating the optic nerve was conceived by = Mortimer and=20 Veraart (1998) (1= 51)=20 at the beginning of the 1990's. The first implantation was in 1998 and = the=20 patient was able to localize single bright spots of light, but high = spatial=20 resolution cannot be expected with such a stimulation arrangement. This=20 prosthesis may show promise if an ultra-high electrode count array of=20 intraneural electrodes are implanted in the optic nerve for providing = better=20 selectivity of stimulation. Although ingenious, the approach does not = take into=20 account so far the information processing steps taking places in the = retinal=20 ganglionic cells.

At the end of the = 1980's, an=20 entirely new approach was undertaken by the teams of M. Humayun, of John = Hopkins=20 University (1= 49)=20 and that of J. Rizzo of Harvard University (1= 56) ,=20 in association with the Massachusetts Institute of Technology. They = developed an=20 implantable electrode array for the retina itself, further referred to = as=20 retinal implant, in order to stimulate the retinal ganglionic = cells (1= 52) ,=20 whose extensions form the optic nerve. This prosthesis is referred to as = "epiretinal implant". Another kind of retinal implant is the subretinal = implant=20 developed by Chow and colleagues (1997) (1= 53)=20 in Chicago and Zrenner in Tubingen (1997) (1= 54)=20 .Both teams (1= 55,=20 1= 56),=20 have stimulated the retina of blind patients with epiretinal electrodes = that=20 were transiently inserted into the eye through a scleral opening. Both = groups=20 reported a sensation of light patterns by the patients, but perception = of=20 geometric patterns was reported in only a few instances. Recently a = permanent=20 implantation has been made in a blind volunteer (1= 57)=20 .

All results in the = field in=20 the past 30 years are still far from true object recognition. However, = they do=20 demonstrate the feasibility of generating perception of light patterns = in blind=20 people.

Spinal Cord=20 Stimulation in motor disorders

Apart from the pain = suppression of=20 chronic intractable pain, peripheral vascular disease and angina = pectoris,=20 spinal cord stimulation has been employed in motor disorders for control = of=20 spasticity in SCI patients. Attempts in this direction have been carried = out in=20 the 1980s for the first time by Richardson et al. (1979) (1= 61) .=20 Recently Pinter et al. (2000) (1= 62)=20 stimulated the L2-L3 dorsal roots of the spinal cord in SCI patients. = Results=20 demonstrated reduction of the muscle hypertonia of the lower=20 extremities.

A possible future = application of=20 SCS is to contribute to the restoration of the motor functions of the = lower=20 extremity (1= 58,=20 1= 59) .=20 The reasoning behind this idea is that if we are able to control the = Central=20 Pattern Generator (CPG) in the motor spinal cord we circumvent many of = the=20 selectivity problems pointed out so far. There is accumulating evidence = for the=20 existence of CPG of the locomotion in primates and men (1= 60).=20 This requires a Multi Electrode Array to be placed on the spinal cord = such that=20 it is able to stimulate the musculotopically-organized motor pools of = the lower=20 limbs.

Theoretical=20 Modeling studies

As part of the design of = different=20 types of electrodes for stimulation a substantial amount of theoretical = and=20 experimental research on selectivity has been performed. The electrical = behavior=20 of the myelinated nerve fiber can be represented by a simple cable = network. The=20 first to introduce this model was McNeal (1976) (27= ) in=20 order to calculate how a stimulation-induced extracellular field affects = nodal=20 transmembrane voltages. According to this model, the node of Ranvier, = which is=20 closest to the cathode, will be excited first when the stimulus current = is=20 sufficiently high. The results of this theoretical approach are in = accordance=20 with the general observation that the threshold stimulus of a nerve = fiber=20 excitation is smallest near the cathode and rises with the increase of = the=20 distance (23= ) .=20

Research on=20 spatially-selective nerve stimulation

The feasibility of = selective=20 activation of peripheral nerve fascicles was demonstrated by McNeal and = Bowman=20 (1985) (31= ) ,=20 who found that with proper fit and positioning a single circumneural = sleeve with=20 multiple electrode contacts could control selectively the activation of = two=20 antagonist muscle groups innervated by a common nerve trunk. In their = study,=20 Sweeny et al. (1990) (42= )=20 performed numerical modeling and experimental testing of a nerve cuff = technique=20 for selective stimulation of superficial peripheral nerve trunk regions. = Two=20 basic electrode configurations ("snug" cuff monopolar and tripolar=20 longitudinally aligned dots) have been considered. Both modeling and=20 experimentation suggested that longitudinally aligned tripolar dot = electrodes on=20 the surface of a nerve trunk would restrict excitation to superficial = nerve=20 trunk regions more successfully than monopolar dot electrodes would do.=20 Transverse anodal "steering" improved the spatial selectivity of both = monopolar=20 and tripolar electrode configurations (42= )=20 .

With a sufficient number = of=20 electrodes within a so-called =93cuff electrode=94, high selectivity of = stimulation=20 can be achieved by either longitudinal or transversal currents produced = by=20 appropriately switched electrodes (41= ) .=20

Goodall et al. (1996) = (45= )=20 found that transverse current from an anode positioned opposite the = stimulating=20 cathode improved spatial selectivity, and position selectivity was = enhanced when=20 the ratio of transverse current to longitudinal current was increased. = Based on=20 computer modeling Deurloo et al. (2003) concluded that transverse = steering=20 provides more selective stimulation than longitudinal steering (44= )=20 .

Figure=20 7. Transverse section of the 3D volume conductor model of=20 a monofascicular nerve surrounded by an insulating cuff with an = electrode=20 contact on its inner surface.

B Recruitment contours = showing=20 excitation regions in the nerve trunk. c- cathode, a =96anode; a: = central=20 cathode b: longitudinal tripole + additional anode c: = transverse=20 tripole.

Courtesy: K Deurloo, = from (96= ) A=20 p. 15 and B p.30

Selectivity was = dependent on the=20 relative location of the electrode contacts and the nerve fascicles, as = well as=20 the size and relative spacing of neighboring fascicles (43= ) .=20

Deurloo et al. (1998) = (1= 63)=20 performed theoretical research on how to improve the selectivity = performance of=20 multi-contact cuff electrodes for stimulation of peripheral nerves. As=20 combination of controlled fiber size and spatial selectivity seems hard = to=20 achieve, the focus was primarily on spatial selectivity. They found that = the=20 transverse tripole is the only configuration that maximizes activation=20 selectivity for a small (cylindrical) bundle of fibers in the periphery = of a=20 monofascicular nerve trunk (1= 63)=20 (see also Fig 7). Inverse recruitment was less pronounced than for the = other=20 configurations. Therefore, they recommended transverse tripolar = stimulation=20 since it did not change the shape of the recruitment contours, despite = the=20 lowering of the excitation threshold, which might occur in chronic = implantation=20 fibrosis on the implantation site.

However, in acute animal = experiments, where the recruitment characteristics of muscle selective = nerve=20 stimulation by a multi-contact nerve cuff electrode was studied, the = results=20 showed that only in a few cases transverse bi- and tripolar stimulation = provided=20 a better selectivity than monopolar stimulation (1= 64) .=20 In accordance with the results of the modeling studies, bi- and tripolar = stimulation required higher stimulus currents than monopolar = stimulation,=20 whereas maximum recruitment and slopes of recruitment curves were lower. = Due to=20 the variability in the number and size of the fascicles and their = position in=20 this nerve, sufficient reproducibility for the selectivity could not be=20 obtained.

The theoretical research = performed=20 by Rutten et al. (1991) (56= ) and=20 Yoshida, and Horch (1993) (49= )=20 suggested that intraneural electrodes should give better spatial = selectivity=20 than cuff electrodes. In this line of reasoning Rutten et al. (1999) (1= 65)=20 argue that the best way to control individual fibers is to stimulate in = close=20 proximity of the nodes of Ranvier, which implies use of intrafascicular=20 electrodes. However, the distribution of the nodes of Ranvier in the = peripheral=20 nerves makes the stimulation a probabilistic process. The experimental = studies=20 show that, despite the theoretical expectations, when the topography of = the=20 motor nerve fibers is unknown, the implanted intraneural electrode may = simply=20 miss the target fiber population. Several attempts for such stimulation = have=20 been made so far with 1D arrays. The obtained information gave insight = on how to=20 improve the design (shape, distance between the electrodes) of the later = on=20 produced 3D arrays.

In acute nerve = implantation=20 experiments eight 5- to 24-wire-MEAs were used in order to investigate = whether=20 the electrodes could selectively stimulate single motor units. The = results=20 revealed partial blocking of neural conduction, similar to that reported = with=20 microneurographic insertion with single needles (1= 66) .=20 The eight arrays were capable of evoking threshold forces selectively = with an=20 average efficiency of 0.81 (or 81%)

Frieswijk et al. (1998) = (1= 67)=20 performed animal experiments and model simulations of monopolar, = intrafascicular=20 nerve stimulation in order to study force-current relationships = (recruitment=20 curves). They found that the conductivity of the extraneural medium is = of prime=20 importance to the resulting recruitment curves: an insulating = extraneural medium=20 generally leads to steeper curves with lower threshold currents than a=20 well-conducting extraneural medium. The statistical comparison of = experimental=20 and model results suggested clustering of the motor fibers, originating = from a=20 single muscle, within the same fascicle. This clustering manifested = itself=20 mainly by an increased spread in threshold currents, as opposed to the = situation=20 where the fibers are distributed uniformly throughout the entire=20 fascicle.

In conclusion, the = insufficient=20 neuroanatomical knowledge of the spatial organization and topography of = fibers=20 in the peripheral nerve hampers the definitive choice for the design of = the=20 electrode.

Research on=20 fiber size selective stimulation

In myelinated axons, = there is a=20 positive correlation between the internodal distance and the axonal = diameter.=20 Thus, the large fibers (A, B) have nodes further apart than the small = fibers. As=20 a result, in an electric field the larger fibers have a larger potential = difference between adjacent nodes. This leads to a lower threshold of = the large=20 fibers in comparison with the small ones. Therefore, during stimulation, = the=20 large myelinated fibers fire first. Unfortunately, this is the reverse = of the=20 natural order of recruitment, and it results in fast development of = muscle=20 fatigue. By activating/blocking stimuli delivered by multiple cuff = electrodes=20 the order of recruitment can be reversed, but the fibers still can not = be chosen=20 (1= 68) .=20 Better fiber size selectivity can be achieved by intraneural = stimulation, as=20 outlined by Rutten et al. (1999) (1= 65)=20 .

The order in which the = nerve=20 fibers in a peripheral nerve or a spinal root are excited by a stimulus = pulse is=20 predominantly related to both the fiber diameter and the distance = between the=20 fiber and the cathode (1= 69) .=20 In the conducting media around the electrode, the current density is = inversely=20 proportional to 2nd- 3rd power of the distance.=20 Accordingly, the threshold current is increased at the same rate as = shown=20 empirically (23= ) .=20 In clinical applications, due to the generally limited amplitude range, = only the=20 large fibers will be recruited. For example in spinal cord stimulation, = the=20 maximal therapeutic amplitude should not exceed 170% of the paresthesia=20 threshold perception. Calculations show that the nerve fibers smaller = than 9um=20 in diameter will not be recruited. Another relevant aspect of the = recruitable=20 large fibers is their density within the fascicle (169) = .

 Fang and Mortimer = (1991) (1= 70,=20 1= 71)=20 studied selective activation of small fibers without activating larger = fibers in=20 the same nerve trunk. In the proposed nerve stimulation system,=20 quasitrapezoidal-shaped current pulses were delivered through a tripolar = cuff=20 electrode to effect differential block by membrane hyperpolarization. = The=20 quasitrapezoidal-shaped pulses with a square leading edge, a 350 = microsecond(s)=20 plateau, and an exponential trailing phase ensured the block of = propagating=20 action potentials and prevented the occurrence of anodal break = excitation. The=20 tripolar cuff electrode restricted current flow inside the cuff and thus = eliminated the undesired nerve stimulation due to a "virtual cathode." = The=20 subsequent animal experiments confirmed that larger alpha motor axons = could be=20 blocked at lower current levels than smaller alpha motor axons, and that = all=20 alpha fibers could be blocked at lower current levels than gamma fibers, = and the=20 blocking threshold correlated with the fiber diameter Fang and Mortimer = (1991 b)=20 (1= 71).=20 For the same purpose, van Bolhuis et al. (2001) (1= 72)=20 suggested the use of two pulse generators independently supplying short=20 supramaximal cathodal stimulating pulses (0.5 ms) and long subthreshold = cathodal=20 inactivating pulses (1.5 s) to the sciatic nerve. Results showed that=20 propagation of action potentials was selectively blocked in nerve fibers = of=20 different diameters by adjusting the strength of the inactivating = current (1= 72)=20 .

It has been shown that = cathodal=20 pre-pulses inverse the recruitment order

(1= 73,=20 1= 74) .=20 Grill and Mortimer (1997) (1= 73)=20 demonstrated that subthreshold membrane depolarization generated a = transient=20 decrease in neural excitability and thus an increase in the threshold = for=20 stimulation by a subsequent stimulus pulse. When a depolarizing stimulus = pulse=20 was applied immediately after the subthreshold depolarization, nerve = fibers far=20 from the electrode could be stimulated without stimulating fibers close = to the=20 electrode. Thus subthreshold depolarizing pre-pulses allowed selective=20 stimulation of nerve fibers far from the electrode

In a realistic model of = a nerve=20 fiber surrounded by a cuff electrode Deurloo et al. (2001) (1= 74)=20 showed that it is also possible to stimulate small fibers without = exciting large=20 ones. The applied model requires that, in the case of monopolar = stimulation with=20 a cuff electrode, the cuff length should not exceed twice the internodal = length=20 of the fibers to be blocked. Similarly, the distance between cathode and = anodes=20 should not exceed the internodal length of these fibers when tripolar=20 stimulation is used (1= 74) .=20

Conclusions

The principal = requirements to any=20 substituting structure are features mimicking some of the biological = functions=20 of nerves and replacing these functions depending on the scope of = implantation.=20 Profound knowledge about the development, functional and structural = organization=20 of the nervous system is a prerequisite for any attempt to establish = meaningful=20 recording or stimulation in order to substitute for a given function or=20 modality.

A number of proposed = ideas for=20 electronic implants are based, however, on a more "engineer-like" way of = thinking rather than considering the complexity of the biological = systems. The=20 necessary for the engineering development reductionist approach often=20 substitutes basic problems for secondary ones. For example, the concept = of=20 spatial selectivity in stimulation is often substituted for = fascicle=20 selectivity, which equalizes the fiber representation of a = particular muscle=20 contraction (dynamic view) to a coincidentally delimited anatomical = region along=20 the course of a nerve (static view).

The presented overview = of the FES=20 applications shows that despite the substantial amount of research = performed in=20 the field which led to successful development of cardiac and phrenic=20 pacemakers and cochlear prostheses, a number of fundamental=20 scientific problem still remains to be solved before we see a comparable = degree=20 of effectiveness and penetration in common medical practice for the = locomotion=20 neuroprostheses and urological FES appliances.

Although FES of = locomotion=20 gains clinical acceptance, it is still in its experimental phase of=20 development.  There are several interrelated, but different,=20 issues

-        =20 Effectiveness and reliability of the devices

-        =20 Technical support

-        =20 The place of the devices in the complex treatments of the CVA, SCI, = multiple=20 sclerosis etc.

Despite the significant = technical=20 progress achieved in the last 10 to 15 years in the FES field, there is = a=20 consensus that these systems are not sufficiently advanced and that they = need=20 further development. Complexity of human motion greatly diminishes the = area of=20 the animal experimentation in this field and puts the stress on computer = modeling. This complexity, however, makes the leap from a model to a = patient=20 even more difficult than from an animal model to human, which one could = see in=20 the performance on many implantable FES systems. This has only been = done in=20 limited number of cases, which in turn diminishes the validity of the = obtained=20 results and leads to case descriptions rather than generalizations. This = in turn=20 increases the interval between trial and error (the most prominent = approach in=20 experimentation) and as a result slows down the research and development = process=20 for new applications.

Nevertheless, the = present FES=20 treatments combined with conventional occupational and physical therapy = still=20 remain the most promising approach in rehabilitating SCI patients and = stroke=20 patients. The need of training, which is seen by some as a shortcoming = of FES=20 (97= )=20 , in our opinion may be turned into advantage if it is integrated in the = overall=20 treatment and rehabilitation process.

The mechanism of action = of=20 electrical neuromodulation is still poorly understood, which leaves it = in a=20 rather empirical state of operation. The Brindley neurostimulation = method is a=20 real FES application. Until now hundreds of patients have been treated=20 successfully with the Brindley approach in bladder voiding disorders. = However,=20 the posterior rhizotomy, which is required, is a rather crude approach = towards=20 blocking the spinal reflexes. Nevertheless, FES is effective in = improving the=20 bladder function in the overactive bladder states and in SCI patients it = gives=20 long-term favorable results, which makes it a viable therapeutical = option for=20 the indicated groups of patients.

The research performed = in the=20 field of the visual prostheses showed the complexity of the = information=20 processing by the (human) visual system. Even the modest goals of the = projects=20 so far are ambitious compared with the information content of the = reported=20 visual phenomena. We would like to finish with a quotation from Dobelle = (1= 50) ,=20 which applies in the end to any prosthetic treatment: = =93Development of=20 implanted medical devices such as this artificial vision system = progresses in=20 three stages. First there is speculation, then there is hope, and = finally there=20 is promise.=94

 

 

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