functional electrical stimulation for neuromuscular applications

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Annu. Rev. Biomed. Eng. 2005. 7:327–60 doi: 10.1146/annurev.bioeng.6.040803.140103 c 2005 by Annual Reviews. All rights reserved Copyright First published online as a Review in Advance on March 23, 2005

FUNCTIONAL ELECTRICAL STIMULATION ∗ FOR NEUROMUSCULAR APPLICATIONS Annu. Rev. Biomed. Eng. 2005.7:327-360. Downloaded from arjournals.annualreviews.org by University of Southern California on 11/02/09. For personal use only.

P. Hunter Peckham Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106; Department of Veterans Affairs, Cleveland, Ohio 44106; MetroHealth Medical Center, Cleveland, Ohio 44109; email: [email protected]

Jayme S. Knutson Department of Veterans Affairs, Cleveland, Ohio 44106; email: [email protected]

Key Words motor neuroprosthesis, spinal cord injury, stroke rehabilitation, bladder stimulator, phrenic nerve pacing ■ Abstract Paralyzed or paretic muscles can be made to contract by applying electrical currents to the intact peripheral motor nerves innervating them. When electrically elicited muscle contractions are coordinated in a manner that provides function, the technique is termed functional electrical stimulation (FES). In more than 40 years of FES research, principles for safe stimulation of neuromuscular tissue have been established, and methods for modulating the strength of electrically induced muscle contractions have been discovered. FES systems have been developed for restoring function in the upper extremity, lower extremity, bladder and bowel, and respiratory system. Some of these neuroprostheses have become commercialized products, and others are available in clinical research settings. Technological developments are expected to produce new systems that have no external components, are expandable to multiple applications, are upgradable to new advances, and are controlled by a combination of signals, including biopotential signals from nerve, muscle, and the brain. CONTENTS INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PHYSIOLOGICAL AND TECHNOLOGICAL PRINCIPLES OF FES . . . . . . . . . . Electrical Activation of the Neuromuscular System . . . . . . . . . . . . . . . . . . . . . . . . Configurations of Neuroprosthetic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CLINICAL APPLICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Upper Extremity Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lower Extremity Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bladder and Bowel Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Respiratory Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ The U.S. Government has the right to retain a nonexclusive, royalty-free license in and to any copyright covering this paper.

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FUTURE DIRECTIONS AND DEVELOPMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . Emerging Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Emerging Control Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Annu. Rev. Biomed. Eng. 2005.7:327-360. Downloaded from arjournals.annualreviews.org by University of Southern California on 11/02/09. For personal use only.

INTRODUCTION Functional electrical stimulation (FES) is the application of electrical current to excitable tissue to supplement or replace function that is lost in neurologically impaired individuals. In addition to the chronic applications for restoration of function described in this paper, electrical stimulation has also been used for many therapeutic applications. The purpose of therapeutic electrical stimulation is to improve tissue health or voluntary function by inducing physiological changes that remain after the stimulation is used. In contrast, the purpose of an FES intervention is to enable function by replacing or assisting a person’s voluntary ability. In FES applications, stimulation is required to achieve a desired function; therefore, FES systems are usually designed to be worn by the user. FES devices or systems that are used as a substitute for lost neurological function are often called neuroprostheses. Both sensory and motor function can be restored with FES. Auditory and visual neuroprostheses are examples of FES used to restore sensory system functions. This review is limited to applications of FES to the neuromuscular system. The concept is to provide functional restoration through electrical activation of intact lower motor neurons using electrodes placed on or near the innervating nerve fibers. Appropriate electrical stimuli can elicit action potentials in the innervating axons, and the strength of the resultant muscle contraction can be regulated by modulating the stimulus parameters. A functional limb movement can be produced by properly coordinating several such electrically activated muscles. This article begins with a review of the physiological and technological principles of electrical stimulation applied to the neuromuscular system. Next, the development and status of neuroprostheses for restoring upper extremity, lower extremity, bladder and bowel, and respiratory functions are highlighted. Finally, future directions and developments of emerging FES technology and control methods are presented.

PHYSIOLOGICAL AND TECHNOLOGICAL PRINCIPLES OF FES Electrical Activation of the Neuromuscular System Electrical pulses applied to nerves can elicit action potentials. The stimulating electrode creates a localized electric field that depolarizes the cell membranes of nearby neurons. If the depolarization reaches a critical threshold, an influx of sodium ions from the extracellular space to the intracellular space produces an action

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potential that propagates in both directions away from the site of stimulation. Action potentials that propagate proximally in the peripheral nerve axons will ultimately be annihilated at the cell body, and action potentials that propagate distally will be transmitted across the neuromuscular junction and cause muscle fibers to contract. In general, large-diameter axons (which innervate the larger motor units) are activated with less current than small axons because the wider spacing between nodes of Ranvier in large axons produces larger induced transmembrane voltage changes (1). The activation of large motor units before small motor units is known as reverse recruitment order and is the opposite of the physiological size principle, where small motor units are initially recruited, followed by larger motor units. FES applications for motor function operate under the fundamental principle that electrical stimulation generally activates nerve rather than muscle. This is because the threshold charge for directly eliciting muscle fiber action potentials is much greater than the threshold for producing action potentials in neurons (2), as shown in Figure 1. Thus, for FES to be effective, the lower motor neurons must be intact from the anterior horns of the spinal cord to the neuromuscular junctions in the muscles that are to be activated. Lower motor neuron damage prevents the application of FES in cases of polio, amyotrophic lateral sclerosis (ALS), and peripheral nerve injuries (e.g., brachial plexus). Additionally, the neuromuscular junction and muscle tissue must be healthy for electrical stimulation to be effective. This hampers the application of electrical stimulation in muscular dystrophies. Neuromuscular electrical stimulation may be used when the lower motor neurons are excitable and the neuromuscular junction and muscle are healthy, as is usually the case with spinal cord injury (SCI), stroke, head injuries, cerebral palsy, and multiple sclerosis. To date, most motor neuroprostheses have been targeted toward the SCI population.

Figure 1 Strength-duration curve for nerve and muscle tissue. Stimulus magnitude required to produce a constant muscle response in normal and pharmacologically denervated cat tibialis anterior. Modified after figure 20 in Reference 2.

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Electrical activation of neuromuscular tissue requires at least two electrodes to produce a current flow. The electrodes are typically arranged in a monopolar or bipolar configuration. With both configurations, one electrode, generally referred to as the active electrode, is placed near the peripheral nerve to be stimulated. In monopolar stimulation, the other electrode, known as the indifferent or return electrode, is placed in a remote area near less excitable tissue, such as tendon or fascia. Often the reference electrode has a larger surface area than the active electrode. In bipolar stimulation, the reference electrode is placed near the active electrode. Multichannel monopolar systems reduce the number of electrodes and leads required by using only one remote return electrode with several active electrodes placed near motor points or nerves targeted for excitation. In multichannel bipolar systems, each active electrode has its own return electrode, requiring more leads; however, bipolar stimulation may allow greater selectivity of activation because each electrode pair creates a more localized electric field (3). Stimulation is delivered as a waveform of electrical current pulses, which are characterized by three parameters: pulse frequency, amplitude, and duration. The strength of muscle contraction is controlled by manipulating those parameters. If the pulse frequency is too low, the muscle responds with a series of twitches. Above a certain stimulation frequency, known as the fusion frequency, the response becomes a smooth contraction. The cumulative effect of repeated stimuli within a brief period of time is known as temporal summation. Higher stimulus frequencies produce stronger muscle contractions up to a maximum, but also increase the rate of muscle fatigue. Thus, high stimulus frequencies are generally avoided. Typically, stimulus frequency rates of 12 to 15 Hz are the minimum required for summation of muscle twitches if the muscles have been conditioned to have relatively long-duration twitches. An exercise regimen of low-frequency muscle stimulation increases the contraction time and fatigue-resistance of muscle fibers (4, 5). The strength of a muscle contraction may also be increased by increasing the number of motor units activated, an effect known as spatial summation. This is achieved by increasing the stimulus pulse amplitude and/or pulse duration, which effectively increases the electric charge injected, producing a larger electric field and broader region of activation so that more axons and motor units are activated (6). In most neuroprostheses, the strength of muscle contraction is controlled by modulating the pulse amplitude or pulse duration, and the stimulus frequency is set constant and as low as possible to avoid fatiguing the muscle prematurely. Stimulus waveforms are generally either monophasic or biphasic in shape. A monophasic waveform consists of a repeating unidirectional (usually cathodic) pulse. Biphasic waveforms consist of a repeating current pulse that has a cathodic (negative) phase followed by an anodic (positive) phase. The first, or primary, phase elicits an action potential in nearby axons, and the secondary positive pulse balances the charge injection of the primary pulse. The purpose of the secondary pulse is to reverse the potentially damaging electrochemical processes that can occur at the electrode-tissue interface during the primary pulse, allowing neural

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stimulation without causing tissue damage (2). The use of charge-balanced waveforms is especially important when the stimulating electrode is implanted rather than placed on the surface of the skin. It is also important to use stimulus parameters that are appropriate for the dimensions and material composition of the implanted electrode being used so that the injected charge density per phase remains within established safe limits, thereby preventing electrode corrosion (2). Stimulators are designed to regulate either current or voltage. With voltageregulated stimulation, the stimulator output is a voltage, and therefore the magnitude of current delivered to the tissue is dependent on the impedance at the electrode interface (Ohm’s Law). With the use of surface electrodes, the impedance at the electrode-skin interface increases as the electrode dries or loses contact with the skin. As electrode impedance increases, the current delivered with a voltage-regulated stimulator decreases, minimizing the possibility of skin burns owing to high current densities. Thus, voltage-regulated stimulation is often used for surface stimulation applications. The motor response, however, is more variable with voltage-regulated stimulation because of impedance-dependent currents. With current-regulated stimulation, the current is directly controlled and is not affected by changes in the tissue load. Therefore, the quantity of charge delivered per stimulus pulse can be guaranteed. To ensure that the stimulus charge is maintained within safe levels, a current-regulated waveform is often used with implanted electrodes. The use of a current-regulated stimulator also increases the likelihood of obtaining repeatable muscle responses to stimulation.

Configurations of Neuroprosthetic Systems Stimulation may be delivered using surface, percutaneous, or implanted systems (Figure 2). Surface systems, sometimes referred to as transcutaneous systems, utilize electrodes that are placed on the skin and are connected with flexible leads to a stimulator that may be worn around the waist, the arm, or the leg. Usually, a sensor or switch that controls the stimulation is also connected to the stimulator. Surface electrodes are readily available in a variety of sizes from many manufacturers. The electrodes are placed on the skin over the nerves or over the “motor

Figure 2 Neuroprosthetic system configurations. S = stimulator, A = anode (reference electrode), C = cathode (active electrode), ECU = external control unit. Single-channel monopolar stimulation of one muscle near its motor point is shown for a surface, percutaneous, and implanted system.

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points” of muscles to be activated. The motor point is the site of stimulation that produces the strongest and most isolated contraction at the lowest level of stimulation. The advantages of surface systems are that they are noninvasive and relatively technologically simple. Therefore, these systems are easily applied in the clinic, easily reversible, and relatively inexpensive, making them especially well utilized in therapeutic applications. However, the repeated placement of the electrodes in the appropriate locations to get the desired response requires skill and patience. Also, it can be difficult to achieve isolated contractions or activate deep muscles. In sensate skin, the stimulation may generate painful sensations because of cutaneous pain receptor activation. Furthermore, the appearance of the system may draw unwanted attention, especially if there are many stimulus channels and leads, and the donning and doffing and managing of the external leads and components can become unacceptable. These disadvantages have motivated the design of implantable systems. Percutaneous systems make use of intramuscular electrodes that pass through the skin and are implanted into the muscles to be activated. Percutaneous electrodes can activate deep muscles, can provide isolated and repeatable muscle contractions, and are less likely to produce pain during stimulation because they bypass the sensory afferents in the skin. Percutaneous electrodes are generally formed from a multifilament lead within a single insulator that is wound into a helical configuration (7). An electrode is inserted through the skin and implanted in the muscle using a hypodermic needle. The electrode leads exit the skin and are connected to external stimulation equipment. A large surface electrode is used as the return electrode. The percutaneous interface on the skin is protected by placing a junction connector over the skin surface where the electrodes exit. The skin at the electrode site must be cleaned, dressed, properly inspected, and maintained to reduce the risk of complications (8). Percutaneous systems provide a minimally invasive technique for investigating the feasibility of restoring functional muscle contractions without having to prematurely subject research participants to implantable system surgery. Percutaneous systems have served as precursors to fully implanted systems (9) and have provided function in some individuals for periods of years (10). Various reports have indicated the longevity of percutaneous electrodes (8, 11, 12), and they are now being investigated in a life-sustaining application for respiration (13). Implanted neuroprosthetic systems are designed for long-term use. Unlike surface and percutaneous systems, the stimulator is implanted, eliminating the need for wiring outside of the body to an external stimulator. The implanted electrodes are connected by leads under the skin to the implanted stimulator. Thus, the electrodes can be made with larger and more durable leads because they do not pass through the skin. They are often connected to the stimulator using in-line connectors, which permit the surgical removal and replacement of individual electrodes if necessary. The circuitry of the stimulator is generally sealed in a titanium enclosure, which serves as the indifferent electrode. The stimulator is implanted in the chest or abdomen and receives power and command instructions through a

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radio-frequency (RF) telemetry link to an external control unit (ECU). The power demands of multichannel neuromuscular stimulation applications have made the use of implanted batteries impractical, as they would require replacement on the order of weeks, as compared with years for cardiac pacing. Advances in battery technology have made rechargeable implanted batteries with service lives greater than five years a feasible option for future neuroprosthetic systems. The RF link allows the device to be fully passive with no active battery, thereby eliminating the need for replacement of the implanted stimulator because of battery failure. The telemetry link requires no wires through the skin; rather, a circular coil (antenna) connected to the ECU is taped to the skin over the implanted stimulator. The ECU may be worn on the body or carried on a user’s wheelchair. If required, external transducers or switches for control may be connected to the ECU. The ECU supplies power to the entire system through its internal rechargeable batteries, receives signals from the transducers recording control information, and generates control signals that are transmitted to the implanted stimulator. The system is tailored to an individual by programming the ECU with stimulus and control parameters that are required for each individual patient. Implantable stimulators have the capability of using a variety of stimulation electrodes. These electrodes may be implanted on the muscle surface (epimysial electrode) (14), within the muscle (intramuscular electrode) (15), adjacent to a nerve (epineural electrode) (16), or around a nerve (helix or cuff electrode) (17, 18). Epimysial electrodes have proved to be durable in upper (19) and lower (20) extremity applications, and are especially useful for activating broad, superficial, or thin muscles. Intramuscular electrodes allow activation of deeper or smaller muscles, such as the intrinsic muscles of the hand. Nerve-based electrodes are used when it is difficult to access the target muscle directly or when more complete muscle recruitment can be obtained by stimulating the nerve. These technologies and principles of electrical activation of the neuromuscular system form the foundation for FES use in clinical applications.

CLINICAL APPLICATIONS Numerous neuroprostheses for a variety of applications have reached the clinical testing stage of development. Some have progressed to commercialization. Today, there are FDA-approved neuroprostheses for restoring hand function, ambulation, bladder and bowel control, and respiration. Some of these experimental and commercial neuroprostheses are described below.

Upper Extremity Function The objective of upper extremity neuroprostheses is to enable individuals with upper extremity paralysis to use their hands in activities of daily living (ADL). The first upper extremity neuroprostheses were developed in the 1960s (21, 22)

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using surface electrodes to open and close the hand. This pioneering work has led to the development and clinical testing of surface (23–27), percutaneous (28, 29), and implanted (30, 31) hand grasp systems. The primary target population for most of these neuroprosthetic systems has been individuals with SCI, although some systems provide therapeutic and functional benefits to additional populations, such as individuals with stroke and traumatic brain injury. Handmaster (NESS Ltd., Ra’anana, Israel) is the only surface system that is commercially available today. The system consists of an adjustable wrist-hand orthosis with five built-in stimulation electrodes for activating the finger and thumb muscles (23). The user initiates a preprogrammed opening/closing stimulation sequence by pushing a button on the system’s control unit. In a study of seven subjects with C5 or C6 tetraplegia, the system was used at home to practice three ADL for three weeks. At the end of the three weeks, all seven subjects used the system successfully to perform ADL that they were unable to perform without the system. Also, all had increased grip strength, finger motion, and Fugl-Meyer scores when using the system (32). Handmaster is FDA-approved for therapy and for providing hand function to individuals with C5 tetraplegia or hemiplegia caused by stroke. The system has recently become available in the United States through BioNESS Inc., Valencia, CA, a new company that brings together NESS, Ltd. with the BION technology of the A.E. Mann Foundation (see Future Directions and Developments, below). Bionic Glove is a surface system that has also undergone significant clinical testing. Developed at the University of Alberta, the system consists of a fingerless glove with a forearm sleeve that is worn over three or four self-adhesive electrodes previously placed on the hand and forearm (24). The stimulation is controlled with wrist movements, which are sensed by a displacement transducer that spans the wrist joint. Wrist extension beyond a certain angle triggers stimulation of grasp, and wrist flexion triggers hand opening, thus enhancing the tenodesis grasp used by individuals with lower cervical SCI. The stimulation is essentially on or off, with an automatic ramping up and down. Because voluntary wrist extension is required, the system is applicable to patients with C6 level tetraplegia and lower. An initial report of nine subjects and a clinical trial of 12 subjects both demonstrated an increase in the grasp force and a reduction in the time or difficulty in the performing standardized hand function tests with the Bionic Glove (24, 33). Half of the subjects in the second study continued to use the system at home after the study. The main reason subjects discontinued use was insufficient benefit. Reported difficulties with the system included donning and doffing the glove, achieving selective stimulation, and lack of sufficient wrist control for heavy objects. The Canadian company that was marketing the Bionic Glove is no longer active. FESMate (NEC Medical Systems, Tokyo, Japan) is a percutaneous system that is commercially available in Japan (34). It uses up to 30 percutaneous electrodes. Stimulus patterns for several hand grasps and upper extremity motions are based on templates of natural muscle activation previously recorded from able-bodied subjects, which are customized with user-specific stimulus thresholds and maximums

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(28). Several different command sources have been implemented, including head switches, voice, sip and puff, and shoulder motion. This system has been applied to individuals with cervical SCI (C4 to C6) and hemiplegia to produce hand, forearm, elbow, and shoulder function, but no formal assessment of outcomes is available. Freehand is an implanted system, developed at Case Western Reserve University (CWRU) and the Cleveland VA Medical Center (14, 35), to provide lateral and palmar grasp to persons with C5 or C6 tetraplegia. It consists of a stimulator/receiver implanted in the chest and eight epimysial or intramuscular electrodes implanted at the motor points of hand and forearm muscles. The external components include a radio-frequency-transmitting coil taped to the chest over the implant, a programmable external control unit, and a transducer for detecting contralateral shoulder motions. The movement of the shoulder proportionally controls the degree of hand opening and closing. The Freehand system received FDA approval in 1997, and has been implanted in more than 250 people at several centers worldwide (30, 36–39). Fifty-one individuals with C5 or C6 tetraplegia were enrolled in a multicenter clinical study of the safety and effectiveness of Freehand (30). The results showed that the neuroprosthesis increased the pinch force of every subject, and it enabled 98% of the participants to grasp and move more objects in a standardized grasp-release test. The system particularly helped with the heavier objects, but improvement in moving the lighter objects was also seen in weaker subjects. Freehand enabled every participant to perform at least one of the tested ADL tasks with greater independence, and 78% of the participants could perform three tasks with greater independence. Ninety-seven percent of 35 respondents said they would recommend the neuroprosthesis to others, and 91% stated that the neuroprosthesis improved their quality of life. Eighty-four percent of the participants reported regular device usage for functional activities, and an additional 8% used the device for exercise. The implanted electrodes and leads have proven to be safe, reliable, and durable. In an analysis of 238 electrodes, only three electrode-lead failures and one electrode infection occurred, and the stimulus levels required to initiate muscle contractions were stable over time (19). Despite the clinical successes and high patient acceptance, the manufacturer of Freehand recently withdrew from the SCI market and another manufacturer is currently being sought. A second-generation Freehand system has been developed by the same investigators that provides greater upper-limb function and incorporates implanted control methods, thereby eliminating the need for the external shoulder position sensor. Enhanced function is provided through additional stimulation channels, which are used to activate hand intrinsic muscles, triceps, or pronator quadratus. Two new approaches to implanted control have been developed. The first approach employs an implantable joint angle transducer (IJAT) designed to detect wrist movements (40). It consists of a magnet and an array of Hall effect sensors, which are implanted in the lunate carpal bone and radius. Stimulation is proportionally controlled by wrist position. The second approach is to extract control signals from myoelectric (or electromyographic, EMG) signals recorded from muscles that remain under

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voluntary control (41). Potential control muscles include those synergistic to the grasp movement, such as wrist extensors and, to a lesser extent, brachioradialis, as well as nonsynergists such as sternocleidomastoid or trapezius. Because the IJAT and myoelectric signal (MES) control strategies make use of signals derived from the ipsilateral side, they allow the neuroprosthesis to be implemented bilaterally, which is expected to provide significant additional function. New technology was developed to make this implantable control and enhanced function possible. A new implantable stimulator/telemeter (42) was developed with the capacity to activate 10 or 12 muscles and to telemeter control signals to an external control unit. Also, intramuscular electrodes were designed to stimulate small muscles in the hand (15). Finally, the IJAT and recording electrodes were made for detecting control signals. Two configurations of the stimulator/telemeter exist. The first version has 10 stimulation channels and is compatible with the IJAT. The second version has 12 stimulation channels and 2 channels for myoelectric recording (Figure 3). The 12-channel implant also contains circuitry for suppressing stimulus artifact in the recorded myoelectric signals. Eight tetraplegic subjects have received the advanced system. Four subjects have a 10-channel implant with an IJAT at the wrist, one has the 10-channel system but uses an external joystick for control (31), and three subjects have the 12-channel implant with MES control. One of the subjects with the 12-channel system has recently received an additional 12-channel implant for bilateral upper extremity

Figure 3 Schematic representation of the CWRU/VA 12-channel implanted upper extremity neuroprosthesis with myoelectric control capability.

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function. The follow-up period has been as long as 7 years for the 10-channel/IJAT configuration and 1 year for the 12-channel/MES configuration. Each subject has demonstrated the ability to grasp and release objects and use the system for functional purposes. The clinical results thus far indicate a high level of satisfaction with the advanced system, which provides greater functionality through the increased workspace and improved grasp posture. Follow-up assessments and more extended clinical trials are underway.


Lower Extremity Function Much research has been conducted on the use of electrical stimulation in the lower extremity, with various objectives, approaches, and populations being studied. One of the earliest objectives of FES was to prevent the foot from dragging (footdrop) during the swing phase of gait (43), an application that was mainly targeted to individuals with poststroke hemiplegia. Also in the early 1960s, the first report of the use of FES to enable a paraplegic to stand appeared (44). The first FES systems for restoration of walking in hemiplegia and paraplegia were developed in the late 1970s (45). Today, these three objectives—prevention of footdrop, restoration of standing and transfer, and restoration of walking—continue to be the focus of several FES research programs. Following Liberson’s first demonstration of an FES system for hemiplegic footdrop (43), several researchers produced and tested similar single- and multichannel footdrop systems in the 1960s and 1970s (see 46 and 47 for reviews). These systems used surface electrodes positioned on the tibialis anterior and on the common peroneal nerve where it crosses the head of the fibula. A heel switch, worn in the shoe of the paretic side, turned the stimulation on when the foot was lifted off the ground and off at heel strike. Implanted systems were also developed in the United States (48) and in Ljubljana, Slovenia (49, 50). These consisted of a stimulator/receiver implanted in the medial thigh region or calf with a cuff or epineural electrode that stimulated the peroneal nerve directly and an external heel switch for control. Some challenges encountered in these early surface and implanted systems included difficulties in properly placing the surface electrodes, false triggering of the stimulation, inadvertent elicitation of reflex spasms in the plantarflexor muscles, pain or discomfort from the stimulation, mechanical failure of the switch and other components, and difficulty in achieving balanced dorsiflexion with a single electrode. However, these early trials demonstrated the efficacy of FES for footdrop and provided incentive for the development of improved systems. Today, one FES footdrop system is commercially available and four are progressing toward commercialization. The Footlifter (Elmetec A/S, Arhus, Denmark) (51) is a single-channel surface system with a heel switch. It is commercially available in Europe and is used by more than 3500 Danish patients, according to the company Web site. Walkaide, developed at the University of Alberta, is a

FOOTDROP SYSTEMS

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self-contained surface system worn as a cuff below the knee, with a built-in tilt sensor that detects step intention (52). It is the only footdrop system with FDA approval, and has been recently licensed to Innovative Neurotronics, Inc., a new subsidiary of Hanger Orthopedic Group, Inc. The Odstock Footdrop Stimulator (ODFS), developed in Salisbury, U.K., is a single-channel footswitch-triggered surface stimulator (53). It is the only footdrop system that has been tested in a randomized controlled study, which demonstrated that the system increased walking speed and decreased walking effort. The effectiveness of the ODFS has also been studied with positive results in subjects with multiple sclerosis (54). Clinical studies of ODFS in the United States are being initiated. ActiGait (Neurodan A/S, Aalborg, Denmark) is an implanted system that uses a four-channel cuff around the common peroneal nerve (55). The stimulator is implanted on the lateral aspect of the upper thigh. The signal from a wireless external footswitch is RF-telemetered to an external controller worn at the waist. This system has recently received the CE mark, a symbol indicating that it complies with the regulatory requirements that allow it to be legally marketed in the countries within the European Free Trade Association and European Union. The Finetech Dropped Foot System (Finetech Medical Ltd., United Kingdom) is a relatively new implanted system that was developed at the University of Twente, Netherlands (56). It consists of a dual-channel stimulator implanted below the knee, two bipolar epineural electrodes implanted on the two branches of the common peroneal nerve to allow control of inversion and eversion, and an external footswitch. Initial reports of clinical testing indicated that the amount of eversion accompanying dorsiflexion could be adjusted (57) and that the system increased walking speed by 24% (58). A larger trial is underway to fully demonstrate the safety and efficacy of the Finetech Dropped Foot System, and plans are being made to test the system in SCI. Enabling persons with paraplegia to stand from a seated position and transfer to another surface is the objective of some lower extremity FES systems. The functional goals associated with standing include reaching for high objects, having face-to-face interactions with other people, and transferring between surfaces independently or with minimal assistance. The earliest demonstration of standing with FES was achieved by stimulating the quadriceps and glutei muscles for knee and hip extension (44). Later studies showed that standing could be achieved in some subjects with stimulation of the quadriceps alone (59, 60), but a more recent study suggests that adding stimulation of the hip extensors could speed up the rising phase, thereby reducing the overall work effort (61). A balance aid has been required in all FES standing systems. Presently, there are no commercial or FDA-approved systems for FES-aided standing; however, one implantable system has reached the multicenter clinical trial stage of development (62). The implantable standing neuroprosthesis (62) developed at the Cleveland VA Medical Center and CWRU uses the same 8-channel stimulator/receiver as the Freehand system (see Upper Extremity Function, above). Epimysial electrodes are

STANDING/TRANSFER SYSTEMS

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Figure 4 Schematic representation of the CWRA/VA 8-channel implanted standing system.

implanted bilaterally on the vastus lateralis, gluteus maximus, and semimembranosus (or alternatively, the posterior adductor magnus) for knee and hip extension, and intramuscular electrodes are implanted in the lumbar erector spinae for trunk support. The stimulator/receiver is implanted in the anterior lower abdomen, as shown in Figure 4 (63). A command ring worn around the index finger and operated by the thumb is used to send stand and sit command signals to an external control unit worn around the waist. Balance and assistance is provided by the upper limbs and a support device or assistant. In a pilot study of 12 subjects with C6 to T9 SCI, the strength of knee and hip extension produced with stimulation was adequate to achieve standing in all the subjects (62). The subjects generally maintained more than 85% of their body weight on their legs and could stand for periods ranging from 3 to 40 min. While standing, they were frequently able to release one hand from the balance aid and manipulate objects in the environment. Some were even able to use the system for limited swing-through walking with a walker. The system

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also reduced the effort and assistance required to transfer, especially from a lower surface to a higher one. All of the subjects expressed satisfaction with the device and indicated that they would go through the surgery and rehabilitation again to achieve the same results (63, 64). The clinical trial is currently ongoing at multiple centers in the United States. In a separate study at Shriners Hospital in Philadelphia, the 8-channel CWRU/VA stimulator was implanted in nine pediatric paraplegic subjects and was compared with long leg bracing during several functional upright mobility activities. Gluteus maximus, gluteus medius, posterior adductor magnus, and the femoral nerve were stimulated. The rectus femoris was released to prevent hip flexion. Ambulation was possible using a swing through pattern with crutches or a walker and an ankle foot orthosis. The subjects could don the FES system faster than the long leg braces, and could stand from a seated position and transfer into an inaccessible bathroom stall more quickly and independently with the FES system. Walking and stair climbing performance was similar with the two assistive devices. The FES system was preferred for the majority of activities tested (65). The ultimate goal of lower extremity FES systems is to enable individuals with complete paraplegia to walk again. Pioneering work by Kralj, Bajd, and others in Ljubljana, Slovenia, introduced the technique of eliciting a flexion withdrawal reflex of the hip, knee, and ankle by stimulating the peroneal nerve (45, 66). This action, elicited by a single electrode, produces lower extremity motion that can be substituted for the swing phase of gait. Stimulation of the quadriceps for knee extension during the stance phase of gait completes the gait cycle. This stimulation technique gave rise to the only FDA-approved FES system for ambulation available. ParastepTM (Sigmedics, Inc., Fairborn, Ohio) uses four to six channels of bilateral surface stimulation of the quadriceps, peroneal nerves (for reflex withdrawal), and, if necessary, the glutei to enable individuals with T4 to T12 paraplegia to walk with a walker (67). A microprocessor/stimulator unit is worn at the waist, and using a walker with controls built into the handles, individuals with paraplegia can stand and walk with reciprocal gait for limited distances. Use of the system has additional medical benefits, such as increased blood flow to the lower extremities, lowered heart rate at subpeak work intensities, increased muscle mass, reduced spasticity, and psychological benefits. Direct activation and control of individual muscles using either percutaneous or implantable systems is an alternative to eliciting spinal reflexes for ambulation. The percutaneous technique was most extensively developed by researchers at the Cleveland VA Medical Center and CWRU, who synthesized complex lower extremity muscles by activating up to 48 muscles under the control of a programmable microprocessor-based external stimulator (68). Stimulation patterns were selected and initiated by the user through a hand-operated switch. With training, the subjects progressed to using a rolling walker for support, and some could use axillary crutches and were able to climb stairs (69). The walking distance in well-conditioned subjects was consistently 300 m at an average speed of 0.5 m/s

AMBULATION SYSTEMS

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(68). Follow-up has been reported for over 17 years with two subjects who can use their systems for exercise, standing, and walking with stand-by assistance (10). One of these individuals performs exercise walking for five minutes five days per week at a walking rate of approximately 0.6 m/s. The percutaneous system demonstrated the ambulation that is achievable by activating individual muscles, and has allowed the investigators to determine the most useful combination of muscles to be activated in a system with an implanted receiver/stimulator and fully implanted electrodes (70). Several groups have developed implanted systems for ambulation, but few subjects have been studied by any of these groups. A 12-channel system for activation of L2-S2 motor roots was attempted but did not provide adequate selectivity of activation (71). A 22-channel system developed from cochlear implant technology (72) provided standing and limited swing-through gait in two subjects. A 16-channel system consisting of two 8-channel stimulator/receivers implanted bilaterally has provided one subject the ability to stand and walk for 25 m with stand-by assistance (73). This approach, developed in Cleveland, provides a clinical pathway for a subject with an 8-channel system for standing to progress to a walking system by implantation of a second device. Hybrid systems, which use both electrical stimulation and conventional external bracing (74–76), take advantage of the added stability provided by bracing and reduce the energy expenditure required for walking with FES alone. The bracing supports the user’s body weight, and the stimulation provides propulsion. The most widely tested hybrid system is the reciprocating gait orthosis (RGO) (77), which uses surface stimulation of hip extension on one side to cause the RGO mechanism to move the contralateral limb forward. Thus, walking is achieved by alternating stimulation of the hip extensors. Although hybrid RGOs are often successful in allowing users to stand and walk with less energy consumption, they are difficult to put on and are often cosmetically unacceptable, and therefore have low long-term usage rates. In summary, all of the FES systems for standing and walking require the use of a walker or standing frame for stability. Walking with FES requires considerable energy. The physical effort involved in standing and ambulation with FES is estimated to be four to six times greater than normal (67, 68). Few individuals are able to walk with any system without at least minimal assistance. Long and continued periods of muscle strength conditioning are required as well as strategies to avoid muscle fatigue. Because of these limitations, it is not anticipated that FES for walking in paraplegia will soon replace the wheelchair as the primary mobility aide; however, FES systems for standing, transferring, and short distance mobility and maneuvering around barriers are expected to be more widely available in the near future.

Bladder and Bowel Function Injury above the sacral levels of the spinal cord results in loss of bladder and bowel control. Numerous complications related to this loss of function include

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frequent urinary tract infections, renal deterioration, bladder or kidney stones, and autonomic dysreflexia. These complications threaten to compromise the health and quality of life of the individual, and can lead to major long-term, and even deadly, consequences. The functional goal of a bladder neuroprosthesis is to produce effective micturition (bladder voiding) and continence, and also improve bowel function. Micturition and continence are normally performed by the coordinated action of the bladder (detrusor muscle) and the urethral sphincter, two muscles that are controlled by neural circuits in the brain and lumbrosacral spinal cord. Suprasacral lesions generally result in detrusor-sphincter dyssynergia (detrusor and urethral sphincter contract simultaneously rather than reciprocally) and neurogenic detrusor overactivity (NDO), which is characterized by involuntary detrusor contractions during the filling phase. These effects result in elevated bladder pressure, which is the primary risk factor for renal deterioration. Thus, reduction of bladder pressure is also an important objective. The use of electrical stimulation for restoring bladder control has been most advanced by the work of Giles Brindley (78) in the United Kingdom. The FinetechBrindley Bladder System (Finetech Medical Ltd., United Kingdom) is an implanted FES system that enables micturition by inducing a detrusor contraction through stimulation of the sacral spinal nerve roots. Two pairs of tripolar electrodes (active contact flanked on each side with a return contact) are implanted bilaterally on the sacral spinal nerve roots either intradurally on the anterior (motor) roots in the cauda equina via a lower lumbar laminectomy (79), or extradurally on the mixed sacral nerves in the sacral canal via a laminectomy of S1–S3 (80). The advantage of the intradural approach is that it attempts to only activate efferent (motor) fibers in order to minimize activation of reflexes through the posterior sacral roots (Figure 5).

Figure 5 Innervation of bladder and external sphincter from sacral spinal nerves. Modified after figure 1 in Reference 90.

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However, the extradural approach is reported to carry less risk of trauma to the nerves or cerebrospinal fluid leakage. The electrode leads are tunneled to a receiver/stimulator, which is placed in the anterior abdominal wall through a separate incision. Bilateral posterior rhizotomies of the S2–S4 spinal nerves are usually performed to eliminate involuntary detrusor contractions (associated with NDO) and thereby provide continence. The benefits of posterior rhizotomy include abolition of reflex incontinence, increased bladder capacity and compliance, prevention of autonomic dysreflexia triggered from the bladder or bowel, and protection of the kidneys from uteric reflux and hydronephrosis (81). However, posterior rhizotomy also abolishes other potentially useful sacral reflexes, such as reflex erection, ejaculation, defecation, and sacral sensation if present. The implant is powered and controlled by an external control unit with a transmission antenna. The user selects the program for bladder or bowel control and then turns the device on to deliver the programmed pattern of stimulation to the sacral nerves. Normally, during voiding the sphincter relaxes when the bladder contracts, but stimulation of the sacral roots results in contraction of both the detrusor and urethral sphincter. Coactivation occurs because the sacral roots contain both the small-diameter preganglionic parasympathetic axons innervating the bladder via the pelvic nerve and the large-diameter somatic motor axons innervating the external urethral sphincter. Because large fibers have a lower threshold for excitation than smaller fibers, it is difficult to produce contraction of the detrusor without contraction of the external sphincter. Nevertheless, micturition can be produced by intermittent stimulation, a technique that takes advantage of the fact that the relaxation time of the smooth detrusor muscle is longer than that of the striated external urethral sphincter muscle. Intermittent stimulation (3 to 6 s on, 6 to 9 s off) leads to sustained contraction of the bladder and relaxation of the sphincter between stimulus periods. Thus, urine flows during the intervals between stimulus periods and the bladder is emptied in spurts. The system has been implanted in more than 2500 patients worldwide (82). The majority of the first 500 patients had SCI. However, patients with other neurological disorders, including multiple sclerosis, spinal cord tumors, transverse myelitis, cerebral palsy, and meningomyelocele have also received the implant (83). In the United States, the system is known as Vocare and has been approved by the FDA for individuals with SCI. A multicenter study has reported that more than 85% of 184 implant recipients use the system as the primary means of bladder emptying (84). Residual volume in the bladder following system use was less than 60 mL in 95% of the users and less than 30 mL in 89%. A substantial decrease in symptomatic urinary tract infections following use of the implant has been reported in several studies (81, 84–86). Continence is reported in more than 85% of patients (83, 84, 86, 87), largely because of increased bladder compliance following the posterior rhizotomy (88, 89). Most users become free of catheters and urine collection bags and can discontinue anticholinergic medication, which in turn reduces constipation and other side effects such as dry mouth and drowsiness (81, 90). Satisfaction with the system has been reported to be high (81), and the hardware has been reliable (91).

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Bowel evacuation and penile erection are secondary uses of the FinetechBrindley/Vocare system. Regular stimulation of the sacral parasympathetic nerves contributes to transport of stool through the distal colon into the rectum (92). Most users report a reduction in constipation and reduced need for laxatives and stool softeners (92, 93). Some users are able to defecate by a pattern of intermittent stimulation similar to that used for micturition but with longer intervals between bursts of stimulation to allow passage of stool (93). This results in a significant reduction in time that is spent in bowel evacuation (81, 93). Penile erection has been reported in 60% to 87% of men with intradural electrodes implanted on the anterior sacral roots (83, 86, 87). In a smaller group of participants with extradural sacral root stimulation, penile erection by stimulation was achieved in only approximately 10% (90). Methods to prevent coactivation of the bladder and external urethral sphincter, and thereby achieve a more physiological voiding pattern, are being investigated (94). For example, selective stimulation of the small fibers innervating the bladder may be possible by arresting action potentials in the large fibers innervating the sphincter (95) or by elevating the activation threshold of the large fibers above that of the small fibers (96). Researchers are also exploring alternatives to posterior rhizotomy for reducing NDO and providing continence. One approach is to create a neural block that mimics the function of the rhizotomy (97). Another approach is to induce inhibitory reflexes through the natural neurological pathways, a technique known as neuromodulation, which has shown some benefit in able-bodied subjects with urge incontinence (98). A recent study implemented the Finetech-Brindley/Vocare system without posterior rhizotomy but with stimulation of the posterior sacral afferents (to suppress bladder activity) in addition to the anterior efferents (to induce bladder contraction) (99). With this system, neuromodulation increased bladder capacity, but hyper-reflexia of the external urethral sphincter persisted and prevented complete emptying in some cases.

Respiratory Function Individuals with high cervical SCI or central alveolar hypoventilation (CAH) lose the ability to breathe because central neural connections to the diaphragm have been disrupted or because central respiratory centers are impaired. These individuals typically become dependent on a mechanical respirator, which sustains life by continuously forcing air into and out of the lungs through a tracheostomy at the base of the neck. Unfortunately, mechanical respiration is associated with substantial morbidity, mortality, inconvenience, physical discomfort, fear of disconnection, difficulty with speech, impaired sense of smell, and encumbered mobility (100). The purpose of a respiratory neuroprosthesis is to restore breathing by rhythmically activating the diaphragm, and thereby eliminate the need for a mechanical respirator. Electrical stimulation can be used to activate the diaphragm through the phrenic nerve. This technique, known as phrenic nerve pacing, was introduced in the 1960s

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by Glenn and colleagues at Yale University (101). Bilateral synchronous stimulation of the phrenic nerves causes contraction and descent of each hemi-diaphragm, which subsequently causes a fall in intrathoracic pressure and inspiration. Cessation of stimulation results in relaxation of the diaphragm, an increase in intrathoracic pressure, and exhalation. The stimulation cycle is repeated 8 to 14 times per minute to produce a normal breathing pattern. The user may adjust the number of breaths per minute and the duration of each breath. Phrenic pacing systems have allowed users to decrease or even discontinue the use of mechanical respirators and have enabled more normal breathing. The technique has been applied to more than 1200 patients worldwide and has become a clinically accepted intervention in selected individuals (100). Commercially available phrenic pacing systems consist of electrodes implanted bilaterally on both phrenic nerves in the cervical or thoracic region and receiver/ stimulators implanted bilaterally in an accessible area over the anterior thorax (Figure 6). The stimulators receive power and commands from an external control unit through antennae taped directly over each receiver/stimulator. Approximately two weeks after device implantation, diaphragm conditioning is initiated. The time required for conditioning the diaphragm to provide full-time ventilation may range from 3 to 16 months (102). Presently, there are two FES systems commercially available for diaphragm pacing, the Avery Mark IV and the Atrostim system. The differences between these systems are mainly in the type of electrodes and stimulation strategies used. The Avery Mark IV (Avery Laboratories, Commack, NY), developed by Glenn et al. (101, 103), uses either monopolar or bipolar nerve cuff electrodes. Usually, a thoracotomy is made on the anterior chest wall to expose the phrenic nerve

Figure 6

Bilateral phrenic nerve pacing system.

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(103, 104). Alternatively, the stimulator and electrode may be implanted without a thoracotomy through an incision in the neck, but with this approach submaximal diaphragm activation may result because additional accessory branches join the phrenic nerve in the thorax in most individuals. The Avery system is FDA approved and is the most widely used phrenic pacing system. The Atrostim system (Atrotech Ltd, Tampere, Finland), developed at Tampere University of Technology in Finland, uses quadripolar electrodes with four contacts spaced evenly around the phrenic nerve (105). Each of the four contacts in turn serves as the cathode, and a contact on the opposite side of the nerve serves as the anode. Multipole sequential stimulation is intended to reduce fatigue by activating motor units only one fourth of the activation time that occurs with conventional monopolar stimulation. Atrostim is commercially available in Europe and is approved for investigational use by the FDA under the Investigational Device Exemption in the United States. A third system, developed in Austria, and which had been marketed for a time as MedImplant (MedImplant Biotechnisches Labor, Vienna, Austria), used a technique called carousel stimulation (16, 106). Four electrodes were sutured to the epineurium of each phrenic nerve from a single 8-channel receiver/stimulator. Only one of the four electrodes was used to stimulate each nerve during any given inspiration; therefore, the various nerve compartments were stimulated in sequence during subsequent inspirations. Currently, this device is not commercially available (107). With any phrenic pacing system, the diaphragm must be gradually reconditioned after surgery to improve its strength and endurance (108). Conditioning is initiated approximately two weeks after surgery. Phrenic nerve pacing is initially provided 10 to 15 min every hour and is gradually increased over a conditioning phase that may take 10 to 12 weeks or longer, although it is possible to achieve full-time pacing in some patients within 5 weeks (100). Low-frequency stimulation is used during the conditioning phase to promote conversion of fast-twitch fibers to slowtwitch fatigue-resistant fibers. After pacing is achieved throughout the waking hours, pacing is provided during sleep and gradually increased until the pacer is used full time. Early studies reported high incidences of failure to achieve successful ventilatory support (109–111). These failures were mainly due to technical malfunction of the device components or to insufficient phrenic nerve innervation (a patient selection error). Additional complications encountered include diaphragm fatigue, increases in airway resistance caused by the accumulation of airway secretions (requires suctioning), infection, injury to the phrenic nerve, and upper airway obstruction after tracheostomy closure (100). There are only a few studies that have evaluated recent success and complication rates. In one long-term follow-up study of 12 quadriplegic patients, 50% continued to use the Avery system full time (mean 13.7 years), 1 used it part time, 3 stopped using it, and 2 were deceased (one had used the system full time, and one had stopped using it) (102). Those who stopped using the pacer did so because of inadequate social or financial support or medical

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problems associated with the initial injury. All patients demonstrated normal tidal volumes while pacing full time, no patient lost the ability to activate the phrenic nerve, and threshold and maximal currents did not increase over time. In an international study of 64 patients using the Atrostim system, 94% of the 35 pediatric patients and 86% of the 29 adult patients eventually achieved complication-free successful pacing (112). Thirty-four percent of all subjects paced full time, 38% paced only while awake, 14% paced only while asleep, and 2% stopped pacing. The incidences of electrode and stimulator failure were 3.1% and 5.9%, respectively, and the incidences of infection and nerve trauma were 2.9% and 3.8%, respectively. Many individuals with ventilator-dependent tetraplegia are not eligible for phrenic nerve pacing because of complete or partial phrenic nerve injury. For patients with only a single functional phrenic nerve, it may be possible to achieve respiration by activating the inspiratory intercostal muscles in addition to the phrenic nerve (113). In a study of four patients, upper thoracic epidural spinal cord stimulation of the intercostal muscles in combination with phrenic nerve stimulation produced inspiratory volumes equal to that typically achieved with bilateral phrenic nerve pacing (114). These patients were able to achieve substantial time free of mechanical ventilatory support, and all four reported a level of comfort very near normal breathing. Recently, an alternative to direct stimulation of the phrenic nerve has been developed that uses a minimally invasive laparoscopic procedure to position intramuscular electrodes bilaterally near the motor point of the diaphragm (13, 115). Percutaneous electrodes are used with an external stimulator, but the intent is to fully implant the system by internalizing the stimulator. Fourteen subjects have been implanted to date: two are recently implanted, two are in the conditioning phase and are able to achieve adequate tidal volume, and ten have conditioned diaphragms. Nine of the ten subjects with conditioned diaphragms are using the system for extended periods (12 to 24 h per day); one subject was identified as a selection error because extensive denervation of the diaphragm did not allow sufficient ventilatory support. If confirmed in additional patients, diaphragm pacing with intramuscular electrodes via laparoscopic surgery is expected to provide a less invasive and less costly alternative to conventional phrenic nerve pacing.

FUTURE DIRECTIONS AND DEVELOPMENTS Introducing new technology and methodology into the clinic requires a translation from bench research to clinical testing. A number of FES-related advances are being investigated, and many are in or close to clinical testing. This summary can provide only a glimpse of some of these developments, which will expand the capability of FES systems to provide greater function to more people through a wider range of applications.

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Emerging Technology New system configurations and new electrodes for stimulating and recording neural tissue are two major areas of FES technology development. Future systems will be designed around a platform technology, where numerous neuromuscular deficits will be treated using the same basic neuroprosthetic system or a subset of the possible components of an entire system. New electrodes and electrode arrays for interfacing directly with peripheral nerve, the spinal cord, and the cortex are being designed to provide more complete motor recruitment with fewer electrodes, exploit natural neural circuitry, and allow more natural control of neuroprostheses. Surgically implanted stimulator systems powered by an inductive link across the skin and using muscle- or nerve-based electrodes with subcutaneous leads has been the system configuration for many successful neuroprostheses. The implanted neuroprostheses reviewed in this article, as well as several commercially available auditory neuroprostheses, pain relief stimulators, and deep brain stimulation systems all use this approach. In motor applications, precise electrode placement is possible because of the open surgical procedure, and function-enhancing reconstructive procedures (e.g., tendon transfers) can be performed in the same surgery. Years of experience with this approach have established proven techniques for system design and fabrication, known and accepted polymers and metals for packaging and electrodes, and a clear regulatory pathway. Most of these neuroprosthetic systems have been designed to perform essentially only one function in one area of the body. Despite the clinical success of this system configuration, the approach has limited expandability to multiple applications. New system configurations should be suitable for a wide range of applications, expandable to provide more than one function, and compatible with new technological advances as they emerge. This is particularly important for individuals with multiple system dysfunctions (e.g., SCI, stroke) who are interested in using FES to address multiple impairments. Also, new system configurations should eliminate the need for any external components. Two new approaches that are being developed to overcome the limitations of current system configurations are microstimulators (called BIONs) and a networked neuroprosthetic system. The BION approach, which is being developed by the A.E. Mann Foundation and the Mann Institute at the University of Southern California, uses small cylindrical (2 mm outer diameter × 16 mm long) injectable single-channel units (implanted through a 12-gauge trochar) with electrodes at both ends to provide the local stimulation needed to activate nearby nerves (116). BIONs receive power and control information from an external transmitting coil that must encircle each BION. One such transmitting coil can power and control up to 256 BIONs. The use of BIONs eliminates the need for implanted lead wires and reduces the extent of surgery required to implant the system. BION placement cannot be directly visualized, and a trochar introduction approach is used, similar to that developed

SYSTEM CONFIGURATIONS

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by CWRU/VA for implanting percutaneous stimulating electrodes reported above. The use of peripheral nerve-based electrodes is precluded with this approach, as are augmentative surgical procedures unless additional surgery is performed. Studies have begun on the use of BIONs for poststroke shoulder subluxation, chronic osteoarthritis of the knee, urinary urge incontinence, and footdrop. A networked neuroprosthesis is an alternative approach that is being developed at CWRU. The proposed system has the advantage of being fully implantable, with no external components, expandable to multiple applications, and upgradeable to new advances by adding components (e.g., stimulator and sensor modules) to a network. The design calls for a subcutaneous network cable and modules attached to the cable at regions of the body where they are required. The network cable will attach to an implanted central processor unit with a rechargeable power source and programmability through a remote link. For complex disabilities such as SCI, one basic system with peripheral modules could provide the functions needed for multiple organ systems, eliminating the need for multiple devices that are specially designed and difficult to integrate or upgrade. The implantable and external components for this networked neuroprosthesis are in the final stages of design. The implantable techniques that have been used clinically for neural excitation to date have included muscle-based electrodes and first-generation nerve cuff or epineural electrodes. Muscle-based electrodes will continue to be used because of their high level of specificity, but new electrode designs have centered on direct nerve stimulation. The appeal of nerve stimulation is that it may provide more complete muscle recruitment and multiple muscles may be recruited by the same electrode, possibly reducing the number of electrode leads, surgery time, and the number of incisions. New nerve cuff electrodes have been designed to reshape nerve geometry to allow more selective access to particular nerve fascicles for both recording and stimulation (117). Alternatively, methods for “steering” current to different locations within a nerve to selectively activate different muscles have been developed (118). Another option is an electrode cuff with blunt radial projections that slowly penetrate into the interfascicular space, allowing selective stimulation of different nerve fascicles (119). In addition to selective activation, these nerve electrode designs may allow selective recording of neural information that can be used to provide information for closed-loop feedback control or conscious level sensory feedback (18). Another stimulation technique that is being investigated employs small electrode arrays that are placed in the gray matter of the spinal cord to activate the motor unit pools of individual muscle groups (120, 121). These electrodes have been demonstrated in animal models to activate a large percentage of the motor units of individual muscles, thus potentially allowing further centralization of the stimulation events. This approach may make it possible to exploit the natural neural circuitry in the spinal cord to coordinate muscle activity.

STIMULATING AND RECORDING ELECTRODES

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Perhaps the most dramatic potential advancement in neural recording comes from the ongoing research to create a cortical interface for communication, known as a brain-computer interface. Several different approaches are being investigated, including those that use field potentials, such as surface electrodes on the scalp (122), electrodes embedded in the skull (123), flat grids of electrodes implanted subdurally on the surface of the cortex (124), and those that acquire the firing patterns of many individual neurons, such as hair-thin intracortical microelectrode arrays (125, 126) and the larger glass cone electrodes (127). These emerging technologies will be used to develop more natural control strategies for neuroprosthetic systems.

Emerging Control Techniques The control methods that have been used most frequently in upper and lower extremity neuroprostheses have relied on external joint angle sensors, accelerometers, or switches. The development and integration of implantable sensors for control will continue to be an active area of research, as will the development of control algorithms that enable intuitive operation of the neuroprosthesis with little conscious attention. The use of MES for control of a neuroprosthesis was proposed by Vodovnik in the earliest days of FES (22), but has only recently been fully integrated into an implanted system (see Upper Extremity Function, above). Future research in MES control will focus on identifying appropriate control muscles and strategies for additional applications, determining how to optimally process and extract information from the MES, and developing and integrating control algorithms that make use of automated pattern recognition techniques (e.g., artificial neural networks). These techniques may result in a reduction of misclassifications that lead to inadvertent commands and an increase in the number of distinguishable patterns that could be used for controlling more device functions. Cortical control is the concept of using field potentials or the firing activity of multiple individual cortical neurons to provide the command input to the neuroprosthesis. Researchers have demonstrated the feasibility of tetraplegic patients controlling FES-mediated hand opening and closing with signals recorded from electrodes placed on the scalp (128, 129). A patient with locked-in syndrome, a rare neurological disorder characterized by paralysis of voluntary muscles in nearly all parts of the body, can operate a cursor-controlled speech and typing device via control signals recorded with penetrating cortical electrodes (127). In monkeys, several investigators have demonstrated the ability to chronically record control signals and translate those into cursor movement and movement of a robotic arm in the absence of volitional movement of the limb that originally was associated with firing of the cortical cells (130–132). Donoghue and colleagues have recently reported on a tetraplegic subject controlling a cursor using a penetrating electrode array (133). Translation algorithms for decoding the neural signals have been

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developed (134), and the possibility of a cortical interface for control in the human subject is approaching reality. Another potential source of command signal is the electroneurogram (ENG) (135, 136). Investigators at Aalborg University use an implantable amplifier/ telemeter (137) with a tripolar nerve cuff electrode to record, amplify, and telemeter ENG through the skin to an external control unit. These investigators have implemented in a stroke patient an implanted footdrop system that uses ENG recordings from the sural nerve to detect heel strike and foot liftoff in place of an external heel switch (136, 138). Closed-loop control and sensory feedback may ultimately be incorporated into future neuroprostheses. Closed-loop control is a means of improving functional output by automatically adjusting the stimulation in the presence of perturbations or fatigue. The neuroprostheses reviewed in this article all operate in an open-loop fashion. Closed-loop systems require a source of information about the system that is fed back to the controller for system regulation. Small, implantable sensors for force or position feedback are not yet available. However, ENGs from intact sensory (afferent) fibers (135, 136) have been used as feedback signals for system regulation. Haugland et al. (139) found that the signal recorded from the palmar digital nerve innervating the radial aspect of the index finger contained information that could be used under restricted laboratory conditions to detect the occurrence of slips and to adjust electrical stimulation of the thumb muscles to stop the slip (140, 141). Sensory feedback is the creation of a sensory perception that correlates to the FES-mediated action or apprises the user of the current neuroprosthesis state or mode. This is likely to be most beneficial for individuals lacking sensation in the area in which the FES intervention is applied. Also, as more control strategies rely on biopotentials as control signals, the need for feedback regarding the control signal in relation to decision boundaries may be needed to enhance controllability. Sensory feedback would augment visual information and presumably would reduce the user’s conscious effort that is directed toward controlling the neuroprosthesis. Electrotactile, vibrotactile, and auditory feedback may be possible. The limitation, as with closed-loop control, is the lack of appropriate sensors, which are required to generate the information to be delivered to the user. Additionally, the optimal means of delivery has not been developed. A final emerging technique with enormous potential to enhance neuroprosthesis function and control is the idea of an electrical nerve conduction block. The use of electrical current to arrest the propagation of action potentials down nerves in a way that is safe and quickly reversible could be applied to suppress undesired sensation, such as pain, or deleterious motor activity, such as muscle hypertonicity or spasticity. Unwanted or uncoordinated generation of nerve impulses is a major problem in many disabling conditions such as peripheral pain, SCI, stroke, cerebral palsy, and multiple sclerosis. If these impulses can be intercepted along the peripheral nerves, then the disabling condition can be reduced or eliminated. Many previous studies have shown that high-frequency alternating current waveforms produce a nerve block under isolated conditions in frog, rat, cat, and dog models.

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Renewed studies are underway to elucidate the mechanism for high-frequency block and to determine safe and effective parameters for producing conduction block in mammals and humans (97). The capability of using electrical currents to inhibit as well as activate nerve and muscle would significantly increase the potential benefits available with FES technology.


CONCLUSION For more than 40 years, electrical stimulation has been used to restore neuromuscular function to people with paralysis. The principles of safe and reliable activation of neural tissue and the methods of generating stable and controllable muscle contractions have been established. Electrodes, stimulators, transducers, and sensors have been developed and integrated into neuroprosthetic systems that have benefited individuals with spinal cord injury and stroke. Clinical success of several FES interventions has been demonstrated, but commercial success has proven to be more difficult to achieve. Expanding the indications both within the spinal cord injury and stroke populations, and beyond those populations to other disability groups, will increase the number of people benefited as well as the potential market size. Increasing the awareness of FES technology and its benefits among rehabilitation practitioners and involving them in the development and clinical testing of neuroprostheses are important components in increasing the number of FES users and in penetrating the market. Costs can be decreased by developing systems that can be more easily manufactured and mass produced. Technological advancements will increase the benefit of neuroprostheses, making recipients more functional and independent. ACKNOWLEDGMENTS This work was supported in part by grants from the Department of Veterans Affairs Rehabilitation Research and Development Service, the National Institute for Neurological Diseases and Stroke, the Food and Drug Administration, and the National Institutes of Health for the General Clinical Research Center at MetroHealth Medical Center. The Annual Review of Biomedical Engineering is online at http://bioeng.annualreviews.org LITERATURE CITED 1. McNeal DR. 1976. Analysis of a model for excitation of myelinated nerve. IEEE Trans. Biomed. Eng. 23:329–37 2. Mortimer JT. 1981. Motor prostheses. In Handbook of Physiology—The Nervous

System II, ed. JM Brookshart, VB Mountcastle, pp. 155–87. Bethesda, MD: Am. Physiol. Soc. 3. Grandjean PA, Mortimer JT. 1986. Recruitment properties of monopolar

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Annual Reviews

AR248-FM

Annual Review of Biomedical Engineering Volume 7, 2005


CONTENTS FRONTISPIECE, Werner Goldsmith WERNER GOLDSMITH: LIFE AND WORK (1924–2003), Stanley A. Berger, Albert I. King, and Jack L. Lewis

DNA MECHANICS, Craig J. Benham and Steven P. Mielke QUANTUM DOTS AS CELLULAR PROBES, A. Paul Alivisatos, Weiwei Gu, and Carolyn Larabell

BLOOD-ON-A-CHIP, Mehmet Toner and Daniel Irimia BIOCHEMISTRY AND BIOMECHANICS OF CELL MOTILITY, Song Li, Jun-Lin Guan, and Shu Chien

xii 1 21 55 77 105

MOLECULAR MECHANICS AND DYNAMICS OF LEUKOCYTE RECRUITMENT DURING INFLAMMATION, Scott I. Simon and Chad E. Green

151

DETERMINISTIC AND STOCHASTIC ELEMENTS OF AXONAL GUIDANCE, Susan Maskery and Troy Shinbrot

187

STRUCTURE AND MECHANICS OF HEALING MYOCARDIAL INFARCTS, Jeffrey W. Holmes, Thomas K. Borg, and James W. Covell

223

INSTRUMENTATION ASPECTS OF ANIMAL PET, Yuan-Chuan Tai and Richard Laforest

255

IN VIVO MAGNETIC RESONANCE SPECTROSCOPY IN CANCER, Robert J. Gillies and David L. Morse

FUNCTIONAL ELECTRICAL STIMULATION FOR NEUROMUSCULAR APPLICATIONS, P. Hunter Peckham and Jayme S. Knutson RETINAL PROSTHESIS, James D. Weiland, Wentai Liu, and Mark S. Humayun

287 327 361

INDEXES Subject Index Cumulative Index of Contributing Authors, Volumes 1–7 Cumulative Index of Chapter Titles, Volumes 1–7

403 413 416

ERRATA An online log of corrections to Annual Review of Biomedical Engineering chapters may be found at http://bioeng.annualreviews.org/ v