Restoring function after spinal cord injury

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New functional electrical stimulation approaches to standing and walking

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IOP PUBLISHING

JOURNAL OF NEURAL ENGINEERING

doi:10.1088/1741-2560/4/3/S05

J. Neural Eng. 4 (2007) S181–S197

New functional electrical stimulation approaches to standing and walking Vivian K Mushahwar1, Patrick L Jacobs2, Richard A Normann3, Ronald J Triolo4 and Naomi Kleitman5 1 Department of Cell Biology and Center for Neuroscience, University of Alberta, Edmonton, AB, Canada 2 Department of Exercise Science and Health Promotion, Florida Atlantic University, Davie, FL, USA 3 Department of Bioengineering, University of Utah, Salt Lake City, UT, USA 4 Departments of Orthopaedics and Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA 5 Division of Extramural Research, National Institutes of Health/National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA

E-mail: [email protected]

Received 20 February 2007 Accepted for publication 19 June 2007 Published 22 August 2007 Online at stacks.iop.org/JNE/4/S181 Abstract Spinal cord injury (SCI) is a devastating neurological trauma that is prevalent predominantly in young individuals. Several interventions in the areas of neuroregeneration, pharmacology and rehabilitation engineering/neuroscience are currently under investigation for restoring function after SCI. In this paper, we focus on the use of neuroprosthetic devices for restoring standing and ambulation as well as improving general health and wellness after SCI. Four neuroprosthetic approaches are discussed along with their demonstrated advantages and their future needs for improved clinical applicability. We first introduce surface functional electrical stimulation (FES) devices for restoring ambulation and highlight the importance of these devices for facilitating exercise activities and systemic physiological activation. Implanted muscle-based FES devices for restoring standing and walking that are currently undergoing clinical trials are then presented. The use of implanted peripheral nerve intraneural arrays of multi-site microelectrodes for providing fine and graded control of force during sit-to-stand maneuvers is subsequently demonstrated. Finally, intraspinal microstimulation (ISMS) of the lumbosacral spinal cord for restoring standing and walking is introduced and its results to date are presented. We conclude with a general discussion of the common needs of the neuroprosthetic devices presented in this paper and the improvements that may be incorporated in the future to advance their clinical utility and user satisfaction. (Some figures in this article are in colour only in the electronic version)

Introduction Restoring standing and walking after paralyzing injuries or disease is a central goal for many neuroscience researchers, clinicians, rehabilitation specialists and biomedical and neural engineers. Regeneration scientists strive to develop therapeutics that would induce locomotor recovery through the reestablishment of neuronal connections damaged by spinal cord injury (SCI). Neuroprosthetic specialists develop functional electrical stimulation (FES) approaches for 1741-2560/07/030181+17$30.00

reanimating paralyzed limbs after SCI (Stein and Mushahwar 2005). To date, the latter have led the way in translating new technological advancements to human testing. A variety of systems have been tested over the years, including braces, surface electrodes and implanted devices (for review see Peckham and Knutson (2005)). New generations of FES systems for standing and walking are currently under development or in the early stages of testing, as will be described in this paper. Ultimately, hybrid systems including

© 2007 IOP Publishing Ltd Printed in the UK

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combinations of regenerative, pharmacological, rehabilitative and FES strategies are likely to emerge. Functional electrical stimulation utilizes electrical current to restore functions lost to injury or disease of the nervous system. Such stimulating systems may also provide therapeutic physiological benefits to the users through the activation of paralyzed muscles for exercise as well as the performance of activities of daily living (ADLs). In FES, restoration of voluntary movement is elicited by electrical activation of lower motoneurons through stimulation of axons along peripheral nerves or within the spinal cord itself. Such applications require intact lower motoneurons and neuromuscular connections to be effective, making paralysis due to SCI, stroke and some brain injuries attractive starting points for testing new FES systems. The development and commercialization of FES neuroprotheses for these applications has recently been reviewed (Peckham and Knutson 2005). The present discussion will address some of these walking and standing systems, as well as evolving new technologies, with a focus on the development of novel approaches to restoration of function through stimulation of spinal and peripheral motor systems. As new strategies are conceived and developed, it is important to stay in close touch with the users and potential users of such technologies to understand their desires and expectations for FES systems. Acceptance by users is an obvious but often elusive goal. In fact, standing and walking are not the first priorities for individuals with SCI when compared to other functions such as bladder control, breathing, hand and arm function and sexual function (Anderson 2004). A viable and efficient alternative exists (the wheelchair), and the hurdles to the successful use of walking systems are great. Nonetheless, the promise of the independent use of one’s own legs to stand and reach objects, dance with a partner, walk easily up the stairs or even over a curb are great incentives that, for some individuals with SCI, justify the long hours of training and practice involved with the use of even the least invasive FES systems. Others are prepared to embrace implanted technologies, which possess the added advantages of not having to don and doff a system before and after use, and being more consistent and esthetically desirable than braces or external wires. Matters of major concern regarding FES systems for standing and walking include the overall amount of the return of function (e.g., stability of standing, walking speed and distance, resistance to fatigue and reliability), restoration of muscle tone and physiological conditioning and safety of the devices. The appearance of the system is important to users, especially if it is to be used in ADLs, and implanted devices are often preferred. However, safety concerns about implanted systems extend beyond reliable use, to questions of damage caused by surgery and electrode implantation to nerves or muscles or to those spinal or brain circuits spared by the original injury. Design issues that affect the person’s ability of using the system independently include convenient location of the on/off switch, sensors that monitor fatigue or prevent falls, and allowing the user to adjust the stimulation parameters as needed. S182

Apart from these primary concerns, there are many advantages that FES standing and walking systems may also provide. Systems that stimulate peripheral or central nerves to restore standing and walking also provide exercise opportunities that could greatly benefit the health of the users as will be described below (Jacobs and Nash 2001). The ability of standing to look people in the eye and to participate in life more fully are also important benefits reported by those already using FES standing systems. The process of developing a viable, fully implanted FES system to restore relatively normal standing and walking, with safe and natural use, is an arduous one. To meet this challenge, biomedical and neural engineers are exploring a number of new systems for stimulation of muscle, peripheral nerve and spinal cord. Several of these efforts, past, present and future, are described below. Our intention is to describe the goals for these systems, as well as their probable and testable strengths and weaknesses, vis a vis with those of other relevant technologies. The discussion will emphasize the metrics used to evaluate the success of the application in meeting those goals and options to overcome barriers to implementation of the systems. This discussion is intended to focus research efforts that can be undertaken in the coming five to ten years toward maximizing the potential for successful implementation and achieving clinical testing of new standing and walking systems.

1. Perspectives on the applications of surface electrical stimulation for exercise and ambulation after SCI Systems of computerized surface FES were reported to enhance upright mobility in people with neuromuscular disorders as early as 1961 when Liberson and associates corrected foot-drop in an individual with hemiplegia (Liberson et al 1961). Over 25 years ago, Kralj et al demonstrated that a relatively simple transcutaneous FES system could assist individuals with thoracic SCI to stand and step (Kralj et al 1980). Those early systems provided the initial conceptual basis for a battery-powered user-controlled transcutaneous FES walking system designed by Graupe and Kohn (Graupe and Kohn 1994). This commercial system, the Parastep-1, uses surface-applied electrodes over quadriceps and gluteal muscles for knee and hip extension, and over the peroneal nerves below the knees to trigger a flexor withdrawal reflex. A microcomputer-controlled neuromuscular stimulation unit and battery pack are worn on a belt, and finger-activated control switches mounted on a walking frame are used for control and stability (Klose et al 1997). Parastep-1 received approval by the FDA in 1994 and became eligible for the Center for Medicare and Medicaid Services (CMS) reimbursement in 2003, for both the FES equipment and the required training sessions. 1.1. Stakeholders’ perspectives on FES success and function Liberson defined FES as ‘a replacement electrotherapy applied in patients with a central nervous system lesion, so that at

Restoring function after spinal cord injury

Engineer

Therapist

Physician

FES

Payer

Physiologist

User

Figure 1. Schematic depicting the groups of people that interact with FES technology.

the very time of stimulation, the muscle contraction has a functional purpose either in locomotion or in prehension or in other muscle functions’ (Liberson et al 1961). Thus, the success of any FES system depends on one’s idea of the intended ‘functional purpose’. Various groups of stakeholders involved with the development or use of FES systems are illustrated in figure 1. Each of these considers the effectiveness of FES from their own specific perspective, and these perspectives may differ. Systems designed to provide an upright stance and stepping movements have generally been judged from a clinical perspective to be successful if they are used regularly for independent locomotion as an ADL. However, there are other considerations by which the success of FES technologies should also be assessed. A subset of stakeholders, engineers, therapists and physicians involved in developing an FES system, are the first to interpret the ‘success’ or efficacy of the system (figure 1). FES systems for walking are designed to establish patterns of electrically activated muscle contractions sufficient for appropriate users to attain an upright standing posture and achieve stepping motions. The engineer assesses the success in delivering the intended electrical stimulation to the appropriate targets, usually as defined by the clinical collaborators. From clinical perspectives, the physician and therapist generally consider FES walking systems to be ‘successful’ if the test subjects achieve independent upright stances and/or gait with sufficient ease of use and stability to allow standing and/or walking as ADLs. When judged solely from this viewpoint, the current transcutaneous FES walking systems have achieved moderate success at best. For example, Parastep-1 is appropriate for people with complete midthoracic (T4–T11) spinal injury, which is a small subset of people with SCI. Walking with this system is slow (1/4–1/2 mph max) with energy requirements up to eight times that of people without disability walking at the same pace (Jacobs and Mahoney 2002). The users’ ability of performing ADLs in the home or workplace is also limited by the use of their arms for support and balancing on the requisite walker frame. This system may be judged to be more successful by other measures, however, including use as an exercise tool.

Another key group of stakeholders is the payers. Generally, FES systems are considered to be medical devices that require a prescription and training in the clinical setting. Because the systems are rarely affordable to potential users, the payer’s perspective is pivotal in determining the success of the system, i.e., which users benefit from the technology enough to warrant reimbursement. The user’s perspective of FES systems, in particular their satisfaction with walking systems, is dramatically affected by how the technology is presented to them. If the systems are introduced only as a potential means to restore walking as an ADL, the user may be disappointed by their limitations and not consider or appreciate other benefits of their use. For example, the Parastep-1 system has been reported to gain greater rates of acceptance and continued use by users in an Italian program compared with the published reports from American sites (Graupe 2002). The Vicenza program applies some unique training strategies, but also stresses the fitness benefits of the system, i.e., the perspective of the final group depicted in figure 1: the physiologist. The scope of ‘success’ with surface FES systems is broadened by considering the overall physiological benefits of the system to potential users. FES systems have been applied in different groups of people with neurological disorders that result in a limited or complete loss of the volitional motor control needed for independent upright gait. They have been most commonly employed in persons with SCI, a population that typifies physiological deconditioning associated with disuse. Thus, we will review the physiological consequences of SCI and the benefits FES training may have on these altered physiological systems. 1.2. Physiological consequences of paralysis Spinal cord injury not only limits a person’s volitional movements, but commonly leads to dysfunction of physiological systems, which in turn disrupt the individual’s fitness, health and wellness. Moreover, people with SCI generally have sedentary lifestyles with low levels of physical activity and differing degrees of physiological conditioning (Washburn and Figoni 1998). This increases various health risk factors such as obesity, hypertension, abnormal lipid profiles and altered insulin responses. Over time, significantly greater incidences of secondary disabilities and medical complications develop such as heart disease, stroke and diabetes (Blair 1994), which cannot be effectively addressed solely by upper extremity training modalities. Exercise training in the form of wheelchair locomotion or arm crank ergometry provides effective conditioning of the cardiovascular system for those with preserved upper extremity function, however, wheelchair accessible training equipment is not readily available. To those for whom it is available, increased incidents of upper extremity injuries and pain have been reported (Dalyan et al 1999). 1.2.1. Muscle atrophy. One of the most obvious consequences of SCI is muscular atrophy at and below the level of injury. Reductions in lean muscle mass are apparent S183

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in a matter of days after SCI, with significant losses in crosssectional area within the first month (Castro et al 1999a). This decrease in gross muscle mass is due to the diminished size of the individual muscle fibers, which in turn exhibit lower peak contractile forces and lower resistance to fatigue (Castro et al 1999b). Many people sustaining SCI also exhibit a hypertonic condition in which muscle spasms are common due to decreased inhibition of the stretch reflex response. Injuries at the T10 level or above result in damage of the upper motoneurons thereby eliminating the descending inhibitory influences but maintaining intact functioning reflex arcs that can activate the lower motoneurons. The resulting increase in sensitivity to movement and other stimuli is generally unpleasant or painful in people who experience involuntary muscle spasms. These spasms, however, are a form of muscle contraction and, as such, can lessen the extent of muscle atrophy and the shift in mechanical properties. In contrast, people who sustain SCI below T10 generally exhibit flaccid muscular paralysis, without involuntary spasms and are unresponsive to electrical stimulation. Pressure ulcers are not uncommon in these people and have been related to increased pressure over bony protuberances due to reduced thickness and density of the paralyzed muscle tissue. Muscular atrophy due to paralysis is associated with deconditioning of the peripheral vascular structures. Following SCI, lower extremity arterial circulation is dramatically diminished in both flow volume and velocity, which have been associated with the increased rates of thrombosis (Green et al 1992). Arterial flow within the paralyzed lower extremities is in the range of 1/2–2/3 compared with that of people without physical disability (Nash et al 1996). This leads to decreased oxygenation in the paralyzed tissues, slower healing of cutaneous injuries (cuts, burns) and contributes to increased incidence of pressure ulcers. 1.2.2. Risk of bone fracture. Bone demineralization also occurs quickly during the first year following SCI, and continues at a slower pace thereafter. Within the first year postinjury, about 1/3–1/2 of bone density is lost below the spinal lesion. Urinary excretion of calcium and hydroxyproline in time leads to under-hydroxylated and hypocalcific bone (Uebelhart et al 1995). This state of osteoporosis is the norm in people with complete SCI and results in skeletal structures that are quite susceptible to fracture (Belanger et al 2000). 1.2.3. Cardiovascular disease. Cardiac structure and efficiency are affected by changes in peripheral circulation as well as sedentary lifestyles. Reduced tone of paralyzed muscle, lack of movement in those limbs and diminished tone of venous structures contribute to significantly lower venous return from these regions. Lower levels of venous return limit ventricular filling, leading to reduced cardiac output compared with people without disability, both at rest and at matched levels of work output (circulatory hypokinesis) (Jacobs et al 2002). In order to maintain adequate cardiac output, people with paraplegia generally display reduced stroke volume matched by elevated heart rates. Orthostatic S184

hypotension commonly occurs when the body positioning becomes more upright. Cardiovascular disease is the leading cause of death in people with chronic SCI (Bauman and Spungen 1994). Correspondingly, the risk factors of heart disease in this population parallel those exhibited in the general population, but are developed at an accelerated pace. Atherogenic lipid profiles are prevalent in people with SCI with elevated values of total cholesterol, low density lipoproteins, and triglycerides and with reduced high density lipoproteins (Bauman and Spungen 1994). People with SCI also exhibit alterations in body composition including elevated body fat levels, particularly truncal obesity and reduced lean body mass. Therapies that provide effective exercise opportunities with high user acceptability would have significant health benefits for this population. 1.3. Physiological benefits of FES Several forms of surface FES besides walking systems have been used in people with SCI. These include single joint movements such as electrically stimulated knee extension, and more complicated strategies such as FES recumbent cycling and seated rowing. While these forms of FES provide more external stabilization and thereby may increase the potential user population, the physiological training effects are much lower than for upright walking. Systems of FES that use implanted technologies have been developed but little has been published regarding their use for inducing physiological adaptations. Such data are available, however, for users of transcutaneous stimulation systems. Following an initial training period to strengthen the lower extremities, approximately three months of FES walking training with the Parastep-1 system has been shown to provide substantial benefits to various physiological systems. Lower extremity muscle mass is significantly increased, with up to a 50% increase in thigh muscle volume (Jacobs et al 1997b). Interestingly, peripheral vasculature in those paralyzed limbs increased proportionally with the muscular hypertrophy (Nash et al 1997) including the cross-sectional size of and flow through the common femoral artery. Additionally, after training there was an enhanced hyperemic response to ischemia, suggesting positive adaptations in the size and function of more peripheral vascular structures. Central cardiovascular training effects can benefit the use of non-paralyzed muscles as has been shown to occur with participation in FES walking programs (Jacobs et al 1997a). Following thirteen weeks of training, there was a significant improvement in performance on a volitional arm crank stress test. The peak power output reached, time to fatigue, and peak VO2 were significantly increased while heart rate was significantly lower at rest and at matched levels of power output. Thus, the improved performance with the arms, which were not primarily stressed with transcutaneous FES walking, indicates that positive central cardiovascular effects occurred. The values of heart rate and levels of oxygen uptake displayed during FES standing and walking were also within the ranges generally recommended for cardiovascular training.

Restoring function after spinal cord injury

The incidences of most other health risk factors such as carbohydrate intolerance and obesity in those with SCI have not been adequately examined in response to FES walking. Nonetheless, because it is quite apparent that exercise conditioning in the general population does result in positive effects in these and other health risk factors, it is reasonable to expect that they would have similar effects in people with SCI. Many modalities of exercise conditioning are available to the general population, with and without specific equipment. Because devices such as treadmills, stationary cycles and rowing machines allow the users to experience beneficial training stimuli these devices do have a ‘functional purpose’. From the viewpoint of the physiologist and many others, such devices are deemed ‘successful’ if they provide an environment for beneficial physical conditioning. People with SCI have limited exercise options available to them in most communities. Therefore, FES walking may provide a necessary exercise regimen that effectively counteracts the aforementioned physiological dysfunctions. 1.4. Summary Overall, the application of surface FES walking systems in people with SCI to date has been of modest ‘success’ when viewed solely from the clinical perspective of restoring upright stance and gait as an ADL. The pace of walking and endurance are limited, with metabolic requirements that are much greater than for those walking without a disability. The currently available forms of surface FES walking are restricted to a subset of the overall population of people with SCI. While one system has received FDA approval with CMS reimbursement, there has not been a tremendous acceptance of the present technology. The value of the system can be judged by different viewpoints, with that of the potential user being the most important determinant of the overall ‘success’ of FES systems. It is important that potential users be fully informed of both the limitations and the secondary benefits of the device to allow them to make reasonable choices that consider the costs, benefits and risks of the systems they will be using. If a potential user considers transcutaneous FES only as a means to provide upright mobility, to be used consistently in the home and workplace, they may view it less favorably than if it were considered as a mode of exercise that can address the numerous physiological dysfunctions associated with SCI. It is also important to note that the present FDA approved Parastep-1 system represents technology that is more than two decades old. Developing new devices that incorporate more modern electronics, interfaces and other components as well as feedback control strategies would certainly enhance these systems. New and ongoing developments of FES systems are discussed below.

2. Implanted muscle-based FES system for restoring standing and walking after SCI Individuals with paraplegia need options for negotiating architectural barriers, completing essential daily bed, shower or toilet transfers, and gaining access to high cabinets,

Epimysial & Intramuscular Electrodes Implantable Receiver Stimulator In-Line Connectors

Coupling Coil

External Controller Laptop PC Clinical Interface

Figure 2. Schematic representation of the CWRU/VA implanted neuroprosthesis.

cupboards or shelves that are difficult or impossible to reach from a wheelchair. Rather than adapting every environment in which a person with SCI needs to function, the implanted neuroprostheses being developed at Case Western Reserve University (CWRU) and the Department of Veterans Affairs (VA) extend the capabilities of individual users, thus contributing to their intrinsic enablement. The CWRU/VA neuroprostheses utilize FES to activate the otherwise paralyzed trunk, hip, knee and ankle muscles to allow their users to exercise, rise from the seated position and maintain an upright posture to transfer from low-to-high surfaces or retrieve objects from above shoulder height, and to step short distances with a rolling walker to negotiate architectural barriers or gain entry to locations and life opportunities inaccessible from a wheelchair (Davis et al 2001a, 2001b, Hardin et al 2007). They represent new options to enhance the health and personal mobility of individuals with low cervical or thoracic level injuries. The general configuration of the CWRU/VA implanted neuroprostheses is depicted schematically in figure 2 and consists of a single implanted pulse generator, inline connectors and epimysial and surgically implanted intramuscular electrodes (Akers et al 1997, Letechipia et al 1991, Smith et al 1987). For standing, the system targets the hip (gluteus maximus and semimembranosus or posterior portion of adductor magnus), knee (vastus lateralis) and trunk (lumbar erector spinae) extensor muscles to raise and support the body against collapse, while foot-ankle orthoses protect and stabilize the ankle. For stepping after incomplete SCI, target muscles are customized for each recipient’s individual gait deficits but can include hip flexors (iliopsoas and tensor fascia latae) and ankle plantarflexors (gastrocnemius/soleus) or dorsiflexors (tibialis anterior or peroneus tertius) as needed. External components include a rechargeable wearable external control unit (ECU) with a command ring and transmitting coil, and a clinical programming station (Buckett et al 1998, Vrabec et al 2000). The ECU powers and controls the implant, weighs slightly less than a pound and can operate for 6 h on a single charge. A clinical interface based on a laptop PC allows clinicians to adjust stimulation parameters quickly and download usage information from the external controller. S185

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Users interact with the neuroprosthesis through three command switches mounted on the enclosure of the ECU or worn on a ring around the index finger. The command switches allow users to navigate a menu-driven interface to select, activate or terminate patterns of pre-programmed stimulation customized to the stimulated responses of their individual set of electrodes. With the transmitting coil taped securely to the skin over the implanted-pulse generator and the ECU suspended on a belt around the waist, implant recipients select the desired motion from a menu of pre-programmed patterns of stimulation. For standing, a single depression of one of the command switches activates the standing pattern, which begins with an initial audio tone. A 3 s delay enables the user to prepare to stand by repositioning the body at the edge of the wheelchair and placing the hands on an assistive device. A second audio cue is issued immediately prior to the delivery of the stimulation, and a final audio tone signals the end of the maneuver and cues the subject that continuous stimulation is being applied. A second depression of the command switch reverses the sequence and lowers the user back to the seated position. A similar process is performed to select and activate prescribed patterns of stimulation for exercise. For reciprocal stepping, users have the option of several triggering modes depending on their level of ability and preference. The swing phase of alternating legs can be initiated with successive depressions of a ring- or walkermounted switch. Alternatively, the user can elect to have the customized pre-programmed pattern of stimulation to cycle automatically for longer distance and more dynamic walking. This design obviates many impediments to spontaneous home and community use and was developed with the input of potential consumers (Brown-Triolo et al 2002). First, the system is intimate, private and unobtrusive. Since the stimulator, electrodes, leads and connectors are internal to the body, the system is cosmetic and does not draw attention to itself. Second, the design ensures reliability. Because the electrodes are secured permanently to the nerve entry points of the target muscles, stimulated responses are strong, isolated and repeatable from day to day. External cables and connectors that can tangle or foul in the wheelchair are eliminated. Third, the system is convenient and continuously available. Donning and doffing of the ECU is simple and can be accomplished quickly and easily whenever the need or desire to exercise or stand arises. Finally, users are selfcontained and require no other specialized equipment to be functional. System recipients with strong upper extremities can utilize any standard walker or mechanically stable object in the environment to maintain balance while standing with the neuroprosthesis and do not need to carry around customized assistive devices, further facilitating spontaneous use. 2.1. Results with the CWRU/VA implanted standing neuroprosthesis To date, a total of 17 subjects have received the implanted CWRU/VA neuroprosthesis for standing, including three at collaborating centers. System recipients have varied in age at implant (mean 35 years), time post injury (mean 7 years), S186

Figure 3. Examples of the implanted CWRU/VA standing neuroprosthesis being used outside the laboratory for occupational, recreational and social activities.

height (mean 5
9) and weight (mean 175 lbs). Injury levels have ranged from mid-cervical (C6) to low thoracic (T10) and users have been primarily males with complete motor deficits (ASIA A and B). After implantation, users participate in a program of reconditioning exercise consisting of progressive resistance strength and low-load endurance training with the system, followed by rehabilitation with a physical therapist including training in sit-to-stand, balance, stand-to-reach, transfer and swing-to activities. Study volunteers identify individual tasks of personal importance that are addressed during training, and home visits are performed to resolve potential barriers to use. After demonstrating mastery of the skills for safe unsupervised use, implant recipients incorporate the system into their daily routines and have employed the system to return to work and engage in recreational and social activities, as illustrated in figure 3. The system has been shown to eliminate the heavy lifting and lowering required by caregivers during standing pivot transfers, which becomes particularly important as individuals with SCI and their family members or spouses age. Thus, the neuroprosthesis has the potential to reduce the burden of care and postpone or obviate the need to hire personal assistants or reside in a nursing home due to difficulties with basic mobility. The outcome of application of the CWRU/VA system is being measured in three domains: clinical utility (functional activities, standing duration and body weight distribution), safety (threshold stability and electrode longevity) and satisfaction (usage, perceptions of health and preference). Primary results in each domain are summarized in table 1. With a mean follow-up of approximately 6 years, the implanted components are safe and reliable (Uhlir et al 2004), and the system is utilized routinely at home for exercise or standing (Nogan et al 2004). Long-term users’ perceptions, including subjective ratings of effort and satisfaction with the system, are positive (Agarwal et al 2003). The clinical utility and preliminary safety of the neuroprosthesis is currently the focus of a small-scale multicenter trial, and a commercial trial for marketing approval of an implanted system based on the CWRU/VA standing neuroprosthesis is scheduled to begin in 2008.

Restoring function after spinal cord injury

Table 1. Summary of the preliminary outcome measures of clinical and technical performance of the CWRU/VA implanted standing neuroprosthesis in the first 17 recipients. Clinical utility

Functional abilities: Standing duration Weight distribution Preference

Exercise 100%; independent stand 85%; high transfer 85%; overhead reach 77%; swing-to 64% Mean = 10.25 min; median = 3.75 min. 85% legs; 15% arms Less effort and assistance for high transfers than conventional methods for high transfers

Safety

Recruitment stability Electrode longevity

NSD in thresholds or saturations at follow-up 90% (128/142) functional; >80% survival in 4 yrs.

Satisfaction

Usage Health perceptions Satisfaction

40% of last 30 days surveyed; exercise alone > exercise + standing > standing alone ↑ TPO2 and ↓ peak interface pressures recorded; Users report ↑ overall health, ↓ spasms and ulcers Users would recommend to others or repeat the experience

Table 2. Functional milestones attempted and achieved by recipients of the CWRU implanted standing neuroprosthesis. None of these new functional abilities were possible without the neuroprosthesis. No. subjects Milestone

Attempt

Achieve

%

Exercise Assisted stand Independent stand Assisted high Xfer Independent high Xfer Release hand Retrieve overhead Stand at counter Swing-to gait (10 ft)

17 14 13 14 13 13 13 11 11

17 14 11 14 11 11 10 7 7

100 100 85 100 85 85 77 64 64

N = 17 at 4 sites; mean time post implant ∼ 5.6 yrs.

2.1.1. Clinical utility. Functional outcomes of neuroprosthesis use in terms of activities or milestones that were impossible to complete without the system are summarized in table 2. Due to variations in the injury level and upper extremity involvement, not all implant recipients were able to attempt all activities. Nonetheless, all subjects were able to exercise with the system, and all subjects who completed rehabilitation (the two latest implant recipients are still in the reconditioning exercise phase) were able to stand and transfer with minimal assistance. Approximately two thirds of all system users were able to stand independently and achieve a swing to gait, and greater than three quarters were able to release one hand from a walker or other support to retrieve objects from overhead while standing. Maximal standing times varied, but averaged in excess of 10 min for the group. Standing durations approaching or exceeding 20 min were achieved by several individuals, and a majority of users were able to stand for functionally relevant periods of time (2–3 min) sufficient to retrieve objects from high shelves, perform standing pivot transfers or maneuver in the vicinity of the wheelchair. Median standing time was just over 3 min. On average, implant recipients were able to stand with better than 85% of their body weight on their legs, utilizing the upper extremities only for light touch on an assistive device to make small balance corrections, rather than for support. 2.1.2. Safety. The technical performance of the CWRU implanted standing system is being determined by the stability of the implanted components and recruitment properties over

time. Serial radiographs have shown no discernable changes in the orientation or integrity of the implanted components from immediately post-implant through all follow-up intervals. Stimulus threshold pulse durations were consistently low, and maximal values were high across individuals indicating a wide dynamic range over which to modulate recruitment. Mean stimulus thresholds also showed very low variability. Repeated measures ANOVA performed on the stimulus threshold and maximal values showed no significant differences (p = 0.28) between initial (6 weeks) and follow up (12 month) values. Manual muscle test scores and dynamometer measures of isokinetic strength were similarly consistent over time. Of 142 electrodes implanted in 17 subjects to date, 128 were functioning at the last follow-up, indicating 90% survival. All of the 14 non-functioning electrodes were in the posterior muscles (gluteus maximus, semimembranosus or posterior adductor magnus), where redundancy helped ensure continued system operation without significant compromise of the standing function. When standing was impaired, single electrodes were successfully isolated, disconnected, removed and replaced with a new electrode to return the subjects to their optimal function. Other adverse events include one late-onset methicillin resistant staphylococcus aureus (MRSA) infection requiring explantation and intravenous antibiotic treatment, and one fall while using the system resulting in fracture of the tibia and fibula. The subject resumed standing with the neuroprosthesis after the fractures were repaired, and continues to be a regular system user. 2.1.3. User satisfaction. Patterns of use are monitored by the ECUs and downloaded for analysis at three-month intervals after discharge to home with the system. Usage data for the last 30 consecutive days surveyed for each individual currently in long-term (12–36 months) follow-up show that implant recipients find idiosyncratic and personal ways to incorporate the neuroprosthesis into their daily routines and balance the desire to exercise with the need and opportunity to stand. Some subjects choose to use the system daily, while others only twice per week. Some form of use was logged on 40% of the days surveyed. Overall, implant recipients chose to use the system most frequently for exercise (averaging almost 1 h per day), followed by both exercise and standing, and standing alone. Average standing times logged approached 5 min. In questionnaires administered during follow-up, the most frequently expressed reason for exercising with the S187

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neuroprosthesis was ‘to improve standing’. Other reasons for exercise were more personal such as ‘because it makes me look good’, ‘to reduce spasms’, and ‘because it feels good’. The primary reason offered for why respondents stand with the system was ‘to transfer’. Other, more personal reasons for standing included ‘to be at eye level’, ‘to stretch’, and ‘to reach high objects’. These data highlight the value placed on both exercise and standing by implant recipients as evidenced by the continued use in their daily lives. In formal ratings of effort and preference, recipients preferred the neuroprosthesis over conventional methods of transferring from low to high surfaces, found it easy to use and felt that it has had a positive impact on their general health. A structured follow-up survey to assess user satisfaction with the neuroprosthesis and perception of the effects of stimulation on health-related issues was administered to subjects at least 12 months post-implant by a physician unfamiliar to the users to avoid bias. Implant recipients overwhelmingly agreed that FES offers important and valuable benefits and that use of the neuroprosthesis has improved their general health. No deleterious side effects, such as deep vein thromboses, pain or other complications potentially attributable to FES were reported. Subjects were also consistent in their impressions that FES reduced the frequency of their spasms, urinary tract infections and pressure sores. All implant recipients reported that they were moderately to very satisfied with the system, that the system had lived up to their expectations and that they would go through the experience again or recommend it to others. Furthermore, neuroprosthesis users unanimously agreed that the FES system was safe, easy to use and offered tangible health and functional benefits. Assessing the effects of the FES system on global health, disability and quality of life is a continuing challenge being addressed through the sickness impact profile (SIP) (Antonak and Livneh 1994, McDowell and Newell 1987) and the Quebec Evaluation of Satisfaction with Assistive Technology (QUEST) (Demers et al 1996). These clinical results are encouraging in spite of several inherent limitations of the system. First, while sufficient for the clinically relevant functions described, the muscle-based electrodes currently employed by the system only partially recruit the target muscles. A more complete recruitment of the targeted muscles, as well as their synergists, and the resulting increased stimulated joint moments would improve standing posture, extend standing times and provide a margin for corrective actions to counteract antagonistic actions of multijoint muscles—especially in taller and heavier individuals. In the future, recruitment may be improved through the application of high density nerve-based electrode designs (i.e. nerve cuffs) and implanted pulse generators with a significantly greater number of independent output channels. In preliminary trials in which epimysial electrodes on the vastus lateralis were replaced by multi-contact spiral nerve cuff electrodes on the distal branches of the femoral nerve, standing times more than doubled and the body weight placed on the legs increased by 50% due to the superior recruitment efficiency of the neural interfaces. Second, the system is unresponsive to environmental disturbances and produces only fixed, pre-programmed postures. Functionality and S188

acceptance can be further improved if standing postures could be varied in a task-dependent manner by the implant recipient. Rather than pushing or pulling against a support device to lean toward or away from an object, a feed-forward system allowing the user to optimize his or her posture for a given activity would provide significant additional benefit. Methods to automate the control of standing balance by modulating stimulation in response to perturbations would reduce the need to interact with mechanically grounded objects with the upper extremities to make corrections, potentially freeing both hands from a walker and eliminating the need for ankle braces or other assistive devices. 2.2. Facilitating ambulation with the CWRU/VA implanted neuroprosthesis Incomplete injuries constitute the largest, and still growing, segment of the SCI population. When motor impairment compromises ambulation and resists rehabilitative treatment, the needs of individuals with partial paralysis can be addressed by neuroprosthetic, rather than neurotherapeutic applications of FES. A few channels of stimulation judiciously applied to the weakest muscles and appropriately timed with voluntary activity can make the difference between being completely wheelchair dependent, and being a functional household or community ambulator. The CWRU/VA implanted neuroprosthesis has been configured in such a way to assist with reciprocal gait in incomplete SCI (ASIA C) (Hardin et al 2007, Kobetic et al 2005). Because of the intrinsic variability of the population, the system is customized to address the major gait deficits of each individual. After initial trials with surface stimulation to identify key muscles for implantation, intramuscular electrodes are inserted into the targets, tunneled subcutaneously and connected to the implanted receiver–stimulator. Electrodes have been employed unilaterally in the hip flexors and extensors, knee extensors and ankle dorsiflexors of individuals with incomplete SCI resembling hemiplegia or Brown-Sequard syndrome, or distributed bilaterally and asymmetrically depending on the needs of each user. In an example of the latter case, one non-ambulatory subject with longstanding ASIA C incomplete SCI at C6, who could stand voluntarily but not initiate a step, had electrodes inserted into his iliopsoas, tensor fascia latae, quadriceps and tibialis anterior bilaterally. These muscles exhibited weak or trace volitional strength that was augmented with FES appropriately throughout the gait cycle, while he learned to coordinate voluntary contractions of his hip extensors and ankle plantarflexors during stance. After reconditioning exercise and overground gait training, this user was able to walk using a rolling walker for distances approaching 400 m at speeds approaching one quarter of the normal for someone of his gender and stature. In addition to customizing surgical implementation and optimizing stimulation patterns for each implant recipient, the major challenges to developing neuroprostheses for walking after incomplete paralysis include finding new and reliable ways for automating and seamlessly integrating stimulation with intact voluntary control. The feasibility of integrating stimulation with intact volitional movement via surface

Restoring function after spinal cord injury

electromyographic (EMG) has recently been established for the CWRU/VA implanted neuroprosthesis (Dutta et al 2007, 2005). Using pattern recognition techniques on features extracted from principal component analysis of two channels of EMG of proximal muscles around the hip and trunk, the intent to initiate a step can be detected with a false positive rate of approximately 1%. False negatives were overcome by providing a manual over-ride so that users could trigger a step by depressing the command switch. Performance with the EMG-triggered system was shown to be equivalent or superior to manual triggering in all relevant spatio-temporal gait measures (speed, symmetry, step and stride lengths, etc) and was preferred by the system user because of the more intimate, natural and subconscious control over his body that it afforded. Implementing an EMG-triggered system with completely implanted sensing and stimulation technology remains to be accomplished before systems that are specifically tuned and responsive to the particular needs of large numbers of individuals with incomplete SCI can be a viable clinical option.

3. Stance-like maneuver evoked with intrafascicular multielectrode stimulation of the femoral nerve As described earlier, work is ongoing with FES systems that facilitate sit-to-stand maneuvers, gait, and that enable transfers from a wheelchair to cars and beds, and reaching high objects. Neuroprosthetic interventions, such as the CWRU/VA system, have had significant success in achieving these goals by stimulation of the leg and hip muscles with currents passed via epimysial and/or nerve cuff electrodes (Davis et al 2001a). However, with these electrode systems, the relation between muscle force and stimulation intensity (the muscle’s forcerecruitment curve) is steep and not all muscles, nor all motorunits within a given muscle can be stimulated with epimysial or intramuscular electrodes. Further, the maximal levels of muscle activation that are used with these FES stimulation strategies produce rapid muscle fatigue. The ability of a nonSCI subject to produce both graceful yet strong movements is a result of his/her ability to produce graded and coordinated forces in skeletal muscles. Such physiologically graded force recruitment is achieved primarily by the sequential activation of successively larger numbers of the motoneurons that innervate targeted muscles. Researchers at the University of Utah have proposed a new neuroprosthetic intervention strategy, intrafascicular microelectrode stimulation (IFMS), using microelectrode arrays that penetrate into the nerve fascicles. This intervention provides a physiological recruitment strategy that generates fatigue-resistant, graded forces in the muscles of the hip, knee and ankle. In prior work, the Utah group has demonstrated that arrays of microelectrodes can be implanted intrafascicularly in the feline sciatic nerve, that electrical stimulation via these electrodes can produce physiological muscle forces, and that these forces can be fatigue-resistant (Branner et al 2001, McDonnall et al 2004a, 2004b). The fatigue resistance is achieved by stimulating a number of motoneurons that activate independent motor-unit pools in a targeted muscle. If this

muscle is activated using an interleaved stimulation paradigm by passing currents sequentially through individual electrodes in the implanted microelectrode array, each motor-unit pool will be stimulated at a low, fatigue-resistant rate, but the entire muscle will be excited at a high, ripple-free rate. For example, we have shown that the gastrocnemius muscle force is reduced to about 50% of its initial force within 15 s when stimulated at 60 Hz, but when stimulated with four electrodes in an interleaved manner, with 15 Hz stimuli delivered through each electrode, the muscle force only falls by 30% after 100 s of stimulation (McDonnall et al 2004a). We show herein that this new IFMS intervention strategy can be used to produce a single leg sit-to-stance maneuver in an anesthetized cat, with kinematics that are similar to those of stance maneuvers in a normally behaving cat. Experiments were performed in cats under guidelines of the University of Utah Animal Care and Use Committee. The surgical procedures have been described elsewhere (McDonnall et al 2004a), but are summarized here. Cats were anesthetized with isoflurane, and vital signs (rectal temperature, electrocardiogram, CO2, oxygen saturation) were monitored. The animal was positioned prone in a ‘seesaw’ trough system (top panel, figure 4). Its hind limbs were unsupported and as the trough pivoted clockwise, the hind limbs collapsed, and the animal assumed a sitting posture. Stimulation of the extensor muscles of the left hind limb generated sufficient force to restore the trough to a horizontal position, producing a sit-to-stance-like maneuver in the cat. After exposure of the target femoral nerve, a Utah Slanted Electrode Array (USEA, described below) was positioned adjacent to the nerve and inserted using a high velocity technique (Rousche and Normann 1992). A thin silicone cuff was sutured around the array and nerve to minimize traction on the nerve by the moving musculature (Branner et al 2004). Lead wires were passed through the skin to a percutaneous connector that was mounted to the animal’s skin near the surgical site. All stimuli were delivered to the peripheral nerves via a USEA. This array, described elsewhere (Branner et al 2001), consists of 100 microelectrodes in a 10 × 10 grid. The length of the electrodes varies across the array from 1.5 mm on one end, to 0.5 mm on the other. The electrodes are separated by 400 microns, and each electrode is electrically isolated from its neighboring electrodes by a moat of glass that surrounds the base of each electrode. The tips of the electrodes are metalized with activated iridium, and the entire electrode array except the electrode tips is insulated with parylene. Lead wires are bonded to the rear surface of the array and to a percutaneous connector system. Because the electrodes of the USEA are implanted intrafascicularly and are of different lengths, the entire nerve is uniformly populated with active electrode tips, and no axon is further than 200 microns from an active electrode tip (most are closer). This allows access to individual and small groups of axons in the peripheral nerves. As a result, many electrodes selectively activate fibers that target individual muscles. Further, most of the muscles that are innervated S189

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Figure 4. Top panel: drawing of the cat in the ‘seesaw’ test apparatus. Bottom panels: sequence of images taken of the cat during the sit-to-stand behavior invoked by sequential stimulation of five individual electrodes in a Utah Slanted Electrode Array (USEA) implanted in the femoral nerve.

by the implanted nerves can be selectively accessed by the implanted array (Branner et al 2001). Stimulation was produced with a custom, multichannel, computer-controlled stimulator. Stimuli were pulse-width modulated, constant-voltage (approximately ±1.3 V) biphasic pulses. EMG activity was recorded from muscles expected to be targeted by stimulated axons. 3.1. Electrode placement A normal sit-to-stance maneuver requires selective activation of the extensors of the hip, knee and ankle joints. In the cat, these muscles can be accessed by the muscular branch of the sciatic nerve, the femoral nerve, and the sciatic nerve, respectively. These nerves can be accessed without complex surgical interventions, and the 4 mm × 4 mm size of the USEA is well suited to cover the width of the nerves; however, some nerves were narrower than the implanted USEA, and the outer rows of electrodes in some implants were outside of the nerve. 3.2. Feline sit-to-stance maneuver The goal of the present work was to produce a physiological, graceful sit-to-stand maneuver in the anesthetized cat. Although the project is ongoing, this behavior has been partially achieved by selectively stimulating, in a sequential fashion, the axons of the femoral nerve using an implanted USEA. In the experiment illustrated in the lower panels of figure 4, stimuli were sequentially delivered through five individual electrodes over the course of three seconds to produce a sit-to-stand maneuver. For figure clarity, only photographs depicting the sit-to-stand phase are shown. In this experiment, a single USEA was implanted in the femoral nerve, so the figure does not show ankle or hip extension. The forces generated by the knee extension were sufficient to evoke a sit-to-stand maneuver (lifting about 25% of the animal’s S190

weight, the fraction is not supported by the counterbalancing weight). The experiments described here provide a new therapeutic approach to the restoration of stance in individuals with SCI who are wheelchair dependent: intrafascicular stimulation of motoneurons with a penetrating microelectrode array. The use of arrays of intrafascicular electrodes, like the USEA, permits access to large numbers of individual axons that target the muscles of the hip, knee and ankle. Given that multiple electrodes penetrate individual fascicles, many of the implanted electrodes activate independent motor units. This allows physiologically based recruitment of muscle force. In order to produce a small force, stimuli are delivered through only a few electrodes to excite motor units in a target muscle, whereas larger forces are produced by activation of many more units, with currents passed through larger numbers of electrodes. As shown in figure 4, a stance-like fatigue-resistant maneuver can be produced in the cat by sequential stimulation through a subset of electrodes activating motor units of the knee. Although the results of this experiment provide a proofof-concept, many issues remain. One of the biggest problems is how to optimize stimulation, both in time and space, to evoke the desired skeletal movements and forces. This will require a closed-loop feedback control in which the consequences of activation can be used to control the currents passed through the implanted electrodes. This strategy will in turn require the use of either a extrinsic or intrinsic force and displacement sensors. Work on this problem is ongoing in the Utah laboratories, where the use of EMG and/or externally mounted mechano-transducers is being investigated. Another major problem is a consequence of the large numbers of electrodes that are implanted in the peripheral nerves. Complex computer-controlled stimulators are required to pass currents through appropriate electrodes,

Restoring function after spinal cord injury

and such stimulators are currently under development. These large numbers will also require the use of automated electrode characterization algorithms, and algorithms that can use the sensory information to control the high channel-count stimulators. Finally, much of this work has focused on acute experimentation. A clinical system must perform robustly for decades. It is unclear if such complex penetrating electrode arrays will be tolerated by the peripheral nerves for such long periods. This is a problem that will require considerable effort to resolve. If these problems can be overcome, this new therapeutic approach to musculo-skeletal control could provide graceful, fatigue-resistant movement of the limbs of paralyzed subjects.

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4. Use of intraspinal microstimulation for restoring standing and stepping after SCI Intraspinal microstimulation (ISMS) is a neuroprosthetic approach that focuses on stimulating the central nervous system to restore movements of the legs after SCI. Fine, hairlike microwires are implanted within the spinal cord below the level of the lesion and low-level electrical pulses are passed through these wires to elicit functional leg movements. The use of ISMS for restoring standing and walking after SCI has several advantages. (i) The microwires are implanted far away from contracting muscles, which reduces the chances of electrode damage and dislodgement due to movement of the target tissue. (ii) The spinal cord is surrounded by the spinal column, which provides a protected anchoring area for implanted electronics. (iii) The lumbosacral enlargement, which is the target region for microwire implantation, is small, spanning only 5 cm in humans. The ventral horn of this region contains the cell bodies of motoneurons that innervate all the muscles of the lower extremities, as well as large proportions of the neuronal networks involved in locomotion (Jankowska 1992, Kjaerulff and Kiehn 1996). Therefore, implanting microwires within the small and protected region of the lumbosacral enlargement after SCI provides a means for tapping into the inherent neuronal networks for regulating the movements of the legs. A schematic depiction of the implant as it would be in humans is shown in figure 5. To date, development and testing of ISMS have been conducted primarily in cats. All experimental protocols were approved by the University of Alberta Animal Welfare and Care Committee. The implantation of ISMS microwires is based on surgical procedures initially developed for longterm recording of single cell activity in the dorsal root ganglia of adult, freely moving cats (Prochazka 1984). Under deep general anesthesia and aseptic conditions, a laminectomy is performed to expose the lumbosacral enlargement. Microwires (stainless steel or platinum-iridium, 30 µm in diameter, insulated with polyimide except for 30– 60 µm at the tip) are individually inserted through the dorsal surface of the cord and advanced until their tip reaches target locations within the ventral horn (Mushahwar et al 2002, Mushahwar and Horch 2000b, Saigal et al 2004). Placement of the microwire tips is based on the medio-lateral location and rostro-caudal distribution of the motoneuron pools in

Figure 5. Schematic representation of the location and method of ISMS implantation. (A) A model of a human spinal column is shown highlighting the lumbosacral region which is the target for ISMS implantation. (B) A detailed depiction of the ISMS implant. Note that all implants to date have been conducted in animals. While the implant is usually anchored to the L3 or L4 spinous processes in cats, it is likely to be anchored to the T11 process in humans as illustrated in the figure.

the lumbosacral enlargement (figure 6(a)). The location and distribution of motoneuron pools in the ventral horn is consistent between all animals within a species (e.g., cats: (Mushahwar and Horch 2000b, Romanes 1951, Vanderhorst and Holstege 1997)). They are also well preserved between species including humans (Sharrard 1955). When implanting microwires in the lumbosacral enlargement of cats, a brief assessment of the rostro-caudal extent of the motoneuron pools is obtained by inserting a single ‘test’ microwire in various segments of the cord and characterizing the hindlimb responses evoked during stimulation. For example, ISMS through the tip of a test microwire placed in segment L5 of the spinal cord, 1.8 mm from the midline and 3.6–3.8 mm from the dorsal surface results in the activation of the quadriceps motoneuron pools and evokes knee extension (Saigal et al 2004). Due to the proprioceptive, propriospinal and other interneuronal connections between synergistic motoneuron pools within the ventral horn (Jankowska 1992, Wilmink and Nichols 2003), ISMS of one motoneuron pool also results in the activation of these fiber in passage systems, which in turn leads to the activation of coordinated whole-limb synergies (Lau et al 2006, 2007, Mushahwar et al 2000, Mushahwar et al 2002, Saigal et al 2004). For example, collaterals from a single Ia afferent fiber form synaptic connections with every motoneuron within the homonymous pool as well as connections with motoneurons in synergistic pools (Henneman 1980, Jankowska 1992). Collaterals of all proprioceptive afferents producing patterns of synaptic excitation and inhibition of agonist and antagonist pools are also present in the ventral horn (Jankowska 1992). Furthermore, propriospinal interneurons which interconnect synergistic lumbosacral motoneuron pools separated 1–3 cm rostro-caudally are located within the ventral horn, and the S191

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Figure 6. Location of ISMS microwire implantation in the lumbosacral enlargement of cats. (A) Map of the motoneuron pools of 27 hindlimb muscles in the ventral horn of the lumbosacral enlargement. Each cross-section represents ∼1mm of grey matter tissue and each dot (colored online) represents one motoneuron. Same color dots represent the collection of motoneurons within one pool. The bars below the cross-sections represent the rostro-caudal extent of each pool within the lumbosacral enlargement. The lumbosacral enlargement in cats is 3 cm long. Abbreviations: BFp (biceps femoris posterior), MG (medial gastrocnemius), LG (lateral gastrocnemius), GlutMax (gluteus maximus), CF (caudofemoralis), BFa (biceps femoris anterior), ST (semitendinosus), GlutMed (gluteus medialis), FHL (flexor hallicus longus), TP (tibialis posterior), TA (tibialis anterior), FDL (flexor digitorum longus), EDL (extensor digitorum longus), SMp (semimembranosus posterior), TFL (tensor fascia latae), SMa (semimembranosus anterior), VI (vastus intermedius), AdM (adductor medialis), RF (rectus femoris), VL (vastus lateralis), VM (vastus medialis), SRTa (sartorius anterior), SRTm (sartorius medialis). (B) Composite schematic of ISMS microwire tip locations tested to date. The best locations for eliciting single-joint movements and coordinated multi-joint synergies were in the region of the motoneuron pools in lamina IX.

initial segments of their axons would constitute part of the fiber in passage systems activated by ISMS (Grillner and Wallen 1985, Wilmink and Nichols 2003). Thus, the network of fibers in passage, which interconnects the motoneuron pools and is directly related to the generation of limb movements, is contained within the ventral horn, the location of the ISMS implant. Six to 12 microwires are implanted in each side of the spinal cord, spaced 2–4 mm apart. A drop of cyanoacrylate applied at the point of entry into the cord is used to hold each of the microwires in place. The wires are then secured to the dura mater using ophthalmic sutures and subsequently anchored to a spinous process for further stabilization. The free end of the microwires is tunneled subcutaneously toward the head where it terminates in a connector that is anchored to the cat’s skull (Mushahwar et al 2000). In chronic experiments, initial testing of the implant is conducted 4–7 days after the animal recovers from anesthesia. Testing is then performed once or twice a week for up to 6 months after implantation. To evaluate the viability of ISMS as a neuroprosthetic approach, testing focused on assessing the feasibility and safety of microwire implantation, the stability of evoked responses over time, and the capacity of ISMS to produce fatigue-resistant and kinematically-stable standing and stepping of the hind limbs in adult cats. S192

4.1. Feasibility and safety of microwire implantation Implantation of the ISMS microwires using current methods is tedious as it requires separate manual insertion of each wire. Nonetheless, insertion of each wire into the cord is accomplished with relative ease. Given the small diameter and flexibility of the microwires, minimal tissue damage is incurred due to microwire insertion (Prochazka et al 2001) or movement of the spinal cord. Inspection of spinal cord tissue obtained post-mortem from cats that had been implanted for 6 months showed mild gliosis around the microwires associated with their initial placement in the cord. No signs of chronic inflammation were observed (Prochazka et al 2001). These results were consistent with other studies focusing on chronic stimulation of the central nervous system with penetrating electrodes for restoring bladder function (McCreery et al 2004) or ameliorating the movement disorders associated with Parkinson’s disease (Haberler et al 2000). 4.2. Stability of evoked responses over time Studies conducted in animals that had been implanted with ISMS microwires for 6 months demonstrated that at least 67% of the microwires continued to produce the same responses throughout the duration of implantation (Guevremont and

Restoring function after spinal cord injury

Mushahwar 2007, Mushahwar et al 2000, 2004). Stimulation through individual microwires produced graded single-joint movements or coordinated multi-joint synergies. The synergies consisted of whole limb extension, flexion, forward or backward movements. Large forces, adequate for lifting the animals’ hindquarters were generated during the extensor synergies. Intraspinal microstimulation in the ventral horn of spinally intact animals, i.e., animals with full sensory preservation, produced no signs of discomfort, even when the stimulus amplitudes were increased (up to 300 µA) to produce large and strong contractions. This was an important finding because it suggested that ISMS applied in the ventral horn is not painful and may be used in individuals with incomplete SCI. Application of ISMS in the dorsal horn, on the other hand, could cause discomfort and may not be suitable for the incomplete SCI population. Figure 6(b) provides a composite schematic of ISMS microwire tip locations tested to date. Stimulation within the region of the motoneuron pools (Rexed lamina IX) produced the most functional single-joint movements and coordinated multi-joint synergies. Due to the activation of propriospinal, proprioceptive and other interneuronal projections within this region, ISMS evokes a near normal recruitment order of motoneurons (discussed below) and coordinated multijoint synergies. Stimulation in lamina VII generates flexor withdrawal responses and ISMS in laminae I-VI elicits flexion withdrawal accompanied by reactions to the stimulus that may indicate discomfort in spinally intact animals. Stimulation threshold levels obtained during the first testing session following implantation were usually 15–30 µA in amplitude (for 200 µs pulses). These levels commonly doubled in amplitude over the first month of implantation presumably due to encapsulation of the microwires (Mushahwar et al 2000). The stimulation threshold levels remained constant thereafter, further supporting the lack of mechanical irritation of the tissue induced by the chronically implanted microwires. 4.3. Fatigue-resistant and kinematically-stable standing To determine the capacity of ISMS to produce functional standing, experiments were conducted in adult anesthetized cats. Six microwires were implanted in each side of the spinal cord targeting locations in L5 and L7 within the lumbosacral enlargement that produce knee extension or whole-limb extensor synergy, respectively, when stimulated (Lau et al 2006, 2007, Mushahwar et al 2000, Saigal et al 2004). Two pairs of electrodes were used for ISMS in each side of the cord, one pair for producing knee extension and the other for producing a whole-limb extensor synergy. Stimuli (25 Hz) were interleaved between the two wires in each pair. Stimulation amplitude through each microwire was either held at a constant predetermined amplitude (open-loop control), or modulated based on on-line measurements of ground reaction force and knee and ankle joint angles (closed-loop control). The duration of standing evoked by ISMS, rate of force decay and total injected current were compared to those evoked by

intramuscular stimulation (50 Hz) of the vastus lateralis and lateral gastrocnemius muscles in each leg conducted under the same experimental conditions. The average duration of standing in the hindlimbs with full weight support of the hindquarters achieved by open-loop control of interleaved ISMS was 12.1 min, with 2 of 3 animals achieving 15 min of weight-bearing standing (the maximal duration of the experimental protocol). In comparison, the average duration of standing evoked by open-loop control of non-interleaved intramuscular stimulation was 2.6 min. Using closed-loop control, standing was allowed to continue until loss of ground support occurred. Under these conditions, the average duration of standing achieved by ISMS was 20.9 min, with 2 of 3 animals successfully standing for 28.3 and 32.0 min. In comparison, the average duration of standing achieved by closed-loop control of intramuscular stimulation was 4.2 min with the longest duration of weight-bearing standing achieved being 8.5 min. The rate of decay of ground reaction force was 1.7 and 30.7% body weight/min for open-loop ISMS and intramuscular stimulation, respectively. Closed-loop control improved this rate of decay significantly for intramuscular stimulation but not ISMS; the rate of decay with closed-loop control was 1.6 and 7.6% body weight/min for ISMS and intramuscular stimulation, respectively. Finally, the average amount of current injected throughout the duration of ISMS standing was 1.2 mA during both open- and closed-loop control. In comparison, the average amount of current injected during standing with intramuscular stimulation was 55.1 and 44.5 mA for open- and closed-loop control, respectively. These results suggested that ISMS is capable of producing prolonged durations of weight-bearing standing using less than 3% of the current injected with intramuscular stimulation (Lau et al 2006, 2007). 4.4. Fatigue-resistant and kinematically-stable stepping The capacity of ISMS to restore weight-bearing stepping after SCI was tested. Animals that had received a complete thoracic SCI 2 to 6 weeks earlier were implanted with 15 to 18 ISMS microwires in each side of the lumbosacral enlargement. Trains of stimuli delivered through each microwire were used to identify wires that produced flexor, extensor, forward or backward synergies in each side of the spinal cord. Subsequently, stimuli were patterned through the wires of interest to produce alternating bilateral stepping movements of the paralyzed hind limbs (Saigal et al 2004). The ISMS-evoked stepping was achieved by stimulating through as few as 4 microwires in each side of the spinal cord (Saigal et al 2004). This was an unanticipated finding given the complexity of the locomotor pattern, and suggested that ISMS activates inherent synergies for locomotion residing within the ventral horn of the lumbosacral enlargement. The evoked stepping was kinematically-stable and fatigue-resistant over 140 steps taken (equivalent to ∼200 m, the longest tested to date) (Saigal et al 2004). Ample foot clearance during swing (flexion phase) and full weight-bearing of the hindquarters during stance (extensor phase) were attained. The movements S193

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were also characterized by graded buildup of force and smooth transition between the swing and stance phases, emulating normal stepping. The fatigue-resistant responses evoked by ISMS are attributed to two factors: interleaving the stimuli through microwires that produce similar mechanical actions and the near-normal pattern of motor unit recruitment obtained with ISMS. Interleaving stimuli between multi-site nerve cuff electrodes to elicit a similar mechanical action has been utilized as a method for reducing muscle fatigue in applications for phrenic nerve stimulation to restore independent respiration in people with SCI (Thoma et al 1989). Similar results were obtained using peripheral longitudinal intrafascicular electrodes (Yoshida and Horch 1993) and USEAs (McDonnall et al 2004a). The method of stimulus interleaving entails the delivery of the stimuli through electrodes that activate selective sets of motor units each at a frequency equivalent to a fraction of that required for total muscle fusion. This mimics the naturally asynchronous activation of motor units and their relatively low firing rates; thus significantly reducing muscle fatigue. Given the elongated cigar-like shape of motoneuron pools in the ventral horn of the spinal cord, 2 to 3 microwires are commonly implanted within each pool to facilitate the interleaving of stimuli between these microwires. This interleaved stimulation routine accounts in part for the observed fatigue resistance with ISMS (Lau et al 2006, 2007, Mushahwar and Horch 1997, Saigal et al 2004). In addition to stimulus interleaving, the fatigue resistance obtained by ISMS is also due to its capacity to recruit motor units in a near normal physiological order. Previous studies have shown that graded increases in force are produced with increases in ISMS amplitude (Bamford et al 2005, Mushahwar and Horch 2000a, Snow et al 2006), suggesting an orderly recruitment of motor units according to their size. Furthermore, ISMS preferentially activates slow twitch, fatigue-resistant muscle fibers. In experiments in which the quadriceps muscle group in rats was stimulated either through ISMS or a cuff implanted around the femoral nerve, more than 44% of the muscle fibers activated by ISMS were fatigueresistant. In contrast, more than 99% of the fibers activated by nerve cuff stimulation were fast fatiguing (Bamford et al 2005). This in part accounts for the prolonged durations of functional standing and stepping obtained with ISMS. The near normal recruitment order of motor units by ISMS indicates that ISMS activates motoneurons transsynaptically (i.e., indirectly). Previous studies demonstrated that extracellular stimulation within the spinal cord activates fibers in passage at lower stimulus intensities than neuronal cell bodies (Gaunt et al 2006, Gustafsson and Jankowska 1976, Jankowska and Roberts 1972, McIntyre and Grill 2000, Renshaw 1940). Fibers in passage in the ventral horn are most likely composed of the axonal projections of afferents, propriospinal neurons and other interneurons. Activation of these fibers by ISMS leads to the amplification of the locally applied ISMS, full recruitment of motoneuron pools, and the full recruitment of the muscles they innervate. Moreover, activation of fibers in passage produces transsynaptic activation of motoneurons, which results in an orderly S194

recruitment of the motoneurons according to their size, starting with small ones that innervate fatigue-resistant fibers at low stimulation intensities (Henneman 1980, 1985, Henneman and Mendell 1981). Direct activation of motoneurons does occur at higher stimulus intensities in which the neurons are recruited in a reversed order. Thus, ISMS recruits motor units in a mixed or near normal order according to their size as opposed to the reversed recruitment commonly seen with peripheral forms of FES. Taken collectively, the results to date are encouraging and suggest that ISMS may be a viable neuroprosthetic approach for restoring standing and stepping in individuals with SCI. For clinical implementation of ISMS, improvements in the implantation technique are needed. In its current form, only a single active site for stimulation is available per microwire, which reduces the number of motor responses that can be elicited for a given insertion in the cord. Moreover, the manual implantation of the ISMS microwires is tedious and is subject to inconsistencies between subjects. Both the yield and consistency of ISMS implants can be significantly improved through the use of spinal cord specific multi-site microelectrodes (Snow et al 2006) as well as a standardized and automated microelectrode insertion technique. Methods of non-invasive imaging of the implants in vivo would also be needed to verify the implant location over time and monitor the patterns of neural activation evoked by ISMS. Further development of seamless control strategies for overground ambulation with ISMS is also needed. Results of a recent study demonstrated that neither open-loop nor closed-loop control of FES can independently provide robust propulsive and weight-bearing overground locomotion (Guevremont et al 2007). However, a balanced combination of open- and closed-loop control mimicking the subconscious modulations of normal locomotion may offer an appropriate control strategy for producing functional and metabolically efficient ambulation with ISMS after SCI.

5. General discussion and conclusions In this paper, we presented four neuroprosthetic approaches for restoring standing and walking after SCI. The first two approaches have already been implemented clinically and the last two are at various stages of animal experimentation and preparation for initial clinical testing. Surface electrical stimulation (e.g., the Parastep-1 system) provides a means for standing and walking after SCI. Though the system was evaluated as being moderately successful by clinicians, the physiological benefits of the exercise activities it facilitates cannot be overlooked. Some of the disadvantages of surface FES systems are overcome by the CWRU/VA implanted neuroprosthesis for standing and overground ambulation. Significant successes have been achieved by this system and high user satisfaction has been reported. Issues involving fatigue resistance of this system may be addressed with improved physiological recruitment of motor units and full activation of the target muscles. The USEA approach may provide an improvement in the method of motor unit recruitment for enhanced fatigue resistance during

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stance. Furthermore, by having the implant situated in large proximally located nerve trunks, this approach may also reduce the number of individual muscles implanted with epimysial or intramuscular electrodes (Polasek et al 2004, Tarler and Mortimer 2003). Intraspinal microstimulation may provide a new class of neuroprostheses for restoring standing and walking after SCI. By activating the neural networks within the lumbosacral spinal cord, ISMS has the capacity to generate inherently synergistic movements that are weight-bearing and fatigue-resistant. The implant is likely to be very small and contained within the 5 cm-long lumbosacral enlargement of the spinal cord. The devices presented in this paper can greatly benefit from the use of closed-loop control strategies of FES. These strategies can utilize information provided by gyroscopes, accelerometers, force sensors and EMG activity to modulate the intensity of stimulation as well as determine the appropriate times for switching between the swing and stance phases of stepping. Closed-loop control systems can partly relieve the user from the conscious effort of controlling a standing or walking FES system. Furthermore, closed-loop modulation of stimulus intensity has the benefit of reducing instances of over stimulation which would in return prolong the duration of standing and walking by reducing the rate of force decay. The functional benefits attained by neuroprosthetic devices could be further augmented by the use of other approaches for restoring function after SCI. The combination of FES with rehabilitation interventions such as body weight supported treadmill training (Barbeau et al 2002, Dobkin et al 2006, Field-Fote 2001) and pharmacological agents such as clonidine and quipazine (Barbeau and Rossignol 1991, Brustein and Rossignol 1999, Rossignol 2000), could improve the quality and duration of standing and walking obtained by FES. Furthermore, the potential future successes of neuroregeneration are likely to reduce the severity of SCI and transform complete injuries to ones that are incomplete. The restored connections may be random, dysfunctional or too weak to evoke functional muscle contractions. FES could play an important role in inducing movement-related plastic modifications in the restored connections and augment their strength to produce functional movements. It is recommended that appraisal of the current FES technology and future advancements be based on a more comprehensive consideration of these devices and the effects associated with their use. Evaluations of the ‘success’ of FES technologies should include the application of FES as a means to address the physiological dysfunction and sedentary lifestyles associated with severe neurological disorders. The ultimate judges of FES systems should be the most important group that interacts with SCI, i.e., the users of this technology.

Acknowledgments This paper is based on presentations at a panel discussion at the NIH-sponsored Neural Interfaces Workshop, August, 2006. The review is co-authored by N Kleitman in her private capacity. No official support or endorsement by the National Institutes of Health is intended or should be

inferred. R J Triolo’s work was supported by the US Department of Veterans Affairs (Merit Reviews B3155R and B4451R), the Office of Orphan Product Development of the USFDA (FD-R-001244), and the National Institutes of Health (R01-NS40547 and EB-001889). R A Normann’s work was supported by the National Institutes of Health/National Institute for Neurological Disorders and Stroke (NIH/NINDS, R01-NS39677). Andrew Wilder, Brett Dowden, Scott Hiatt, and Drs Gregory A Clark and Nicholas A T Brown contributed to the IFMS results presented in this review. V K Mushahwar’s work was supported by the National Institutes of Health/National Institute for Neurological Disorders and Stroke (NIH/NINDS, R01-NS44225), the International Spinal Research Trust (ISRT), and the Canadian Institutes for Health Research (CIHR). VKM is an Alberta Heritage Foundation for Medical Research (AHFMR) Senior Scholar. Jeremy Bamford, Lisa Guevremont, Bernice Lau, and Rajiv Saigal contributed to the ISMS results presented in this review. The art work in figure 5 was prepared by Jan Kowalczewski.

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