4
Pathology and Impairment Research

From a medical perspective, the most basic way of investigating potentially disabling conditions is to study them in the performance realms of pathology and impairment. As defined in the conceptual matrix for rehabilitation science and engineering in Chapter 3 (see Table 3-2), research in the pathology and impairment realms of rehabilitation science and engineering includes studies of isolated cells, tissues, and organs derived from human or animal subjects. The performance variables of interest are measures of molecular, cellular, and organ or organ system function. Although the performance of the cells and organs may be assessed in an intact human, humans are not absolutely required for pathology and impairment research; pathology and impairment research may be performed using isolated cells and organs from humans or animals. These preclinical studies are intended to (1) define significant parameters or valid markers of pathology and impairment, (2) illustrate relationships (causal and other) among significant parameters, and (3) identify the mechanisms and factors governing changes in significant parameters.

By examining the different sciences that contribute to rehabilitation science and engineering, the roles and uniqueness of rehabilitation science and engineering are defined. This chapter evaluates the multiple number of scientific disciplines that contribute to knowledge about pathology and impairment and the scientific research that generates it. To better understand the importance of research in these areas and to define their boundaries, the chapter also addresses the major categories of activity limitations experienced by adults and children and the impairments



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--> 4 Pathology and Impairment Research From a medical perspective, the most basic way of investigating potentially disabling conditions is to study them in the performance realms of pathology and impairment. As defined in the conceptual matrix for rehabilitation science and engineering in Chapter 3 (see Table 3-2), research in the pathology and impairment realms of rehabilitation science and engineering includes studies of isolated cells, tissues, and organs derived from human or animal subjects. The performance variables of interest are measures of molecular, cellular, and organ or organ system function. Although the performance of the cells and organs may be assessed in an intact human, humans are not absolutely required for pathology and impairment research; pathology and impairment research may be performed using isolated cells and organs from humans or animals. These preclinical studies are intended to (1) define significant parameters or valid markers of pathology and impairment, (2) illustrate relationships (causal and other) among significant parameters, and (3) identify the mechanisms and factors governing changes in significant parameters. By examining the different sciences that contribute to rehabilitation science and engineering, the roles and uniqueness of rehabilitation science and engineering are defined. This chapter evaluates the multiple number of scientific disciplines that contribute to knowledge about pathology and impairment and the scientific research that generates it. To better understand the importance of research in these areas and to define their boundaries, the chapter also addresses the major categories of activity limitations experienced by adults and children and the impairments

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--> and pathologies associated with these limitations. These categories are presented not to suggest that these pathologies and impairments be studied exclusively but, rather, to prioritize the need for the development of knowledge related to significant functional limitations affecting human independence, autonomy, and productivity in society. The state of knowledge for selected pathologies and related impairments is reviewed to describe the gaps in knowledge that exist and promising areas in which knowledge can be developed through research from the perspective of rehabilitation science and engineering. Sciences Contributing Knowledge to Studying Pathology and Impairment Research Knowledge in the realms of pathology and impairment comes from a variety of disciplines that partially overlap. Biology, engineering, and the physical, social, and behavioral sciences all contribute to rehabilitation science and engineering, in that those disciplines provide knowledge related to the altered cell and organ functions that may lead to disabling conditions. Rehabilitation science and engineering is unique in that it melds the knowledge from these otherwise distinct disciplines and creates a multidisciplinary structure that allows one to understand the nature of disability, that is, how potentially disabling conditions develop, progress, or reverse and the factors that mediate disabling or enabling processes. So, although an array of biological sciences offers knowledge of the normal molecular-cellular and organ-organ system level of performance, as well as of the molecular, cellular, and organ defects that lead to various pathological states and impaired organ system function, many of the factors that determine enabling and disabling processes and movement between the realms of pathology and impairment are related to disciplinary knowledge beyond that from the biological sciences. For example, replacement of organ function may entail an artificial organ (e.g., kidney dialysis machine, mechanical heart, or artificial hip) that emanates from a combination of medical and engineering research. Developments in engineering offer the hope of providing environments to assist with human functioning in the face of disability and impairment. Social sciences provide knowledge of the influence of personal lifestyle and societal conventions on enabling and disabling processes, even disability-related changes in performance at the molecular and cellular (pathology) and the organ (impairment) levels. The health professional disciplines support and stimulate the basic science research relevant to rehabilitation science and engineering and, most importantly, see that new knowledge from the basic sciences and rehabilitation science and engineering is translated into therapeutics and clinical care.

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--> Physiology, Cell Biology, Neuroscience, Developmental Biology, Gerontology, Vascular Biology, and Biochemistry The knowledge generated in the biological sciences, including, physiology, cell biology, neuroscience, developmental biology, gerontology, and biochemistry, has a direct relationship to rehabilitation science and engineering to the extent that this knowledge explains the basis of pathological function of the human biological system. Scientists in these fields study the structures and functions of the molecular, cellular, organ, and organ systems known to be the cause of disabling conditions. Particularly useful to rehabilitation science and engineering are elements of pathophysiology that are specifically associated with disability, including injury processes and intrinsic mechanisms for recovery or compensation of function at the cellular and organ-organ system levels. Of particular interest are markers of disease and disease progression, including ones that vary by gender, race, and age or developmental stage. Because of their seminal contribution to knowledge of human cell and organ function, these sciences are also critical to the development of knowledge that allows investigators to identify and understand complications of disability that present as secondary conditions, such as decubiti, infections, pain, muscle spasticity, joint dysfunction, immunological deficiencies, disease atrophy of skeletal muscle, micturition dyssynergia, and sexual impotence. The biological sciences are also critically important to rehabilitation science and engineering for the development of animal or surrogate (computer or tissue culture) models of disabling diseases and disorders. A major obstacle to effective rehabilitation research is the paucity of good nonhuman models of disabling conditions that can be used to accurately predict treatment efficacy in humans. For example, current animal models that are important to rehabilitation research include models of neuropathic pain, spasticity, decubiti, infection, contractures, arthritic disorders, abnormal ossification, skeletal muscle atrophy, locomotor deficits, scoliosis, bladder and sphincter dyssynergia, thrombophlebitis, peripheral ischemia, bums, visuomotor deficits, postural instability and vestibular ataxia, posture-related autonomic dysfunction, endocrinological deficits, and immunological deficits. Tissue cultures are used to model apoptosis or skin healing. Genetics and Molecular Biology Although many disabling conditions are not intrinsic but are acquired (e.g., because of trauma, aging, infection, or exposure to harmful environmental agents), a significant number have their origins in the genetic inheritance of the individual either as defects of a single gene or as multiple gene disorders or chromosomal abnormalities. Duchenne muscular

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--> dystrophy and cystic fibrosis, for example, are inherited genetic disorders that are associated with progressive pathology and impairment. These manifest primarily with aging and, perhaps, as a result of environmentally determined factors that influence the timing of expression of a defective gene, such as that linked to breast cancer (e.g., BRCA-1) (Hall et al., 1990; Easton, Bishop, Ford et al., 1993). Normal human processes of special interest to rehabilitation science and engineering are growth and healing, repair, and compensatory mechanisms; these processes are critically dependent on the up- and down-regulation of genes and gene products. Similarly, normal human development and maturation are the manifestations of genetics, and thus, genetic disorders and disability are intertwined. At present genetics and molecular biology offer unique perspectives and powerful investigative techniques for providing an understanding of the cause and nature of some diseases at their most fundamental biological levels. It is also hoped that genetics and molecular biology will provide markers of these diseases and that nonhuman animal models can be used to study the factors determining the resultant disabling and enabling processes. Although not yet realized, the promise of this realm of biological science is genetic and molecular biological therapies that will allow for the exogenous replacement of defective and missing genes or the stimulation of expression of existing genes, perhaps even to regrow cells, organs, and limbs. Pharmacology Many pharmacological agents are used in rehabilitation therapeutics. The specific cellular and organ actions of drugs and pharmaceutical agents are often not well understood. Basic pharmacological research focuses on the mechanisms of drug actions. Rehabilitation science and engineering critically needs knowledge of how pharmaceutical agents act on cells with existing pathology and on impaired organs so that agents useful in the management of potentially disabling conditions and the prevention of secondary conditions can be found. For example, the effects of 4-aminopyridine on axonal conduction in an animal model of diabetic neuropathy or spinal cord injury shows promise for human study and application. Pharmacologic agents are also a means of regulating gene expression in the developing and mature organism. Engineering and Physical Sciences Engineering is traditionally viewed as the application of science to the needs of society. The application of engineering to problems of people with impairments and disabling conditions however, is still rather young. Continuity in the application of engineering in rehabilitation can be traced

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--> only to 1945, the end of World War II, as described in Chapter 1. Engineering in rehabilitation has given many people the opportunity to demonstrate what is possible when disabling conditions are transcended through technical assistance. One of the contributions of engineering to rehabilitation science and engineering lies in creating altered, supportive environments (external or internal) for people with disabling conditions, because when engineering of the environment is maximized, the manifestations of pathologies and impairments as functional limitations and disabilities are minimized. In addition, virtual reality systems that are in development may allow for the remote control of function and communication through robots and other engineered devices, such as eye- or voice-controlled power wheelchairs. These engineered environments limit or reverse the functional manifestations of pathology and organ impairment by compensating for or replacing the altered or lost function with engineered structures and devices. The majority of current rehabilitation engineering research is in the fields of materials sciences, biomedical engineering, and engineering technology development. Prosthetics and orthotics, replacement of joints by endoprostheses, neuroprostheses, implantable lenses and pacemakers, and implantable drug delivery systems are examples of engineered exogenous devices that improve function by replacing diseased organs or compensating for their impaired function and that help investigators in rehabilitation science and engineering to build their knowledge of enabling processes. Similarly, pressure-distributed and regulated seat cushions and other devices for people who use wheelchairs exemplify how engineered environments can prevent secondary conditions. Engineering and physical sciences are also critical to the development of tools that can be used to measure outcomes at the cellular, tissue, organ, and organ system levels of performance. These tools allow for the assessment of the development of pathology and impairment and the progression of disabling and enabling processes. The data are derived from biological science research, but the tools are from engineering and physical sciences. The usefulness of the data to rehabilitation however, depends on the validity, reliability, and sensitivity of the measurements of the relevant parameters. In particular, rehabilitation science and engineering research needs outcomes that can be obtained by noninvasive or minimally invasive means and measures that can be used to track pathology and impairment. Social and Behavioral Sciences The significance of social and behavioral sciences to knowledge of pathology and impairment stems from their importance to understanding the effects of the individual and the social environment. Knowledge from psy-

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--> chology, anthropology, sociology, political science, economics, epidemiology and communication science contributes to understanding of pathology and impairment. For example, smoking leads to progressive cellular and respiratory system disease and the resultant functional limitation. Social sciences help to pinpoint who is most at risk for this pathology as well as for other aspects of the enabling-disabling process. Social sciences help to isolate cultural or behavioral elements which contribute to the development of pathologies, including, for example, sexual behavior, dietary habits, and driving behavior. Studies in epidemiology indicate the role that behaviors play in contracting the spread of potentially disabling pathologies. Health and Health Professional Sciences The health professional disciplines are essential to understanding the dimensions of human health and assisting people with achieving health. These sciences, including medicine (physical medicine and rehabilitation), nursing (rehabilitation nursing), physical therapy, public health, exercise physiology and sports medicine, audiology, occupational therapy, speech-language pathology, audiology, and veterinary medicine, among others, are important to rehabilitation science and engineering in that they foster the development of basic and applied science relevant to rehabilitation science and engineering. Relevant and ongoing research is occurring in all these fields and in addition, biomedical engineering and rehabilitation engineering make contributions to solve problems in the area of rehabilitation. It is frequently the clinician-scientist who asks questions about pathology and impairment and the enabling and disabling processes. The non-clinician physiologist, in contrast, may be interested in a pathology only to explain a normal cellular process. The health professional disciplines are also important to rehabilitation science and engineering in that they translate theoretical knowledge in rehabilitation science and engineering into innovations in therapeutics and evaluate their effectiveness. Veterinary science may also contribute to the knowledge of enabling processes in rehabilitation science and engineering. Animals offer companionship and, if properly trained, assistance with mobility, activities of daily living, and communication. There are many examples of animals creating a social and physical environment that limits the negative impacts of pathology and impairment on human function. Animals also offer a means of continuing exercise despite impairments or chronic disease, for example, horseback riding for people with leg paralysis or multiple sclerosis. Uniqueness of Rehabilitation Science and Engineering Although much knowledge of and research on pathology and impairment in rehabilitation science and engineering overlap those of basic bio-

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--> logical, engineering, social and behavioral, and health and health professional sciences, rehabilitation science and engineering is unique in melding this research and knowledge into a conceptual matrix to address the problems of people with disabling conditions (see Table 3-2 in Chapter 3). Rehabilitation science and engineering also includes and combines variables in ways that would not occur in the separate existing sciences, for example, an epidemiological study of the association of a particular pathology (using a biological marker) with a disability (using a social role performance measurement) to evaluate the health of a population. Rehabilitation science and engineering has the potential to organize and coordinate research in the existing disciplines and to fill in gaps in research to ensure that there is an appropriate knowledge base to address disability and rehabilitation. There is significant overlap between many existing sciences and the pathology and impairment realms of rehabilitation science and engineering, and these related sciences have the potential to meet the basic and applied research needs of rehabilitation science and engineering. The highest priorities for rehabilitation science and engineering should be to, from the rehabilitation perspective, focus, coordinate, and support currently fragmented research efforts. Researchers from many disciplines will address the questions of rehabilitation science and engineering if they are introduced to them as priorities and the work is supported. State of Knowledge for Selected Major Causes of Pathology in Adults Since orthopedic and musculoskeletal pathologies and impairments are those most frequently associated with the most prevalent adult activity limitations, the committee reviewed the state of knowledge in selected fields related to the control and function of the musculoskeletal system. The following sections address neural restoration and regeneration, synovial joints and soft tissue, the neuromuscular system, and skeletal muscle in terms of state of knowledge and potential for development as an area of pathology and impairment research in rehabilitation science and engineering. This material is not intended to be a comprehensive review, but rather a summary description. Central Nervous System The inability of the brain and spinal cord to repair and regenerate themselves is one of the most established dogmas in science. In the same way that infectious diseases were regarded as incurable a century ago, clinicians regarded with great pessimism the possibility of effective therapies for brain and spinal cord injuries. Rehabilitation research was domi-

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--> nated by the view not only that the brain and spinal cord are incapable of repair, growth, and reconnection, but that it was impossible to develop therapies to restore brain and spinal cord function. As a consequence, research on neurological impairments has been oriented toward assessing mechanisms of injury, epidemiology, improving outcome measures, and preventing secondary injuries and conditions. This pessimism, however, is beginning to reverse. In the past decade, researchers have overturned the dogma that the brain and spinal cord cannot regenerate. A majority of scientists now believe that it is not a matter of if but when such therapies will become available. Neuroprotective therapies that can be given after injury are already available for spinal cord injury and are in development for traumatic brain injury and stroke. Remyelinative and other reparative treatments are being developed. Thus, the door has been open for new therapies that will have a large impact on preventing and reversing neurological impairments. An exhaustive description of recent therapeutic advances is beyond the scope of this chapter. However, it should be noted that significant advances have been achieved for neural tissue with preventative and regenerative therapies. Preventative therapies stop the process developing from no pathology to pathology. Regenerative therapies reverse the process from pathology to impairment. Prevention of secondary injury is one of the primary goals of rehabilitative therapy, since brain and spinal cord injuries are believed to be immediate and irreversible. Animal studies, however, have suggested for decades that some injuries can be reversed by treatments given shortly after an individual sustains an injury. In 1991, the National Acute Spinal Cord Injury Study showed that high-dose corticosteroids given to individuals within 8 hours after they sustain a spinal cord injury significantly improve their neurological recovery (Bracken et al., 1990, 1992). More than a dozen other therapies have been reported to be neuroprotective in people who have sustained acute spinal cord injuries (Nockels and Young, 1992). To identify the next generation of neuroprotective therapies, scientists are now collaborating in the first multicenter preclinical studies of promising therapies (Basso et al., in press). Laboratory studies have revealed that several classes of therapies significantly reduce ischemic and traumatic brain injuries. One of these, the calcium (Ca2+) channel blocker nimodipine, has been shown to improve neurological recovery after subarachnoid hemorrhage (Allen et al., 1983). Glutamate receptor blockers have shown substantial promise in animal studies and are beginning to be tested in clinical trials (Choi, 1992). Other treatments, including those with opiate receptor blockers and free radical scavengers, as well as hypothermia, reportedly have neuroprotective effects in individuals who have sus-

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--> tained ischemic and traumatic brain injuries (Dietrich, 1992; McIntosh, 1992). The convincing evidence that the central nervous system can regenerate was reported 15 years ago when Aguayo and colleagues reported that central neurons send fibers (axons) into peripheral nerves that are inserted into the brain or spinal cord (Aguayo et al., 1981, 1983, 1990; David and Aguayo, 1981; Benfey and Aguayo, 1982). Although the axons grew long distances in the peripheral nerves, they failed to penetrate back into the central nervous system at the other end of the peripheral nerve inserted into the brain or spinal cord. Aguayo and colleagues suggested that factors in central nervous system tissues prevent growth. In 1987, Schwab and colleagues identified two related proteins in the spinal cord (on the myelin) that appear to inhibit axonal growth (Caroni and Schwab, 1988 a,b; Caroni et al., 1988; Schwab and Caroni, 1988). Blockage of one of these proteins (neurite growth-inhibiting factor) with an antibody allowed regeneration to occur in injured rat spinal cords and improved locomotion (Bregman et al., 1995). This study established the concept that white matter-associated inhibitory proteins prevent regeneration. Cheng, Cao, and Olsen (1996) recently used peripheral nerve bridges and a growth factor to produce functional regeneration in adult rats with fully transected spinal cords. They avoided the inhibitory factors in white matter by bridging spinal tracts from white matter (where the axon tracts are situated) to gray matter (where the neuronal cell bodies are situated). In addition, they used a growth factor called fibroblast growth factor. Although this treatment strategy is not yet applicable to a majority of individuals who have sustained spinal cord injuries, these findings represent a strong refutation of the regeneration dogma. They further confirm the growing conviction of many scientists that regeneration is possible under some circumstances. Several laboratories are working on alternative approaches. For example, several studies have suggested that fetal cells also provide a suitable bridging environment at the injury site. Other researchers have implanted genetically modified cells that express and secrete molecules known to support axonal growth. Synovial Joints and Soft Tissue The human body contains many synovial joints, which comprise capsules, ligaments, tendons, and articular cartilage. These joints vary in size and facilitate different motions to fulfill the activities of daily living. The hip, knee, ankle, shoulder, elbow, and various joints in the hand are synovial joints. Together, they act to guide articulating bones, smoothing the path of motion and reducing friction.

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--> Much collaborative work has been done by biomedical engineers, biochemists, anatomists, and clinicians to gain a basic understanding of the function of articular cartilage, various ligaments and tendons, and the capsular structure around synovial joints. In addition, valuable gait analysis information has characterized the three-dimensional motion of joints, which act both individually and synergistically during ambulation. Some soft tissues will heal spontaneously when they are injured, whereas others will not. Tissues that do not heal are often replaced by surgeons using autologous or allogeneic tissue grafts. Surgical treatment of soft tissue injury often requires a postoperative rehabilitation regimen of physical therapy and activity restrictions. These protocols are generally not based on scientific studies, and thus, considerable research is needed in the area of postoperative rehabilitation to define proper protocols. For example, not known are the acceptable mechanical loads for the tissues in the immediate postoperative period and how over time these loads can be adjusted as the tissue heals. It is generally known that stress and motion are required to promote tissue healing. Without them, tissues will form contractures and joint motion will be limited. In some cases, the loss of function is permanent. Contractures are among the most difficult rehabilitation problems. Prevention of contractures requires placing a load on healing tissues, but the maximal safe load is still undefined. The type, intensity, and frequency of loading necessary to maintain the composition and properties of most nominal soft tissues can vary over a broad range. This is not the case, however, for injured or repaired tissues. It is therefore important to know how and what type of rehabilitation protocol can best maintain tissue composition properties and promote healing. Rehabilitation of synovial joint injuries should focus on (1) regaining the range of motion and function of the joint and (2) restoring the tissue properties to those of normal tissue. To accomplish this, it is necessary to first understand normal tissue and joint function from the structural level all the way down to the molecular level. In this respect, knowledge can build on what has been learned from various biomechanical, biochemical, and molecular biology measurements of normal soft tissue. However, the knowledge base is much smaller when dealing with healing soft tissues. For example, the anterior cruciate ligament of the knee, one of the most frequently injured ligaments, has no ability to heal once it is torn, especially if the injury falls in the midsubstance of the ligament. Clinical experience has shown that more positive results are obtained by replacement of the ligament than by repair. Popular techniques involve reconstruction with tissue grafts. However, there is a great deal of controversy regarding graft configuration, intra-articular graft positioning, initial graft tensioning, and postoperative rehabilitation protocols. Therefore, it is

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--> important that the stress and strain levels in the graft during the postoperative rehabilitation process be evaluated. With this information, the changes in graft tissue properties over time can be charted, yielding quantitative data on the maximal allowable forces and elongation in the anterior cruciate ligament graft and how they change with healing over time. This will allow for the development and optimization of rehabilitation regimens. Articular cartilage repair is another area that has received much attention, because articular cartilage lacks the ability to repair itself. Recently, chondrocyte transplantation and various other surgical techniques have been developed to promote cartilage regeneration. The surgical procedures are controversial, and little attention has been paid to the design of postoperative rehabilitation. Yet, rehabilitation may be the key to the successful outcome of cartilage repair. Additionally, noninvasive probes need to be developed so that the pathological conditions and overall properties of the articular cartilage during the rehabilitation period can be determined. The field of molecular biology has also contributed the idea of using various growth factors to improve the quality of healing tissues. In the proper setting, growth factors could be used as an adjunct to improve healing during the rehabilitation period. This area has a great deal of potential, and the techniques to be developed and studied include the vehicle that should have been used for growth factor delivery, types of growth factors to be used, and how the use of growth factors can be optimized to accelerate tissue repair. It is also well documented that proprioceptive responses in the soft tissues around the synovial joints are important to injury prevention and rehabilitation. Scientific studies in this area have gained momentum in recent years, and this concept must be extended to the postoperative or postinjury rehabilitation of the soft tissues of synovial joints. Proper retraining of proprioceptive responses in injured soft tissues is critical to facilitating healing, restoring nominal kinematics and function, and preventing further injury. Neuromuscular System In peak performance, as exemplified in ballet, basketball, or simple ambulation, the ability of the human neuromusculoskeletal system to produce graceful, meaningful movements is one of the wonders of nature. Neuroscientists are interested in how the central nervous system controls the muscles that produce such graceful human movements. Such knowledge of the control of movement is likely to be important to understanding pathologies of the neuromuscular system. Impressive progress

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--> is being made in the motor control field by a large cadre of neuroscientists, and this progress bodes well for the future rehabilitation of people with neuromuscular disorders. It is not enough, however, to understand the neurological control of the human motor system; the biomechanical system of the body must also be understood if there is to be a thorough understanding of the neuromuscular system. Biomechanicists have been investigating this system of muscles, tendons, ligaments, tissues, and bones almost from the time of Leonardo da Vinci and Galileo Galilei. Today the field of human biomechanics is burgeoning as never before. Throughout the world, thousands of investigators connected with fields such as biomechanical engineering, robotics, physical therapy, orthopedics, physical medicine and science, sports medicine, exercise science, limb prosthetics, orthotics, psychology, and behavioral science are working in the field of biomechanics. Some are beginning to pull together neuroscience and biomechanics, a union that is important to understanding the complete system. This multidisciplinary array of scientists, engineers, and clinicians is gaining knowledge that promises to provide not only an understanding of the complex human motor system, but also the scientific and technical knowledge required to assist impaired or nonfunctional neuromuscular systems. Present research in neuroscience and biomechanics will enable clinicians, rehabilitation engineers, and others to provide effective assistance to people with neuromuscular impairments. This assistance may be provided through suggestions for structural modifications through surgery. On the other hand, it may be provided through suggestions for therapeutic modifications (i.e., exercise) or the use of implanted assistive technical systems such as muscle stimulators or external devices such as mechanical bracing or limb replacement. Effective replacement or artificial assistance for parts of the human neuromuscular system are some of the most challenging problems of biomedical science and engineering. Nonetheless, the possibilities have already been shown by the advances that have been made in the areas of limb prostheses, total joint replacements, and functional electrical stimulation of paralyzed muscles. The extensive and remarkable advancements in cardiac pacing provide an excellent example of what can be accomplished through human muscle stimulation. It should be remembered, however, that the advancement of cardiac pacemakers came about over a long period of time and as the result of extensive funding of a large number of investigators. Engineers and scientists in the field of robotics research and design also have interest in the human neuromuscular system. Study of this system may assist with the design of new robotic arms or robotic walking systems. Such robotic designs might assist with obtaining an understanding of the human neuromuscular system itself, because often an under-

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--> standing of simpler technical systems aids in providing an understanding of more complex biological systems. Subtle aspects of the performance of the neuromuscular system may be observable by motion analysis equipment. Gait analysis has been helpful in providing an understanding of human and animal movement since the scientific work of Marey in France during the latter part of the 19th century and the photographic work of Muybridge in the United States at about the same time. Gait and movement analysis systems are ubiquitous today, and their use for neuromuscular investigations should be encouraged. Sensitive analysis of integrated activities such as standing, walking, and pointing may prove to be effective in the early diagnosis of movement disorders of the neuromuscular system. Measurements of this kind may also be useful in assessing the propensity for falling among people who are aging. Multidisciplinary efforts are necessary for rapid progress in these areas. Engineering measurement equipment, coupled with knowledge of the neuromuscular systems, has the potential to quantify muscle spasticity. Quantification equipment of this kind, along with other kinds of instrumentation, will likely be important in measuring neuromuscular treatment outcomes and in monitoring patient compliance with the use of therapeutic and assistive devices supplied to assist them with their neuromuscular impairments. Mathematical and computer modeling of the neuromuscular system can also have important impacts on understanding neuromuscular systems. Musculoskeletal models of the human arm and leg systems are already showing promise in understanding the ''crouch gait" of people with spastic diplegia. Models of this nature can also be used to predict the results of surgical procedures involving muscle transfers. Likewise, biomechanical measurement equipment can assist surgeons with obtaining the precise "tone" desired in muscle transfers. Computer-aided surgery and computer-assisted surgical decision making are already prevalent in orthopedics, and their use will continue to expand. Skeletal Muscle Skeletal muscle is the largest tissue mass in the human body and as such, it plays a dominant role in metabolism, thermal regulation, and fluid and electrolyte balance in the human body, in addition to being the contractile tissue responsible for all voluntary movement. Skeletal muscle is also requisite for exercise and the beneficial physical and psychological effects of exercise conditioning. A considerable body of knowledge in the scientific disciplines of physiology, biophysics, anatomy, and biochemistry covers the normal physiology of muscle, including the molecular basis

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--> of force production, muscle shortening, the intracellular cycling of calcium (transduction of chemical energy into mechanical energy), and the steps in the excitation-contraction coupling process that transforms the electrical signal on the muscle cell membrane into a chemical signal (Ca2+) that activates the contractile proteins. The field of skeletal muscle physiology has a long history, and much of the definitive work has been through studies of nonmammalian, such as amphibian, crustacean, and striated muscle. This information obtained from studies of nonmammalian muscle is highly relevant, however, in that the most basic structure-function relationships in skeletal muscle hold true for species ranging from frogs to humans; even the diameters of the cells of a skeletal muscle are in the same range in a variety of species. What varies is the complexity of cell organization, their activation by nerves, and the number of cell phenotypes expressed. Interestingly, exercise physiologists have been a major force in advancing the study of mammalian tissue, and their work has been bolstered by the biochemists and anatomists interested in the more complex mechanisms of mammalian tissue and seeking answers to the basis for the different phenotypes of skeletal muscle cells in mammals, despite a singular genotype. The normal physiology of human skeletal muscle appears to be the same as that of skeletal muscle from other mammals. Paralysis Any disruption of motor neuron function, in the neuromuscular junction, or in the spread of the action potential of the muscle fiber will cause paralysis of that muscle fiber. This accounts for the skeletal muscle paralysis in individuals who have sustained spinal cord injury, in individuals with direct motor neuron or muscle trauma, or in individuals with the disease myasthenia gravis, in whom the receptors for the chemical that carries the signal from nerve to muscle in the neuromuscular junction (acetylcholine receptors) are diminished by an abnormal autoimmune process. Paralysis of skeletal muscle can have consequences beyond the loss of voluntary limb movement. It can alter respiration, because the diaphragm and intercostal muscles of the respiratory system are also skeletal muscles. The pelvic floor musculature is also made up of skeletal muscle, and weakness is known to contribute to stress urinary incontinence (see Miller, Kasper, and Sampselle, 1994). Normally, one motor neuron branches to supply a variable number of muscle fibers within a given muscle. This organization of the motor neuron with multiple fibers is termed the motor unit. All of the fibers in a motor unit are thus stimulated simultaneously and equally, and they all respond by becoming the same phenotype. Each time the motor neuron

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--> sends a signal to contract, each fiber in the motor unit contracts maximally in a twitch that lasts 100 to 200 milliseconds. In normal human skeletal muscles, the fiber type composition is cross-sectionally mixed, and the same type of fibers of each motor unit are distributed throughout the muscle rather than located in physical proximity to each other. Gradations in muscle force generation are achieved by activating motor units of various sizes over time (Henneman, Somjjn, and Carpenter, 1965a,b). This allows for delicate or forceful movement and for short-duration or sustained force generation. The normal compensatory mechanisms for the loss of the motor neuron in a motor unit include branching of a motor neuron from an adjacent motor unit to the denervated fiber this mechanism is operative in recovery from polio (Wiechers, 1985). This knowledge of normal motor unit organization and function is significant to rehabilitation science and engineering, in that methods of exogenously stimulating skeletal muscle will best mimic normal movement if motor neurons are stimulated. The motor neurons in turn will activate skeletal muscle fibers in their physically distributed motor unit. This is in contrast to direct electrical stimulation of skeletal muscle by an exogenous electrode, which activates the clumps of fibers closest to the electrode and which, as a nonphysiological stimulus, can cause hypercontracture damage and pain. Barring direct trauma, relatively few diseases are intrinsic to skeletal muscle per se. Most often these are genetic defects. If the genetic defect is severe, the animal dies at birth because it cannot sustain movement or respiration. However, because of the remarkable plasticity and compensatory processes of skeletal muscle, not all genetic defects are fatal. Duchenne muscular dystrophy is a notable example in which the gene for the structural protein dystrophin is defective or missing from a fiber and contraction causes abnormal damage to the skeletal muscle fibers. The damage increases as the developing child uses skeletal muscles to stand and walk. Attempts are being made to use genetic and molecular biological therapies to treat this disease, but they are hampered by the very large size of the gene to be transferred into the fibers and the structures of the fibers themselves. Skeletal muscle fibers are multinucleated as a result of the fusion of mononuclear myocytes early in development. As a result, any gene replacement must occur in the many nuclei that are distributed along the length of each hair like fiber. Some promising research on nuclei (Eppley, Kim, and Russell, 1993; Kasper and Xun, 1996) and their control in skeletal muscle fibers is in progress and will likely have relevance for gene therapies as well as growth, repair, and phenotypic determination of skeletal muscle fibers. At present the rehabilitation of individuals with pathologies and impairments such as muscular dystrophy is primarily sup-

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--> portive, engineered physical environments in which the individual uses assistive devices (braces, wheelchairs, etc.). Atrophy Atrophy of skeletal muscle is a term used to determine a complex process associated with a reduction in the size (diameter) of muscle fibers or cells. Among the changes associated with atrophy is the decline of metabolic enzyme content. Skeletal muscle may undergo atrophy from disuse secondary to many conditions. Atrophy from disuse is associated with reversible changes in the muscle fiber; however, athrophy caused by dennervation may or may not be reversible. The recovery of skeletal muscle from atrophy is an important aspect of recovery from spinal cord injury and other causes of paralysis or from bed rest with no inherent paralysis (i.e., individuals in a non-weight-bearing state). Similarly, decreased movement due to arthritic pain can lead to the secondary condition of skeletal muscle atrophy. Loss of weight-bearing activity for a period as short as days or weeks can cause significant skeletal muscle fiber atrophy and weakness, making it difficult for the person to resume standing or walking activities. Similarly, use of mechanical respirators can cause diaphragm and intercostal muscle atrophy, and may cause difficulty for people during weaning from these devices. Some relevant and promising research related to the recovery of skeletal muscle from disuse atrophy is being conducted. Overuse, even in the form of normal weight bearing, can cause fiber damage (Kasper, White, and Maxwell, 1990); however, researchers are developing protocols that can be used to test for the degree of even initial postural use (i.e., intervals of standing before walking) of skeletal muscle while tracking recovery versus damage at the cellular and molecular levels. Skeletal muscle exercise and strengthening programs designed for people with postpolio muscular atrophy are a specific example of the use of findings from basic and applied research to understanding and monitoring use versus overuse of skeletal muscle fibers. The promising findings from this line of research is that muscle tissue remains highly plastic and adaptable well into old age (see Thompson, 1984). In addition, exercise for people with rheumatoid arthritis can result in recovery from skeletal muscle atrophy without exacerbating the joint disease (see Rall and Roubenhoff, 1996). Future Needs In terms of the conceptual model of rehabilitation science and engineering, basic and applied research studies of skeletal muscle need to continue and new studies should be initiated. Person-specific and social-

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--> environmental influences that promote or discourage optimum maintenance of muscle function are significant, because optimum maintenance will ultimately determine recovery from skeletal muscle disuse and paralysis and these influences need to be studied. Similarly, the impact of the physical environment on skeletal muscle performance is very important and needs to be studied as well. In summary, because of the importance of skeletal muscle tissue and function to human performance and well-being, research on the adaptability and usage requirements for maintaining adequate skeletal muscle strength and function is important to rehabilitation science and engineering. Research specifically related to maintenance or recovery of skeletal muscle function for individuals with activity limitations is important as the scientific basis of rehabilitation and the prevention of secondary conditions. Conclusions Based upon evaluation of the current state and relevance of knowledge in the pathology and impairment realms of rehabilitation science, the committee determined that basic and applied research from many sciences and engineering is essential to innovations in rehabilitation. Basic and applied research in the pathology and impairment realms is critical for the development of interventions that restore organ and cellular function in the person and, thus, minimize the biological basis of functional limitations and disability. Basic and applied research relevant to restoration of biological function might address repair or regeneration of cell/organ/limb structure in the organism or might address replacement of biological structure and function employing engineered devices. The rehabilitation-related research in the pathology and impairment realms is likely to employ animals and animal tissue culture models as well as human subjects, organs, and cells. Another significant real and potential impact of basic and applied research in rehabilitation science is that of knowledge related to development of secondary conditions in the face of primary disabling conditions. This knowledge is essential to the development of health strategies and interventions as well as determining essential environmental factors that are related and modifiable by engineering other approaches. Great achievements in meeting the challenges of disability have emanated from the melding of basic and applied research in the biological and engineering sciences. The committee determined that strength in basic and applied research in the pathology and impairment realms of rehabilitation science has contributed significantly to the successful approaches in existing enabling processes and offers the promise of dramatic innovations of

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--> the future. The new rehabilitation science offers the added benefit of integrating behavioral and social science perspectives into the pathology and impairment realms. Given the past impact of basic and applied research in science and engineering on the advances in physical medicine and rehabilitation and on outcomes for persons with disabling conditions, the committee was surprised that the review of abstracts from the major federal funding agencies of research did not reflect an inclusion of this type of research in the portfolio identified as rehabilitation related. Only the VA portfolio reflected research utilizing animals and tissue culture subjects/cells and a balance of research activity across the research realms (pathology, impairment, functional limitations, disability) of rehabilitation science. The NIH and NIDRR portfolios of agency-identified rehabilitation-related research, reviewed as abstracts (see Appendix A), were less balanced in that pathology and impairment types of research were less prevalent and the subjects in these studies were primarily human. The committee was unable to ascertain the reason for noninclusion of basic science studies of animals, especially in the NIH portfolio. However, the committee did feel a need to emphasize the significance of animal and basic science and engineering research and development to rehabilitation science. It also concluded that each of the research funding agencies might benefit from establishing specific research priority areas in basic science and engineering from the rehabilitation science perspective. At the very least this would help basic scientists in general to identify additional relevance of their work. It also might give impetus to basic research areas that are most likely to lead to applied advances in rehabilitation. It might also be useful to have the research review committees seeded with basic researchers who are also rehabilitation scientists, especially since part of the merit of a proposal is judged on the basis of its perceived relevance to science in general. The following recommendations of the committee reflect these suggestions to enhance the basic research activity in pathology and impairment realms of rehabilitation science. Recommendations Recommendation 4.1 Multidisciplinary research teams, including basic biological, behavioral, social, health and health professional, and engineering scientists are needed, to broaden the scope of molecular-cellular and organ-organ system research and increase its relevance to rehabilitation science and engineering. Additional funding would be needed to support these activities.

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--> Recommendation 4.2 Based on the National Institutes of Health model, consensus panels should be used to identify areas of pathology and impairment research in rehabilitation science and engineering that are of high priority on the basis of the readiness of the knowledge of the basic science in these areas to be translated to clinical care and potential impact on quality of life and cost to society. Recommendation 4.3 National Institutes of Health should increase the number of peer reviewers who are rehabilitation scientists on all research review committees that consider grants in the pathology and impairment realms of rehabilitation science and engineering.