Pathophysiological tissue changes associated with repetitive movement: a review of the evidence.

Work-related musculoskeletal disorders (WMSDs) of the upper extremity (UE) account for a small, but significant, proportion of injuries in US private industry and may contribute to high medical costs and long-term disability. A recent review of over 600 articles on this subject by the US National Institute of Occupational Safety and Health (NIOSH) concluded that repetitive motions, particularly in combination with high force or awkward postures, increase the risk of developing WMSDs. (1) In recognition of the seriousness of this occupational health problem, the US Occupational Safety and Health Administration (OSHA) developed guidelines for workplace ergonomic programs, which received congressional and presidential approval in the final weeks of the Clinton administration. (2)

In March 2001, however, the US Congress repealed the OSHA final Ergonomics Program Rule. Although the future of government regulation of ergonomic risk factors and WMSDs is uncertain, the basic program elements outlined in the OSHA Ergonomics Program Rule echo those recommended by NIOSH, (3) the National Safety Council, (4) and many private companies. (5-7) Among these program elements is job hazard analysis and control, which includes reduction of biomechanical risk factors such as repetition rate and forcefulness of exertions. In addition, OSHA explicitly recognized the role of physical therapists in the management of employees with WMSDs. Among these responsibilities is the assessment of an employee's readiness to return to his or her job duties. In preparation for the next iteration of proposed ergonomics regulation in the US workplace, some employers seeking the professional guidance of health care professionals and ergonomists are asking the question, "How many repetitions and how much force are safe for my employees?"

The NIOSH, through its research programs, has developed a lifting equation to assist employers in determining the maximally safe limits to manual material handling for individual employees performing specific lifting tasks, (8) and this equation has been validated in a cross-sectional study. (9) To date, no such equation or quantitative guide is available for hand- and UE-intensive tasks. This lack of an easily used quantitative guide for the UE stems, in part, from the fact that the effects of repetition rate and force on the UE in particular and the musculoskeletal system as a whole are incompletely understood. This lack of understanding is problematic given that employers may want to make adjustments to workplace practices for affected workers. Furthermore, it is likely that business groups will continue to challenge future OSHA ergonomics rules based on this lack of precise exposure-response data. The scientific and health care communities, in our view, should provide direct evidence of tissue injury to support the epidemiological evidence linking physical risk factors in the workplace to the development and exacerbation of musculoskeletal disorders. More research is needed to describe the pathophysiological responses of tissues to UE-intensive tasks and then to establish clear criteria for their prevention and management. The former goal may best be accomplished through the study of animal models of repetitive movement tasks because the analysis of tissue specimens is feasible in animals.

The objectives of our review are (1) to characterize the scope of UE WMSDs based on recent epidemiologic and clinical research, (2) to discuss recent research regarding the relationship between repetition rate and forcefulness of reaching movements and WMSDs in humans, (3) to discuss cellular responses to injury in both in vivo and in vitro experimental models, and (4) to discuss recent findings from animal injury models of repetitive or forceful tasks. A conceptual framework for the development of WMSDs in general will be proposed. Areas in need of further research will be identified, with an emphasis on animal models of UE WMSDs. The use of such models for future studies of the response of injured tissues to therapeutic interventions will make important contributions to physical therapy practice in occupational health care settings. We hope that this review will assist investigators in identifying key characteristics of such models and in selecting tissues and therapeutic outcomes for future study.

Scope of Upper-Extremity WMSDs

Epidemiological Evidence

The US Bureau of Labor Statistics survey from 1994 estimated that of the more than 2.25 million injuries and illnesses in US private industry resulting in lost workdays, about 332,000 were attributed to repetitive motion. (10) Although the number of occupational injuries and illnesses due to repetitive motion involving days away from work in the US has declined steadily from its peak in 1994, there were still about 247,000 cases reported in 1999 out of the 2.75 million lost workday injuries and illnesses in US private industry during that year. (11) These injuries continue to pose a substantial source of worker pain and discomfort as well as potential long-term disability and high economic toll.

Injuries of the wrist and hand constitute the majority of repetitive motion injuries of the upper limb and are also the most disabling and costly. According to a recent study of approximately 186,000 federal workers during the period from 1993 to 1994, for example, carpal tunnel syndrome (CTS) accounted for 93% of all mononeuritis claims and for 67% of all direct medical costs, with an average of $2,948 per claim. (12) Brogmus et al (13) examined the Liberty Mutual Insurance Company workers' compensation database, which contains data on a subset of US private industry workers' compensation claims. They found that the incidence of work-related musculoskeletal and nerve entrapment syndromes of the upper limb increased from less than 0.5% of all injuries and illnesses in 1986 to more than 2.5% of all injuries and illnesses in 1993. Upper-extremity WMSD claims for computer-related injuries increased from 1.6% of all UE WMSD claims in 1986 to 14.6% of all such claims in 1993. (14) Carpal tunnel syndrome was second only to forearm muscle strain injuries among computer-related WMSDs. (14) If the treatment for CTS requires surgery, this disorder can result in direct medical costs on the order of $10,000 per patient and may lead to prolonged worker absenteeism and permanent disability.

The term work-related musculoskeletal disorder has been defined by OSHA as a disorder of the muscles, nerves, tendons, ligaments, joints, cartilage, blood vessels, or spinal disks in the neck, shoulder, elbow, forearm, wrist, hand, abdomen (hernia only), back, knee, ankle, and foot associated with exposure to risk factors. (2) According to OSHA, these disorders may include muscle strains and tears, ligament sprains, joint and tendon inflammation, pinched nerves, spinal disk degeneration, and medical conditions such as low back pain, tension neck syndrome, carpal tunnel syndrome, rotator cuff syndrome, DeQuervain syndrome, trigger finger, tarsal tunnel syndrome, sciatica, epicondylitis, tendinitis, Raynaud phenomenon, hand-arm vibration syndrome, carpet layer's knee, and herniated spinal disk. (2) Data from epidemiological and field studies suggest that there is a relationship between the onset and severity of WMSD and the performance of highly repetitive or forceful work tasks, particularly in harsh (ie, cold or vibrating) environments, (1,15-24)

Common WMSD Diagnoses and Their Etiologies

Among jobs requiring repetitive movements of the upper limb, CTS is the most common work-related neuritis. (25-28) Because the median nerve passes through the carpal tunnel along with the long finger and thumb flexors, it is susceptible to mechanical compression or friction by the tendons themselves. Positions and movements of extreme wrist flexion, particularly in conjunction with non-neutral forearm pronation-supination, contribute to increases in carpal tunnel pressure and tensile or compressive loading of the median nerve. (29-39) This increase in pressure within the carpal tunnel may occlude blood supply, resulting in ischemic damage to both the tendons and the median nerve. (40-42)

Anoxia damages the endothelial lining of venules and capillaries, increasing their permeability and resulting in localized edema. The edema can lead to an influx of monocytes, and this influx of monocytes can induce the proliferation of fibroblasts and synoviocytes in synovial tissues, which deposit collagen. (43,44) If this collagen deposition is excessive, it may directly contribute to compression of the median nerve. (45) Other physical risk factors, such as vibration from hand-held tools, may contribute to the development of CTS. (22,46) Carpal tunnel syndrome is associated with deficits in sensation along the median nerve distribution, weakness of the thenar muscles innervated by the median nerve, hand and wrist pain, and long-term disability, including decreased endurance as measured by the rate of repetitive pinching as well as weakness and clumsiness of grasping ability. (47,48)

Musculoskeletal injuries associated with WMSD include tendinitis, tenosynovitis, ganglionic cysts, focal dystonia, fibromyalgia, myositis, bursitis, osteoarthritis, and synovitis. (49-53) Byl et al (54) were able to detect decrements in kinesthesia among patients with tendinitis associated with cumulative trauma disorder (CTD) and decrements in graphesthesia (the ability to discern and reproduce figures drawn on the dorsum of the hand with eyes closed) and manual form perception (measured as the ability to identify and later visually match objects palpated while blindfolded) among patients with focal dystonia associated with CTD. Two research teams have reported vasodilatation and subsequent increased micro-circulation to affected muscles among patients with CTD-related myositis. (55-57)

Vascular and neurovascular disorders such as Raynaud disease or reflex sympathetic dystrophy (RSD) have also been associated with WMSDs. Reflex sympathetic dystrophy has been associated with the use of hand tools that vibrate, particularly in cool working environments. (49,50) Hansford et al (58) studied workers in the suture-manufacturing industry, workers who performed repetitive upper-limb movements. They demonstrated decreased circulation in the radial and ulnar arteries at the wrist after only 1.5 hours of work. Pritchard el al (59) later found vasoconstriction of the radial arteries in workers with complaints of diffuse forearm pain associated with repetitive work. These findings suggest that repeated movements may impair circulation, with the potential for causing ischemic injury to musculoskeletal tissues and peripheral nerves.

Relationship Between Repetition-Force and WMSDs

Psychophysical Estimates of Repetition-Force Exposure

Although the localized responses of tissues to mechanical or ischemic injury are well documented, there is still considerable doubt as to the exposure-response relationship between the repetitiveness and forcefulness of a task and the onset of pathophysiology. Several researchers have attempted to establish criteria for maximum acceptable forces and movements for hand tasks based on psychophysical outcomes. Snook et al (60,61) tested female subjects who performed repetitive, forceful wrist flexion and extension or radial and ulnar deviation tasks for 7 hours per day over a period of 3 weeks. Based on subjects' symptoms, the maximum acceptable forces for a power grip task performed at a rate of 15 motions per minute were estimated for women to be 26 N (approximately 5% body weight [BW]) for wrist flexion, 15 N (approximately 3% BW) for wrist extension, and 14 N (approximately 2.5% BW) for wrist ulnar deviation. There was a decrease in maximum acceptable torque with increasing hours in the day and days of exposure in the week, with a concomitant increase in symptom and error rates as well as tactile sensitivity.

Lin and Radwin (62) used psychophysical ratings of perceived exertion (RPEs) collected in their laboratory, as well as data published by other researchers, (61,63,64) to develop a frequency-weighted filter to estimate discomfort from continuous biomechanical measurements. The resulting model showed that wrist flexion angle, force, and repetition rate during a wrist flexion task using a power grip contributed to discomfort ratings. Although Lin and Radwin did not consider duration of exposure longer than 1 hour, they confirmed the influence of repetition rate and force as risk factors for developing perceived discomfort in occupational hand-intensive tasks. Presumably, performance of such tasks for periods greater than 1 hour would only increase worker discomfort, an eventuality that has implications for activities performed throughout a typical 6- to 8-hour work shift.

Grant et al (65) demonstrated relationships between certain electromyographic (EMG) measurements of upper-limb muscles and of RPE and grip force. Although the number and weight of the EMG and RPE variables depended on the specific task in question, grip force could be predicted to a moderate degree ([r.sup.2]=.52-.63). Grant et al, therefore, helped to establish a relationship between muscle physiology, worker perception, and functional activity.

Biomechanical Estimates of Repetition-force

In their classic study, Silverstein et al (24) performed job analyses of industrial workers that included videotaping job task cycles (ie, the basic sequence of movements required to perform the task goal). Based on these measurements, the authors defined high repetition rate as less than 30 seconds per cycle and low repetition rate as greater than 30 seconds per cycle. Surface EMG recordings of the forearm flexors were obtained during grip exertions of known force. Using these reference EMG recordings, estimates of hand force were made from EMG recordings collected during the performance of job cycles and were used to define low force as hand force below 1 kg and high force as hand force above 4 kg. The authors reported prevalence ratios for WMSDs of 3.6 for high-repetition-low-force tasks, 4.9 for low-repetition-high-force tasks, and 30.3 for high-repetition-high-force tasks. This and later work strongly suggest that the interactive effects of repetition and force are more than additive in contributing to the risk for development of WMSDs. (19,23,28)

Given that force is a continuous variable, defining discrete levels of force that are relevant to the occupational setting in which workers are at risk for WMSDs may be crucial to investigations of this injury process. Many authors have defined force levels based on estimates of force needed for components of tasks, observations of workers, or direct measurements. Table 1 summarizes a number of such studies (19,24,28,36,65-68) and the resulting force level definitions for hand-intensive work tasks. These data show that, despite the differences in methods of force estimation, there is a consensus that an exertion requiring less than 15% of maximum grip force can be considered negligible to low and exertions requiring greater than 50% of maximum grip force can be considered high. This leaves the range of 16% to 49% of maximum grip force as a moderate force range for gripping or grasping tasks.

Direct Observation of Tissues Exposed to Repetitive or Forceful Tasks

Although researchers in studies such as those already cited in this review have attempted to quantify and relate perceived exertion and WMSD symptoms, their use of noninvasive methods to estimate worker performance or risk creates limitations in studying pathophysiology in human subjects. Investigators are unable to easily relate psychophysical and biomechanical measures with pathophysiological changes. Using an invasive approach, Dennet and Fry (69) performed open biopsies on affected first dorsal interosseous muscles in patients with painful chronic overuse syndrome and found histological and ultrastructural changes in muscle fibers consistent with denervation or ischemic loss of type II muscle fibers and hypertrophy of type I fibers. Larsson et al (70) showed the presence of cellular pathology related to mitochondrial dysfunction in trapezius muscle biopsies from assembly-line workers with localized chronic myalgia of the trapezius muscle related to static shoulder postures during precision manual tasks. The observed changes were consistent with localized hypoxia and were correlated with reduction in muscle blood flow.

The number of such tissue studies in humans is very small because of the invasiveness of tissue analysis techniques. In addition, it is impossible in these studies to control (or even accurately measure) the amount of repetitive activities performed by a person with a WMSD. Consequently, many questions about the interaction of repetition rate and force and the precise pathophysiological changes of the tissues remain unanswered. The extent to which such behaviors impair the motor control system and lead to functional limitations and chronic disability are just beginning to be recognized. This lack of knowledge is, in part, responsible for the persistent controversy in the United States and other industrialized nations surrounding the degree to which musculoskeletal disorders are the outcome of repetitive occupational tasks as opposed to the usual and expected consequences of typical activities of daily life. In addition, individual predisposing factors, such as comorbid medical conditions, may contribute to the onset and severity of WMSD. Thus, regulatory progress to prevent and manage these disorders, despite the strong epidemiological evidence for their existence, continues to be impeded.

A more precise understanding of the effects of repetitive and forceful tasks on tissues may help to guide therapeutic strategies for preventive and early care of affected individuals, rehabilitation approaches for subacute and chronic conditions associated with WMSD, and prevention of chronic disability. Given the impediments to observing the tissues directly in humans in either the workplace or health care settings, animal injury models provide an alternative means of elucidating the exposure-response relationship between repetition-force and WMSDs.

Cellular Indicators of Injury

There are expected cellular and biomechanical changes to tissues that researchers may use to study in animal injury models. Structural damage to most tissues results in the proliferation of progenitor cells of that tissue. (43,45,71) A simultaneous infiltration of lymphocytes, macrophages, and other phagocytic cells occurs in response to a diffusion of intracellular factors through damaged plasma membranes. (72,73) The combination of these proliferative and infiltrative processes can lead to tissue changes over time. For example, mechanical injury to muscle fibers results in disruptions of the sarcolemma and sarcomere, which causes leakage of cellular components into the extracellular matrix and diffusion of serum components into and around the myofibers. (74-76) These alterations of the extracellular matrix can lead to tissue regeneration or scarring. (74,75) Repeated muscle injury results in expansion of extracellular matrix and collagen deposition around the myofibers (ie, fibrosis) and fiber necrosis. Direct damage to tendons and ligaments causes a similar process of fibroblast proliferation, which leads to fibrosis and collagen dysplasia. (77-81)

When cells experience mechanical or metabolic stresses, whether acute or chronic, they react by increasing the production of a family of proteins called heat shock proteins (HSPs). (82,83) These proteins are produced following inflammation, infection, hyperthermia, ischemia, nerve crush or transection, neural degenerative diseases, or exposure to various toxins. (84,85) A variety of cell types produce these proteins in response to injury, including neurons, glia, fibroblasts, and muscle cells. These proteins have been shown to have a protective role in the cell. (86) During periods of cellular stress or injury, the inducible HSP-70/72 increases to recognize and restore denatured proteins to their native state. (87,88) The presence of these stress proteins in peripheral tissues following a repetitive motion task would indicate that a repair process has begun, resulting from the accumulation of denatured proteins. (89,90) Various disrupters of cellular proteins that may occur in WMSDs include ischemia, microtears in the cell membranes, or the release of cytotoxic free radicals from damaged cells. The study of the induction of these proteins in response to repetitive movements could lead to clinical interventions that may halt the progression of chronic WMSDs and disability.

Primary tissue damage also results in a cellular release of cytokines, which are mediators of inflammation, cell proliferation, cell migration, and regeneration, (91-93) Many peripheral tissue cell types, including fibroblasts, myocytes, and endothelial cells, respond to damage by upregulating a number of proinflammatory proteins, including interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha (TNF[alpha]), and prostaglandin E2. (91-93-95) Cytokines released during acute inflammation (eg, IL-1[alpha], IL-1[beta], TNF[alpha]) mediate the proliferation and maturation of macrophages and other mononuclear cells as well as fibroblasts. (96-99) Activated macrophages and other mononuclear cells then produce even more cytokines, such as IL-l, IL-6, and IL-11, that further stimulate inflammation. (71,98,100,101) Interleukin-1 enhances the expression of COX2, a proinflammatory enzyme with an important role in the synthesis of prostanoids, such as prostaglandin E2. Interleukin-land TNF[alpha] also serve as potent stimulators of osteoclast activity, (102-106) The phagocytic action of the activated inflammatory cells and osteoclasts can result in direct tissue damage. Thus, a vicious cycle of tissue damage can be initiated, leading to chronic inflammation. (96) We hypothesize that in repetitive tasks, this injury cycle is prolonged and thus amplified by continued task exposure. This hypothesis, among others, can be tested in animal models of repetitive movement disorders.

Animal Models of Repetitive Movement Disorders

Although many epidemiological and clinical studies of human subjects have demonstrated a link between repetitive, forceful motor tasks and the development of localized musculoskeletal and peripheral nerve injury, a clear relationship between the amount of repetitive activities and the pathophysiological findings has not been established. Animal models of both repetitive movements as well as other mechanisms of injury have provided some valuable information in this regard. Those studies that represent a cross-section of the literature or that make a unique contribution to this review are discussed in detail in the paragraphs that follow. A more extensive list of such studies * is summarized briefly in Tables 2 and 3.

Involuntary Movement Models

Repetitive passive flexion and extension of the tails of rats at 25 Hz for 2 hours per day, 6 days per week, for 8 weeks have resulted in histological changes in tail vertebrae. (107) Intervertebral disk and bone changes included disk protrusion into the vertebral end plate, disk prolapses without protrusion at the disk-end plate interface, growth plate dislocation and thickness variation, and trabecular irregularity in the vicinity of disorganized growth plate regions. Cartilage changes included clumping of chondrocytes and decreases in both number and organization of chondrocyte columns. The histological findings were not accompanied by any symptoms or behavioral indicators of discomfort or functional loss, which demonstrates that skeletal tissues, as well as soft tissues and nerves, may be sensitive to repetitive, submaximal loading and that tissue disruption may precede symptoms and functional impairments.

A model of repetitive movement injury using the scratch reflex movement of the rabbit hind limb resulted in histological changes consistent with localized Achilles tendon inflammation after a training period of 6 to 8 weeks. (78) High and low load-repetition protocols were followed for 1 to 2 hours per day, 3 days per week. Although gross morphological changes were not observed in any of the loaded tendon specimens, inflammatory cells and areas of hypercellularity were observed in the outer tendon after 6 and 8 weeks regardless of loading protocol. Expression of the inilammatory mediators IL-1[beta] and TNF[alpha] was also increased. (108) These findings suggest an injury response to submaximal repetitive loading that is consistent with the nature of the complaints of patients with WMSDs such as dull, burning aches associated with localized inflammation. This work also illustrates the usefulness of animal models in which amount of repetitive activity can be controlled and the response of tissues can be observed directly.

Repeated forced-lengthening, or stretch, has speed-specific effects on rat soleus muscle. (74,109) In these studies, the soleus muscle was electrically stimulated while repeated stretching through forced ankle plantar flexion and dorsiflexion was carried out at slow and fast speeds every other day for 4 weeks. Slow stretching resulted in an increase in muscle mass that was caused by muscle fiber hypertrophy. Fast stretching also resulted in an increase in muscle mass, but the reason for the increase in mass in this case was an increase in noncontractile tissues without muscle fiber hypertrophy. In addition, the fast-stretch protocol resulted in the appearance of many smaller, less mature muscle fibers, which suggests myofiber regeneration in response to muscle injury. These results illustrate the gradation of effects of forceful and repetitive movements on the muscular tissues and suggest that a threshold exists between acceptable loads and rates of loading and those that cause tissue injury. It is important for clinicians to be able to estimate how close the force and repetition requirements of a particular job are to this injury threshold.

Pain and Peripheral Nerve Injury Models

Numerous researchers have shown that chronic pain leads to neuroplastic changes in the spinal cord of rats. Chronic pain, particularly chronic intense pain, results in repeated activation or chronic stimulation of nociceptive afferents from application of capsasin or formalin or from joint inflammation. (110-112) The sustained nociceptive afferent barrage causes a release of excitatory neurotransmitters and neuropeptides such as glutamate (113) and substance P (SP). Substance P activates its receptor, neurokinin-1 (NK-1), located on dendrites of postsynaptic neurons in dorsal horn superficial laminae. Glutamate activates the N-methyl-D-aspartate (NMDA) receptors that are co-localized with NK-1. Activation of both receptors has been shown to stimulate complex cascades of intracellular events within the postsynaptic cell. One action is the release of a retrograde messenger, nitrous oxide, which stimulates an increased release of glutamate from the presynaptic cell and thus further activates NMDA receptors postsynaptically. (114) Other cascades result in alterations in genes that lead to an upregulation of receptors as well as hormones, peptides, and enzymes in the postsynaptic cell. (115) The end results are hyperalgesia and allodynia via the potentiation of the pre-existing synapse and an increase in the responsiveness of the postsynaptic cell to afferent inputs of any type. (116-118) In people with WMSDs, this is manifested as painful sensations in response to nonpainful stimuli. Such a complaint among people with chronic pain may be interpreted by clinicians as "symptom amplification," a term that connotes a psychological basis for symptoms when a pain response elicited on examination seems to exceed the intensity expected from the clinical signs.

Nerve constriction also causes neuroplastic changes, including decreases in SP in the dorsal horn, increases in NK-1 receptor in the dorsal horn, and de novo expression of neuropeptide Y (an excitatory neuropeptide) in the dorsal root ganglion (DRG). (117,119) Central neuroplastic-changes may occur with acute, localized inflammation and peripheral nerve compression brought about by the performance of repetitive, forceful tasks. There is evidence of activity-induced synaptic modification of central neuronal networks. (120,121) These neuroplastic changes may occur at multiple levels of the somatosensory pathways following peripheral nerve injury and CTS. (122,123) These hypotheses are as yet untested in an in vivo WMSD injury model of a voluntary repetitive movement task.

Voluntary Movement Models

Repetitive grasping movements of the upper limb and hand have been shown to induce dedifferentiation of topographical fields in the S1 (Brodman's area 3b) somatosensory cortical region in owl monkeys. (124,125) In animals that performed the task with simultaneous closing followed by opening of all digits, the somatotopic changes were consistent with other findings of surgical syndactyly and supported the idea that the central representation of digital independence is reliant on the timing of somatosensory input. (137,138) Animals using the simultaneous digit movement pattern experienced a decrement in task performance and related functional activities after 3 or 24 weeks of training that was consistent with occupational hand cramps. The results of this work suggest that neuroplasticity induced by highly constrained and repetitive behaviors may contribute to the behavioral consequences of such tasks irrespective of localized injury. Histological analysis of hand and wrist tissues by these investigators using hematoxylin and eosin staining yielded no evidence of acute, localized inflammation. This finding supports the idea that there were neurologically induced behavior changes. Based on these findings, it is arguable that maladaptive behavior in highly repetitive tasks is, in part, centrally mediated and may be unresponsive to interventions that address only localized injury.

In our laboratory, we have developed an in vivo, voluntary repetitive movement injury model in the rat that simulates an occupational paced reaching and grasping task. An example of a paced task would be repeatedly placing small objects that are traveling on a conveyor belt into a package crate. In such a job, the pace is controlled by the rate of speed of the conveyor belt, and the same reaching and grasping cycle is repeated throughout the task shift. This model allows us to observe the effects of repetition on tissues and on motor behavior. In this model, adult Sprague-Dawley (albino) rats 12 weeks of age are trained to reach into a narrow tube placed at shoulder height to retrieve small, spherical food pellets dispensed at a predetermined rate. Reach repetition rate, reach success, and gross movement behavior are recorded during task performance sessions. Several cohorts of animals have worked from 2 to 9 weeks at a target repetition rate of 4 reaches per minute for 2 hours per day, 3 days per week.

Using this model, we have shown that 2 increasingly reach movement patterns emerged in rats trained to perform the reaching and grasping task for up to 9 weeks. (51) The scooping pattern, in which the digits were semiflexed and the pellet was dragged along the floor of the feeding tube and scooped into the mouth, was observed in 80% of trained animals by week 7. The raking pattern, in which the digits were extended and the pellet was contacted repeatedly in an inefficient raking motion until it was advanced toward the tube opening, was observed in 100% of trained animals by week 8. Heat shock protein-72-IR cells were increased over control levels in the myofibers and loose connective tissues of the lumbrical muscles by 3 weeks of training, and in the tendons and muscle bellies of the distal forelimb flexor muscles by 4 weeks. COX2-IR cells were also present in these tissues and in the radiocarpal ligaments by 6 weeks of training. These latter 2 findings suggest progressive injury to forelimb tissues.

Macrophage infiltration, as indicated by ED1 expression, was quantified in the radiocarpal ligament and the flexor muscles and associated tendons of the palms and distal forelimbs of trained animals as well as controls. The numbers of ED1-IR macrophages increased as much as 1,000 times above control levels in the muscle and tendon of forelimbs used to reach (reach limbs) from 3 to 5 weeks of task performance, with a return toward control levels by 6 weeks. The progressive increase in EDI-IR cells was also observed in contralateral, nonreach limbs, but lagged that in reach limbs by 1 week and had a twofold to threefold lower response magnitude. The IL-1[beta] levels showed a pattern of increase similar to that of ED1-IR cells. The presence of a lower response magnitude in the nonreach limbs that lags that in the reach limbs suggests a systemic inflammatory response to a high-repetition-negligible-force reaching and grasping task. This possibility warrants further investigation, particularly in light of the sometimes vague and nonlocalized complaints of patients with WMSDs who may be affected by such widespread effects of localized task performance.

We have recently begun to explore the consequences of increased task forcefulness on peripheral tissues, behavior, and neuroplasticity. We believe such investigations are enhanced by our model of a voluntary repetitive movement paradigm. The insights into the physiological and behavioral adaptations of organisms to the adverse effects of such task demands should be even more applicable to the human condition than reflexive or other involuntary movement models.

A Conceptual Schematic for WMSDs

A summary of the pathophysiological changes arising from cumulative trauma injury, regardless of its work-relatedness, in various species and experimental paradigms is provided in Tables 2 and 3. Based on our review of the literature, a conceptual schematic for the development of WMSD resulting from the performance of a repetitive, forceful, posturally constrained movement is proposed (Figure). Noted in this figure are the points in this injury process when clinicians are most likely to intervene. This time frame for clinical intervention may be too late to reverse some of the pathophysiological and neuroplastic changes that have already taken place, which perhaps explains why chronic disability is an increasing consequence of WMSDs.

[FIGURE OMITTED]

Areas for Further Research

Because of the intricacy of the responses to the performance of repetitive tasks over time, a complete understanding of pathophysiological and behavioral phenomena requires an in vivo animal injury model that reasonably approximates humans. We view the essential elements of such a model to be as follows:

1. The repetitive task must be voluntary in order to engage the entire motor control system; therefore, the animal species must be trainable by standard operant-conditioning procedures.

2. The anatomy of both the musculoskeletal and nervous systems must be well described and sufficiently similar to that of humans. This would limit the potential species to mammals.

3. Investigators should be able to monitor motor behavior in terms of both target task speed and accuracy as well as other indicators of motor function such as strength and movement patterns; therefore, a species should be chosen for which the target movement has been described and test procedures have been validated.

4. Methods must be well described and supplies commercially available for immunohistochemical/biochemical analyses of the tissues of the musculoskeletal and nervous systems. In order to ensure the usefulness of any models in multiple laboratories for corroboration of findings, we should preclude the use of immunohistochemical/biochemical assays developed in specific laboratories, which is common in this field of investigation.

In our laboratory, we have recently developed such an injury model using the Sprague-Dawley (albino) rat. The literature on the training, testing, and tissue analysis of this species is rich and meets all 4 of the criteria we listed. The fact that the rat is a quadruped animal raises concerns regarding exposure amplification to the forelimb due to normal weight bearing. This variable can best be controlled through the use of control animals. The reaching behavior, anatomy, and physiology of the rat are well described. In addition, procedures for assessing all of these attributes are available in the scientific literature and, to a large extent, commercially available equipment exists to do so. This makes the use of this species attractive.

Animal models can be used to elucidate the exposure-response relationship between risk factors and the onset and severity of WMSDs. Several animal models of different species and subspecies of mammals are currently in use and show consistent results that corroborate clinical findings in humans. Thus, it would appear that despite genetic variations between species or genetic homogeneity of a particular subspecies, animal models may help to answer mechanistic questions that are inapproachable in humans. Risk factors that can be studied in animal models include repetition rate and forcefulness of exertions to perform tasks. These risk factors could be studied alone or in combination Exposure to different levels of risk for variable work shift duration would also help to elucidate these exposure-response relationships.

The effects of therapeutic interventions could be tested in animal models. Rats would be amenable to a variety of therapeutic approaches, including, for example, the implementation of work-rest cycles, aerobic fitness programs, job rotation schemes, pharmaceutical interventions, and environmental controls. Although studies of more cortically intensive interventions would be impractical in the rat, some sensorimotor integration techniques might be feasible in this species.

Conclusion

In the Guide to Physical Therapist Practice, (139) the model definition of physical therapy includes examining work barriers, ergonomics, and body mechanics as well as the impairments and functional deficits associated with musculoskeletal and motor dysfunction. Physical therapists, therefore, may be called upon to identify workplace risk factors that can be modified to relieve, reduce, or prevent musculoskeletal injury. Yet, our current knowledge of the magnitude of risk given a particular level of exposure is limited by the fact that few researchers have observed the onset of tissue injury directly. The use of animal models will enhance the ability of investigators to make predictions of risks, thereby informing clinicians about more effective management of WMSDs.

Animal models permit the exploration of tissues and components of the motor control system heretofore unreported in the occupational health literature. Although we assume that the injuries sustained from repetitive, forceful work are primarily in the peripheral musculotendinous and neural tissues near the exposure site, there is increasing evidence that a systemic response may develop and that neurological reorganization may take place more centrally in the spinal cord and even in the cerebral cortex. Neuroplastic reorganization may precede the onset of motor decrements, thereby contributing to the onset of localized injury. If repetitive movements cause cortical plasticity, it is probable that spinal cord and brain-stem plasticity has also occurred, because sensory inputs to the cortex originate in the periphery. Such alterations may be more amenable than cortical regions to direct therapeutic intervention, and strategies for clinical management of WMSDs may have to include restoring and maintaining somatotopic differentiation of central nervous system representations of involved body segments and treatment of distant musculoskeletal tissues rather than simply improving the physical capacity of the tissues near the exposure site. (140) Therefore, the extent of the reversibility of such distant tissue and neuroplastic changes in the context of a repeated-movement behavioral paradigm needs to be demonstrated. An in vivo, voluntary movement model in the rat is well suited for the investigation of physical risk factors, such as repetition rate and forcefulness of exertions, and provides an opportunity to examine the interactive effects of multiple risk factors on both the motor behavior and pathophysiological consequences of repetitive movements.

Table 1.
Summary of Studies Investigating Repetition-Force Levels of Hazardous
Hand-Intensive Occupational Tasks (a)

Reference                                     Method of Force
No.         Study Type          Sample        Estimation

66          Cross-sectional     N= 161        Task-based with subsample
                                                of direct measurements

36          Experimental        N= 12 UE      Manipulated according to
                                  (cadaver)     Armstrong et al, 1982

65          Experimental        15 males      Direct measurement of grip
                                                force with different
                                                object masses

67          Statistical model   Literature    Stress-strength
                                  data          interference model

19          Cross-sectional     N= 230        Weight of object and
                                                estimated maximum
                                                strength of workers

68          Clinical            N= 33         Electromyographic
              intervention                      biofeedback of upper
                                                trapezius muscle

24          Cross-sectional     N= 574        Direct measurement of
                                                subsample

28          Cross-sectional     N= 652        Weight of tools/materials

Reference
No.         Study Type          Force Levels       Findings

66          Cross-sectional     High> 100 N        OR= 1.11 for wrist
                                                     pain at high force
                                                     level

36          Experimental        Range of applied   Nonlinear,
                                  loads: 23, 46,     monotonically
                                  65, 80 N           increasing
                                                     relationship
                                                     between applied
                                                     load and finger
                                                     flexor tendon
                                                     strain, with creep
                                                     evident within a
                                                     physiological load
                                                     range

65          Experimental        Grip force         RPE (Borg)
                                  categories: Lt     reflects grip
                                  [congruent to]     load, which is in
                                  14% MVC grip       turn related to
                                  Med [congruent     object mass
                                  to] 23% MVC        (Lt=0.5 kg, Med=
                                  grip Hvy           1.1 kg, Hvy=2.3
                                  [congruent to]     kg)
                                  31% MVC grip

67          Statistical model   High>100 N         Probability of
                                                     tendon failure
                                                     increases above
                                                     high force level

19          Cross-sectional     Neg [less than     Force was most
                                  or equal to]       highly weighted
                                  <15% MVC Lt=       risk factor in
                                  16%-30% MVC        regression
                                  Md=31%-50% MVC     analysis for UE
                                  Hvy=51%-75%        WMSD morbidity
                                  MVC VHvy>75%
                                  MVC

68          Clinical            Critical value:    Musculoskeletal
              intervention      10% MVC              symptoms decreased
                                                     if upper trapezius
                                                     muscle activation
                                                     stayed below
                                                     critical value

24          Cross-sectional     Avg low=3 kg       Plant adjusted OR
                                Avg high=12.7kg      for hand and wrist
                                                     WMD:
                                                     LOF.LOR=10
                                                     HIF.LOR=4.9
                                                     LOF.HIR=3.6 *
                                                     HIF.HIR=30.3

28          Cross-sectional     High>40 N grasp    OR for hand and
                                Low<10 N grasp       wrist tendinitis:
                                                     LOF.LOR = 1
                                                     HIF.LOR=6.1
                                                     LOF.HIR=3.3
                                                     HIF.HIR=29.4

(a) OR=odds ratio, LOF=low force, LOR=low repetition, HIF=high force,
HIR=high repetition, RPE=Borg scale for rating of perceived exertion,
MVC:maximal voluntary contraction, Avg=average, Lt=light, Med=medium,
Hvy=heavy, VHvy=very heavy, Neg=negative, WMSD=work-related
musculoskeletal disorder, UE=upper extremity. Asterisk indicates lack
of statistical significance.
Table 2.
Musculoskeletal Changes in the Pathophysiology of Cumulative Trauma
Injury

                                      Species             Reference No.

Tendon and tendosynovial changes
  Tendinitis, tenosynovitis           Human; guinea pig   52; 53
  [down arrow] kinesthesia            Human               54
  Microdamage due to tension,         Human               36
    compression,
    and shear
  [up arrow] production of            Human; rabbit       52, 81; 78
    collagen and rearrangement of
    fibers
  [up arrow] fibroblasts              Rabbit              45
  Tendon and tendon-axon adhesions    Human; rabbit       36; 45
  [up arrow] protaglandin E2 and      Human               92, 94
    leukotriene B4
  Synovitis, destruction of           Human               37, 50
    synovial membranes
  [up arrow] inflammatory cells and   Rabbit; rat         78, 108; 51
    cytokines
  Connective tissue thickens and      Rabbit; rat         78, 108; 45,
    becomes fibrous                                         74
  Altered expression of matrix        Rabbit, rat         78, 108; 51
    components and proinflammatory
    cytokines
  Vascular proliferation around       Rabbit              45
    tendon and in synovium
Flexor retinaculum changes
  [up arrow] vimentin, [down arrow]   Human               80
    tubulin
  Fibroblasts converted to            Human               80, 126
    myofibroblasts
  Collagen dysplasia                  Human               81
Muscle changes
  [up arrow] inflammatory cells       Rat                 51
  [up arrow] heat shock protein       Rat                 51
  [down arrow] grip strength          Human               47, 48
  [up arrow] number of muscle         Human               69
    fibers
  Hypertrophy of muscle fibers        Human; rat          69; 109
  Mitochondrial changes in Type II    Human               70
    fibers
  [up arrow] blood flow in general    Human               55-57
    forelimb area
Loose connective tissue changes
  [up arrow] inflammatory cells       Rat                 51
  [up arrow] heat shock protein       Rat                 51
Bone and cartilage changes
  Intervertebral disk protrusion/     Rat                 107
    prolapse
  Vertebral growth plate thickness    Rat                 107
    defects
  Chondrocyte clumping/               Rat                 107
    disorganization
Table 3.
Neurological Changes in the Pathophysiology of Cumulative Trauma
Injury (a)

                                      Species             Reference No.

Neuronal changes
  Excursions and strain in the        Human               36, 39
    median nerve
  Wallerian degeneration of           Guinea pig          127, 128
    myelinated fibers
  Prolongation of distal motor        Human; guinea pig   129; 128
    latency
  Slowing of median sensory NCV at    Human               17, 129, 130
    wrist
  Cytoskeletal changes in cutaneous   Human               131
    sensory receptors
Perineuronal changes
  Endoneurial swelling above          Guinea pig; human   53; 132
    compression site
  Intraneural fibrosis                Human               37, 40
  [down arrow] intraneural blood      Human; rabbit       40, 58; 42
    flow due to nerve compression
Glial changes
  Progressive thickening of           Guinea pig          53
    epineurium and perineurium
  Degradation and progressive         Guinea pig; human   127, 128; 132
    thinning of myelin
  Distortion of myelin fiber          Guinea pig          53
    internodes
  [up arrow] GAP 43 in Schwann        Rat                 133
    cells
Central nervous system changes
  Psychomotor deficits                Human               47
  [down arrow] in NGF in dorsal       Rat                 134
    horn
  Degradation of hand                 Nonhuman primate    124, 125,
    representation in S1                                    135, 136
  [up arrow] expression of            Rat                 110-113
    ubstance P

(a) NCV=nerve conduction velocity, NGF=nerve growth factor.

* Reference 17,36,37,39,40,42,45,47,48,50-58,69,70,74,78,80,81,92,94, 107-1036.

References

(1) Bernard BP, ed. Musculoskeletal Disorders (MSDs) and Workplace Factors: A Critical Review of Epidemiologic Evidence for Work-Related Musculoskeletal Disorders of the Neck, Upper Extremity, and Low Back. Washington, DC: US Dept of Health and Human Services, National Institute of Occupational Safety and Health; 1997. Publication No. 97-141.

(2) Ergonomics Program; Final Rule: 29 CFR Part 1910, US Dept of Labor, Occupational Safety and Health Administration. Federal Register. 2000;64(part II):68262-68870.

(3) Elements of Ergonomics Programs: A Primer Based on Workplace Evaluations of Musculoskeletal Disorders. Washington, DC: US Dept of Health and Human Services, National Institute of Occupational Safety and Health; 1997. Publication No. 97-117.

(4) Management of Work-Related Musculoskeletal Disorders [working draft]. Itasca, Ill: National Safety Council, Accredited Standards Committee Z365; 2000

(5) Feuerstein M, Marshall L, Shaw WS, Burrell LM. Mulitcomponent intervention for work-related upper extremity disorders. J Occup Rehabil. 2000;10:71-83

(6) Moore JS, Garg A. Participatory ergonomics in a red meat packing plant, part II: case studies. Am Ind Hyg Assoc J. 1997;58:498-508.

(7) Ergonomics: Effective Workplace Practices and Programs. Transcripts of presentations for conference sponsored by National Institute of Occupational Safety and Health and Occupational Safety and Health Administration, Chicago, Ill, 1997. Available at: http://www.cdc.gov/niosh/homepage.html.

(8) Waters TR, Putz-Anderson V, Garg A, Fine LJ. Revised NIOSH equation for the design and evaluation of manual lifting tasks. Ergonomics. 1993;36:749-776.

(9) Waters TR, Baron SL, Piacitelli LA, et al. Evaluation of the revised NIOSH lifting equation: a cross-sectional epidemiological study. Spine. 1999;24:386-394.

(10) Safety and Health Statistics. Table R33. US Dept of Labor, Bureau of Labor Statistics. 1994. Available at: http://stats.bls.gov/oshhome.htm.

(11) US Dept of Labor, Bureau of Labor Statistics. 2001. Available at: http://www.bls.gov/datahome.htm.

(12) Feuerstein M, Miller VL, Burrell LM, Berger R. Occupational upper extremity disorders in the federal workforce: prevalence, health care expenditures, and patterns of work disability. J Occup Environ Med. 1998;40:546-555.

(13) Brogmus GE, Sorock GS, Webster BS. Recent trends in work-related cumulative trauma disorders of the upper extremities in the United States: an evaluation of possible reasons. J Occup Environ Med. 1996;38: 401-411.

(14) Fogleman M, Brogmus G. Computer mouse use and cumulative trauma disorders of the upper extremities. Ergonomics. 1995;38: 2465-2475.

(15) Crumpton-Young LL, Killough MK, et al. Quantitative analysis of cumulative trauma risk factors and risk factor interactions. J Occup Environ Med. 2000;42:1013-1020.

(16) Macfarlane GJ, Hunt IM, Silman AJ. Role of mechanical and psychosocial factors in the onset of forearm pain: prospective population based study. BMJ. 2000;321:676-679.

(17) Latko WA, Armstrong TJ, Franzblau A, et al. Cross-sectional study of the relationship between repetitive work and the prevalence of upper limb musculoskeletal disorders. Am J Ind Med. 1999;36:248-259.

(18) Viikari-Juntura ERA. The scientific basis for making guidelines and standards to prevent work-related musculoskeletal disorders. Ergonomics. 1997;40:1097-1117.

(19) Moore JS, Garg A. Upper extremity disorders in a pork processing plant: relationships between job risk factors and morbidity. Am Ind Hyg Assoc J. 1994;55:703-715.

(20) Schoenmarklin RW, Marras WS, Leurgans SE. Industrial wrist motions and incidence of hand/wrist cumulative trauma disorders. Ergonomics. 1994;37:1449-1459.

(21) Armstrong TJ, Buckle P, Fine LJ, et al. A conceptual model for work-related neck and upper-limb musculoskeletal disorders. Scand J Work Environ Health. 1993;19:73-84.

(22) Ranney D. Work-related chronic injuries of the forearm and hand: their specific diagnosis and management. Ergonomics. 1993;36: 871-880.

(23) Stock SR. Workplace ergonomic factors and the development of musculoskeletal disorders of the neck and upper limbs: a meta-analysis. Am J Ind Med. 1991;19:87-107.

(24) Silverstein BA, Fine LJ, Armstrong TJ. Hand wrist cumulative trauma disorders in industry. Br J Ind Med. 1986;43:779-784.

(25) Davis L, Wellman H, Punnett L. Surveillance of work-related carpal tunnel syndrome in Massachusetts, 1992-1997: a report from the Massachusetts Sentinel Event Notification System for Occupational Risks (SENSOR). Am J Ind Med. 2001;39:58-71.

(26) Ranney D, Wells R, Moore A. Upper limb musculoskeletal disorders in highly repetitive industries: precise anatomical physical findings. Ergonomics. 1995;38:1408-1423.

(27) Hagberg M, Morgenstern H, Kelsh M. Impact of occupations and job tasks on the prevalence of carpal tunnel syndrome. Scand J Work Environ Health. 1992;18:337-345.

(28) Silverstein BA, Fine LJ, Armstrong TJ. Occupational factors and carpal tunnel syndrome. Am J Ind Med. 1987;11:343-358.

(29) Keir PJ, Wells RP. Changes in the geometry of the finger flexor tendons in the carpal tunnel with wrist posture and tendon load: an MRI study on normal wrists. Clin Biomech. 1999;14:635-645.

(30) Cobb TK, Bond JR, Cooney WP, Metcalf BJ. Assessment of the ratio of carpal contents to carpal tunnel volume in patients with carpal tunnel syndrome: a preliminary report. J Hand Surg Am. 1997;22: 635-639.

(31) Netscher D, Mosharrafa A, Lee M, et al. Transverse carpal ligament: its effect on flexor tendon excursion, morphologic changes of the carpal canal, and on pinch and grip strengths after open carpal tunnel release. Plast Reconstr Surg. 1997;100:636-642.

(32) Werner R, Armstrong TJ, Bir C, Aylard MK. Intracarpal canal pressures: the role of finger, hand, wrist and forearm position. Clin Biomech. 1997;12:44-51.

(33) Kerwin G, Williams CS, Seiler JG III. The pathophysiology of carpal tunnel syndrome. Hand Clin. 1996;12:243-251.

(34) Rempel D, Bach JM, Gordon L, So Y. Effects of forearm pronation/ supination on carpal tunnel pressure. J Hand Surg Am. 1998;23:38-42.

(35) Yoshioka S, Okuda Y, Tamai K, et al. Changes in carpal tunnel shape during wrist joint motion. J Hand Surg Br. 1993;18:620-623.

(36) Goldstein SA, Armstrong TJ, Chaffin DB, Matthews LS. Analysis of cumulative strain in tendons and tendon sheaths. J Biomech. 1987;20: 1-6.

(37) Armstrong, TJ, Castelli WA, Evans FG, Diaz-Perez R. Some histological changes in carpal tunnel contents and their biomechanical implications. J Occup Med. 1984;26:197-201.

(38) Armstrong TJ, Chaffin DB, Foulke JA. Some biomechanical aspects of the carpal tunnel. JBiomech. 1979;12:567-570.

(39) Wright TW, Glowczewskie F, Wheeler D, et al. Excursion and strain of the median nerve. J Bone Joint Surg Am. 1996;78:1897-1903.

(40) Sunderland S. The nerve lesion in carpal tunnel syndrome. J Neurol Neurosurg Psychiatry. 1976;39:615-626.

(41) Lundborg G, Rydevik B. Effects of stretching the tibial nerve of the rabbit. J Bone Joint Surg Br. 1973;55:390-401.

(42) Ogata K, Naito M. Blood flow of peripheral nerve effect of dissection, stretching and compression. J Hand Surg Br. 1986; 11:10-14.

(43) Cannon JG, St Pierre BA. Cytokines in exertion-induced skeletal muscle injury. Mol Cell Biochem. 1998;179:159-167.

(44) Youker KA, Birdsall HH, Frangogiannis NG, et al. Phagocytes in ischemia injury. Ann NY Acad Sci. 1997;832:243-265.

(45) Lluch AL. Thickening of the synovium of the digital flexor tendons: cause or consequence of the carpal tunnel syndrome? J Hand Surg Br. 1992;17:209-212.

(46) Viikari-Juntura E, Silverstein B. Role of physical load factors in carpal tunnel syndrome. Scand J Work Environ Health. 1999;25:163-185.

(47) Jeng O, Radwin RG, Rodriguez AA. Functional psychomotor deficits associated with carpal tunnel syndrome. Ergonomics. 1994;37: 1055-1069.

(48) Weinstein SM, Herring SA. Nerve problems and compartment syndromes in the hand, wrist, and forearm. Clin Sports Med. 1992;11: 161-188.

(49) Piligian G, Herbert R, Hearns M, et al. Evaluation and management of chronic work-related musculoskeletal disorders of the distal upper extremity. Am J Ind Med. 2000;37:75-93.

(50) Hales TR, Bertsche PK. Management of upper extremity cumulative trauma disorders. Am Assoc Occup Health Nur J. 1992;40:118-128.

(51) Barr AE, Safadi FF, Garvin RP, et al. Evidence of progressive tissue pathophysiology and motor behavior degradation in a rat model of work related musculoskeletal disease. In: Proceedings of the International Ergonomics Association/Human Factors and Ergonomics Society 2000 Congress; San Diego, Calif; July 30-August 4, 2000. 2000.

(52) Schuind F, Ventura M, Pateels JL. Idiopathic carpal tunnel syndrome: histological study of flexor tendon synovium. J Hand Surg. 1990;15:497-503.

(53) Ochoa J, Marotte L. The nature of the nerve lesion caused by chronic entrapment in the guinea-pig. J Neurol Sci. 1973;19:491-495.

(54) Byl N, Wilson F, Merzenich M, et al. Sensory dysfunction associated with repetitive strain injuries of tendinitis and focal hand dystonia: a comparative study. J Orthop Sports Phys Ther. 1996;23:234-244.

(55) al-Nahhas AM, Jawad ASM, Norman A, McCready VR. 99Tcm-MDP blood-pool phase in the assessment of repetitive strain injury. Nucl Med Commun. 1997;18:927-931.

(56) al-Nahhas AM, Jawad ASM, McCready VR, Kedar R. Detection of increased blood flow to the affected arm in repetitive strain injury with radionuclide and Doppler ultrasound studies: a case report. Clin Nucl Med. 1995;20:615-618.

(57) Cooke ED, Steinberg MD, Pearson RM, et al. Reflex sympathetic dystrophy and repetitive strain injury: temperature and microcirculatory changes following mild cold stress. J R Soc Med. 1993;86:690-693.

(58) Hansford T, Blood H, Kent B, Lutz G. Blood flow changes at the wrist in manual workers after preventive interventions. J Hand Surg Am. 1986;11:503-508.

(59) Pritchard MH, Pugh N, Wright I, Brownlee M. A vascular basis for repetitve strain injury. Rheumatology. 1999;38:636-639.

(60) Snook SH, Vaillancourt DR, Ciriello VM, Webster BS. Maximum acceptable forces for repetitive ulnar deviation of the wrist. Am Ind Hyg Assoc J. 1997;58:509-517.

(61) Snook SH, Vaillancourt DR, Ciriello VM, Webster BS. Psychophysical studies of repetitive wrist flexion and extension. Ergonomics. 1995;38:1488-1507.

(62) Lin ML, Radwin RG. Agreement between frequency-weighted filter for continuous biomechanical measurements of repetitive wrist flexion against a load and published psychophysical data. Ergonomics. 1998;41: 459-475.

(63) Kim CH, Fernandez JE. Psychophysical frequency for a drilling task. Int J Ind Ergonom. 1993;12:209-218.

(64) Marley RJ, Fernandez JE. Psychophysical frequency and sustained exertion at varying wrist postures for a drilling task. Ergonomics. 1995;38:303-325.

(65) Grant KA, Habes DJ, Putz-Anderson V. Psychophysical and EMG correlates of force exertion in manual work. Int J Ind Ergonom. 1994;13:31-39.

(66) Burdorf A, van Riel M, Brand T. Physical load as a risk factor for musculoskeletal complaints among tank terminal workers. Am Ind Hyg Assoc J. 1997;58;489-497.

(67) Miller SA, Freivalds A. A stress-strength interference model for predicting CTD probabilities. In: Proceedings of the 12th Triennial Congress of the International Ergonomics Association; Toronto, Ontario, Canada; August 15-19, 1994. 1994;2:170-172.

(68) Parenmark G, Engvall B, Malmkvist A-K. Ergonomic on-the-job training of assembly workers. Appl Ergonom. 1988;19:143-146.

(69) Dennet X, Fry HJH. Overuse syndrome: a muscle biopsy study. Lancet. 1998;23:905-908.

(70) Larsson SE, Bodegard L, Henriksson KG, Oberg PA. Chronic trapezius myalgia: morphology and blood flow studied in 17 patients. Acta Orthop Scand. 1990;61:394-398.

(71) Cantini M, Massimino ML, Bruson A, et al. Macrophages regulate proliferation and differentiation of satellite cells. Biochem Biophys Res Commun. 1994;202:1688-1696.

(72) Komulainen J, Kytola J, Vihko V. Running-induced muscle injury and myocellular enzyme release in rats. J Appl Physiol. 1994;77: 2299-2304.

(73) Vuori J, Rasi S, Takala T, Vaananen K. Dual-label time-resolved fluoroimmunoassay for simultaneous detection of myoglobin and carbonic anhydrase III in serum. Clin Chem. 1991;37:2087-2092.

(74) Stauber WT, Knack KK, Miller GR, Grimmett JG. Fibrosis and intercellular collagen connections from four weeks of muscle strains. Muscle Nerve. 1996;19:423-430.

(75) McNeil PL, Khakee R. Disruptions of muscle fiber plasma membranes: role in exercise-induced damage. Am J Pathol 1992;140: 1097-1099.

(76) Stauber WT, Clarkson PM, Fritz VK, Evans WJ. Extracellular matrix disruption and pain after eccentric muscle action. J Appl Physiol. 1990;69:868-874.

(77) Carpenter JE, Flanagan CL, Thomopoulos S, et al. The effects of overuse combined with intrinsic or extrinsic alterations in an animal model of rotator cuff tendinosus. Am J Sports Med. 1998;26:801-807.

(78) Archambault JM, Herzog W, Hart D. The effect of load history in an experimental model of tendon repetitive motion disorders. In: Proceedings of the Marconi Research Conference 1997 (Marshall, CA). 1997:21.

(79) Sheon RP. Repetitive strain injury, 1: an overview of the problem and the patients. Postgrad Med. 1997;102:53-56, 62, 68.

(80) Allampallam K, Chakraborty J, Bose KK, Robinson J. Explant culture, immunofluorescence and electron-microscopic study of flexor retinaculum in carpal tunnel syndrome. J Occup Environ Med. 1996;38: 264-271.

(81) Stransky G, Wenger E, Dimitrov L. Collagen dysplasia in idiopathic carpal tunnel syndrome. Pathol Res Prac. 1989;135:795-798.

(82) Tytell M, Barbe MF, Brown IR. Induction of heat shock (stress) protein 70 and its mRNA in the normal and light-damaged rat retina after whole body hyperthermia. J Neurosci Res. 1994;38:19-31.

(83) Patrusky B. A biological imperative. Mosaic. 1990;21:2-11.

(84) Santoro MG. Heat shock factors and the control of the stress response. Biochem Pharmacol. 2000;59:55-63.

(85) Nowak TS Jr. Protein synthesis and the heat shock/stress response after ischemia. Cerebrovasc Brain Metab Rev. 1990;2:345-366.

(86) Barbe MF, Tytell M, Gower DJ, Welch WJ. Hyperthermia protects against light damage in the rat retina. Science. 1988;241:1817-1820.

(87) Freeman BC, Morimoto RI. The human cytosolic molecular chaperones hsp90, hsp70 (hsc70) and hdj-I have distinct roles in recognition of a non-native protein and protein refolding. EMBO J. 1996;15: 2969-2979.

(88) Martin J, Horwich AL, Hartl F-U. Prevention of protein denaturation under heat stress by the chaperonin Hsp60. Science. 1992;258: 995-998.

(89) Morimoto RI, Santoro MG. Stress-inducible responses and heat shock proteins: new pharmacological targets for cytoprotection. Nature Biotech. 1998;16:833-838.

(90) Pelham HRB. Speculations on the functions of the major heat shock and glucose-regulated proteins. Cell. 1986;46:959-961.

(91) Gallo RL, Dorschner RA, Takashima S, et al. Endothelial cell surface alkaline phosphatase activity is induced by IL-6 released during wound repair. J Invest Dermatol. 1997;109:597-603.

(92) Almekinders LC, Banes AJ, Ballenger CA. Effects of repetitive motion on human fibroblasts. Med Sci Sports Exerc. 1993;25:603-607.

(93) Cannon JG, Fielding RA, Fiatarone MA, et al. Increased interleukin-1[beta] in human skeletal muscle after exercise. Am J Physiol. 1989;257: R451-R455.

(94) Almekinders LC, Baynes AJ, Bracey LW. An in vitro investigation into the effects of repetitive motion and nonsteroidal antiinflammatory medication of human tendon fibroblasts. Am J Sports Med. 1995;23: 119-123.

(95) MacIntyre DL, Reid WD, McKenzie DC. Delayed muscle soreness: the inflammatory response to muscle injury and its clinical implications. Sports Med. 1995;20:24-40.

(96) Cotman CW, Hailer NP, Pfister KK, et al. Cell adhesion molecules in neural plasticity and pathology: similar mechanisms, distinct organizations? Prog Neurobiol. 1998;55:659-669.

(97) Johnson CS, Keckler DJ, Topper MI, et al. In vivo hematopoietic effects of recombinant interleukin-1[alpha] in mice: stimulation of granulocytic, monocytic, megakaryocytic, and early erythroid progenitors, suppression of late-stage erythopoiesis, and reversal of erythroid suppression with erythropoietin. Blood. 1989;73:678-683.

(98) Leibovich SJ, Polverini PJ, Shepard HM, et al. Macrophage-induced angiogenesis is mediated by tumour necrosis factor-[alpha]. Nature. 1987; 329:630-632.

(99) Schmidt JA, Mizel SB, Cohen D, Green I. Interleukin 1, a potential regulator of fibroblast proliferation. J Immunol. 1982;128:2147-2152.

(100) Leng SX, Elias J. Molecules in focus: interleukin-11. J Biochem Cell Biol. 1997;29:1059-1062.

(101) Nathan CF. Secretory products of macrophages. J Clin Invest. 1975;79:319-326.

(102) Kusano K, Miayaura C, Inada M, et al. Regulation of matrix metalloproteases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calavaria: association of MMP induction with bone resorption. Endocrinology. 1998;139:1338-1345.

(103) Hogasen AKM, Nordsletten L, Aasen AO, Falch JA. There is no difference in spontaneous and 17[beta]-estradiol-induced interleukin-1[beta] release by peripheral blood mononuclear cells from nonosteoporotic women with different rates of early postmenopausal bone loss. J Clin Endocrinol Metab. 1995;80:2480-2484.

(104) Votta BJ, Bertolini DR. Cytokine suppressive anti-inflammatory compounds inhibit bone resorption in vitro. Bone. 1994;15:533-538.

(105) Sabatini M, Boyce B, Aufdermorte T, et al. Infusion of recombinant human interleukin-1a and b cause hypercalcemia in normal mice. Proc Nat Acad Sci USA. 1988;85:5235-5239.

(106) Tashijian AH, Voelkel EF, Lazzaro M, et al. Tumor necrosis factor a (cachectin) stimulates bone resorption in mouse calavaria via a prostaglandin-mediated mechanism. Endocrinology. 1987;12:2029-2036.

(107) Revel M, Andre-Deshays C, Roudier R, et al. Effects of repetitive strains on vertebral end plates in young rats. Clin Orthop. 1992;279: 303-309.

(108) Hart DA, Archambault JM, Kydd A, et al. Gender and neurogenic variables in tendon biology and repetitive motion disorders. Clin Orthop. 1998;351:44-56.

(109) Stauber WT, Miller GR, Grimmett JG, Knack KK. Adaptation of rat soleus muscle to four weeks of intermittent strain. J Appl Physiol. 1994;77:58-62.

(110) Chapman V, Buritova J, Honore P, Besson JM. Physiological contributions of neurokinin 1 receptor activation, and interactions with NMDA receptors, to inflammatory-evoked spinal c-Fos expression. J Neurophysiol. 1996;76:1817-1826.

(111) Bennett GJ. Animal models of neuropathic pain. In: Gebhart GF, Hammond DL, Jensen TS, eds. Progress in Pain Research and Management: Proceedings of the VIIth World Congress on Pain. Seattle, Wash: IASP Press; 1994:485-510.

(112) Dubner R, Ruda MA. Activity-dependent neuronal plasticity following tissue injury and inflammation. Trends Neurosci. 1992;15: 96-103.

(113) Urban MO, Gebhart GF. The glutamate synapse: a target in the pharmacological management of hyperalgesic pain states. Prog Brain Res. 1998;116:407-420.

(114) Meller ST, Gebhart CF. Nitric oxide (NO) and nociceptive processing in the spinal cord. Pain. 1993;52:127-136.

(115) Zimmermann M, Herdegen T. Plasticity of the nervous system at the systemic, cellular and molecular levels: a mechanism of chronic pain and hyperalgesia. Prog Brain Res. 1996;110:233-259.

(116) Baranauska G, Nistri A. Sensitization of pain pathways in the spinal cord: cellular mechanisms. Prog Neurobiol. 1998;54:349-365.

(117) Malmberg AB, Chen C, Tonegawa S, Basbaum AI. Preserved acute pain and reduced neuropathic pain in mice lacking PKCy. Science. 1997;278:279-282.

(118) Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitization in mammals and aplysia. Trends Neurosci. 1991;14:74-78.

(119) Al-Ghoul WM, Volsi GL, Weinberg RJ, Rustioni A. Glutamate immunocytochemistry in the dorsal horn after injury or stimulation of the sciatic nerve of rats. Brain Res Bull. 1993;30:453-459.

(120) Fitzsimonds RM, Song HJ, Poo MM. Propagation of activity-dependent synaptic depression in simple neural networks. Nature. 1997;388:439-448.

(121) Nussbaumer JC, Wall PD. Expansion of receptive fields in the mouse cortical barrelfield after administration of capsaicin to neonates or local application on the infraorbital nerve in adults. Brain Res. 1985;360:1-9.

(122) Tinazzi M, Zanette G, Volpato D, et al. Neurophysiological evidence of neuroplasticity at multiple levels of the somatosensory system in patients with carpal tunnel syndrome. Brain. 1998;121(pt 9) :1785-1794.

(123) Noguchi K, Kawai Y, Fukuoka T, et al. Substance P induced by peripheral nerve injury in primary sensory neurons and its effect on dorsal column nucleus neurons. J Neurosci. 1995;15;7633-7643.

(124) Topp KS, Byl NN. Movement dysfunction following repetitive hand opening and closing: anatomical analysis in owl monkeys. Mov Disord. 1999;14:295-306.

(125) Byl NN, Merzenich MM, Cheung S, et al. A primate model for studying focal dystonia and repetitive strain injury: effects on primary somatosensory cortex. Phys Ther. 1997;77:269-284.

(126) Scurch W, Seemayer TA, Gabbiani G. Myofibroblast. In: Sternberg SS, ed. Histology for Pathologists. New York, NY: Raven Press; 1992: 109-144.

(127) Fullerton PM, Gilliatt RW. Median and ulnar neuropathy in the guinea-pig. J Neurol Neurosurg Psychiatry. 1967;30:393-402.

(128) Anderson MH, Fullerton PM, Gilliatt RW, Hern JE. Changes in the forearm associated with median nerve compression at the wrist in the guinea-pig. J Neurol Neurosurg Psychiatry. 1970;33:70-79.

(129) Pierre-Jerome C, Bekkelund SI, Mellgren SI, Tobergsen T. Quantitative magnetic resonance imaging and the electrophysiology of the carpal tunnel region in floor cleaners. Scand J Work Environ Health. 1996;22:119-123.

(130) Stetson DS, Silverstein BA, Keyserling WM, et al. Median sensory distal amplitude and latency: comparisons between nonexposed managerial/professional employees and industrial workers. Am J Ind Med. 1993;24:175-189.

(131) Vega JA, Llamosas MM, Huerta JJ, Garcia-Fernandez JM. Study of human cutaneous sensory corpuscles using double immunolabelling and confocal laser scanning microscopy. Anat Rec. 1996;246:557-560.

(132) Neary D, Ochoa J, Gilliatt RW. Sub-clinical entrapment neuropathy in man. J Neurol Sci. 1975;24:283-298.

(133) Coggeshall RE, Reynolds ML, Woolf CJ. Distribution of the growth associated protein GAP-43 in the central processes of axotomized primary afferents in the adult rat spinal cord: presence of growth cone-like structures. Neurosci Lett. 1991;131:37-41.

(134) Ren K, Thomas DA, Dubner R. Nerve growth factor alleviates a painful peripheral neuropathy in rats. Brain Res. 1995;699:286-292.

(135) Recanzone GH, Merzenich MM, Schreiner CS. Changes in the distributed temporal response properties of SI cortical neurons reflex improvements in performance on a temporally based tactile discrimination task. J Neurophysiol. 1992;67:1071-1091.

(136) Merzenich MM, Nelson RJ, Kaas JH, et al. Variability in hand surface representations in areas 3b and 1 in adult owl and squirrel monkeys. J Comp Neurol. 1987;258:281-296.

(137) Wang X, Merzenich MM, Sameshima K, Jenkins WM. Remodelling of hand representation in adult cortex determined by timing of tactile stimulation. Nature. 1995;378:71-75.

(138) Merzenich MM, Jenkins WM. Reorganization of cortical representations of the hand following alterations of skin inputs induced by nerve injury, skin island transfers, and experience. J Hand Ther. April-June 1993:89-104.

(139) Guide to Physical Therapist Practice. 2nd ed. Alexandria, Va: American Physical Therapy Association; 2001.

(140) Byl NN. The neural consequences of repetition. Neurol Rep. 2000;24:60-70.

AE Barr, PT, PhD, is Assistant Professor, Physical Therapy Department, College of Allied Health Professions, Temple University, 3307 N Broad St (602-00), Philadelphia, PA 19140 (USA) ([e-mail]). Address all correspondence to Dr Barr.

MF Barbe, PhD, is Associate Professor, Physical Therapy Department, College of Allied Health Professions, Temple University, and Department of Anatomy and Cell Biology, Temple University Medical School, Philadelphia, Pa.

Both authors provided concept/project design, writing, data collection and analysis, project management, and fund procurement.

This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, a part of the National Institutes of Health (grant 1 R03 AR 46426-01), the New Investigator Fellowships Training Initiative of the Foundation for Physical Therapy awarded to Dr Barr, and Temple University.

This article was submitted January 12, 2001, and was accepted August 3, 2001.