Mamta Amin

Chronic repetitive reaching and grasping results in decreased motor performance and widespread tissue responses in a rat model of MSD.

This study investigated changes in motor skills and tissues of the upper extremity (UE) with regard to injury and inflammatory reactions resulting from performance of a voluntary forelimb repetitive reaching and grasping task in rats. Rats reached for food at a rate of 4 reaches/min, 2 h/day, and 3 days/week for up to 8 weeks during which reach rate, task duration and movement strategies were observed. UE tissues were collected bilaterally at weekly time points of 3–8 weeks and examined for morphological changes. Serum was tested for levels of interleukin‐1α (IL‐1) protein. The macrophage‐specific antibody, ED1, was used to identify infiltrating macrophages and the ED2 antibody was used to identify resident macrophages. Rats were unable to maintain baseline reach rate in weeks 5 and 6 of task performance. Alternative patterns of movement emerged. Fraying of tendon fibrils was observed after 6 weeks in the mid‐forelimb. After 4 weeks, a general elevation of ED1‐IR macrophages were seen in all tissues examined bilaterally including the contralateral, uninvolved forelimb and hindlimbs. Significantly more resident macrophages were seen at 6 and 8 weeks in the reach limb. At 8 weeks, serum levels of IL‐1α increased significantly above week 0. Our results demonstrate that performance of repetitive tasks elicits motor decrements, signs of injury and a cellular and tissue responses associated with inflammation.

Median nerve trauma in a rat model of work-related musculoskeletal disorder.

Anatomical and physiological changes were evaluated in the median nerves of rats trained to perform repetitive reaching. Motor degradation was evident after 4 weeks. ED1-immunoreactive macrophages were seen in the transcarpal region of the median nerve of both forelimbs by 5-6 weeks. Fibrosis, characterized by increased immunoexpression of collagen type I by 8 weeks and connective tissue growth factor by 12 weeks, was evident. The conduction velocity (NCV) within the carpal tunnel showed a modest but significant decline after 9-12 weeks. The lowest NCV values were found in animals that refused to participate in the task for the full time available. Thus, both anatomical and physiological signs of progressive tissue damage were present in this model. These results, together with other recent findings indicate that work-related carpal tunnel syndrome develops through mechanisms that include injury, inflammation, fibrosis and subsequent nerve compression.

Inflammatory biomarkers increase with severity of upper-extremity overuse disorders

MSDs (musculoskeletal disorders) from overuse are common occupational health problems that cause pain, functional loss and loss of work time. The aim of the present study was to determine whether a relationship exists between the severity of early-onset overuse-related MSDs of the upper extremity and serum levels of IL-1beta (interleukin-1beta), TNF-alpha (tumour necrosis factor-alpha), IL-6 (interleukin-6) and CRP (C-reactive protein). Twenty-two subjects with upper-extremity MSDs due to overuse for no longer that 12 weeks were stratified according to the severity of upper-extremity signs and symptoms as determined by a UBMA (upper-body musculoskeletal assessment). Nine asymptomatic subjects also participated. Serum cytokines were analysed using ELISA, and CRP was analysed using a laser nephelometry technique. CRP was strongly correlated, and TNF-alpha, IL-1beta and IL-6 were moderately correlated, with UBMA scores. Only CRP and TNFalpha were significantly associated with UBMA scores in an ordinal logistic regression analysis in which age and BMI (body mass index) were covariates. These results are of clinical importance as they suggest that early-onset overuse-related MSDs may have an inflammatory component. The possibility of using a combination of serum biomarkers to follow the progression of overuse-related MSDs or their response to therapeutic intervention may be of interest to clinical practitioners and should be the focus of future research.

Serum and Tissue Cytokines and Chemokines Increase with Repetitive Upper Extremity Tasks

We investigated inflammation in rats performing a low repetition, negligible force (LRNF) or high repetition, negligible force (HRNF) task of reaching and retrieving food pellets at target rates of two or four reaches/min for 2 h/day, for 6–8 weeks. Serum was assayed for 11 cytokines and chemokines; forelimb tissues for four cytokines. Macrophages were counted in forelimb tissues of LRNF rats to add to results from our previous studies of HRNF rats. In HRNF rats, serum IL‐1α, IL‐1β, TNFα, MIP2, MIP3a, and RANTES were elevated in weeks 6 and 8. In contrast, only MIP2 and MIP3a increased in serum of LRNF rats. In 8 week HRNF reach limb tissues, IL‐1α, IL‐1β, TNFα, and IL‐10 increased in distal bones, IL‐1α and ‐β in muscles, and TNFα in tendons. Only IL‐10 increased in LRNF reach limb muscles in week 8. Serum IL‐1α and MIP2 correlated with macrophages in LRNF loose connective tissues, serum MIP3a and MIP2 correlated negatively with grip strength, while serum TNFα, MIP3a, and MIP2 correlated positively with total number of reaches. Thus, several tissue and circulating cytokines/chemokines increase in an exposure dependent manner following short‐term performance of repetitive reaching tasks and correlate with macrophage infiltration and decreasing grip strength.

Exposure‐dependent increases in IL‐1β, substance P, CTGF, and tendinosis in flexor digitorum tendons with upper extremity repetitive strain injury

Upper extremity tendinopathies are associated with performance of forceful repetitive tasks. We used our rat model of repetitive strain injury to study changes induced in forelimb flexor digitorum tendons. Rats were trained to perform a high repetition high force (HRHF) handle‐pulling task (12 reaches/min at 60 ± 5% maximum pulling force [MPF]), or a low repetition negligible force (LRNF) reaching and food retrieval task (three reaches/min at 5 ± 5% MPF), for 2 h/day in 30 min sessions, 3 days/week for 3–12 weeks. Forelimb grip strength was tested. Flexor digitorum tendons were examined at midtendon at the level of the carpal tunnel for interleukin (IL)‐1β, neutrophil, and macrophage influx, Substance P, connective tissue growth factor (CTGF), and periostin‐like factor (PLF) immunoexpression, and histopathological changes. In HRHF rats, grip strength progressively decreased, while IL‐1β levels progressively increased in the flexor digitorum peritendon (para‐ and epitendon combined) and endotendon with task performance. Macrophage invasion was evident in week 6 and 12 HRHF peritendon but not endotendon. Also in HRHF rats, Substance P immunoexpression increased in week 12 peritendon as did CTGF‐ and PLF‐immunopositive fibroblasts, the increased fibroblasts contributing greatly to peritendon thickening. Endotendon collagen disorganization was evident in week 12 HRHF tendons. LRNF tendons did not differ from controls, even at 12 weeks. Thus, we observed exposure‐dependent changes in flexor digitorum tendons within the carpal tunnel, including increased inflammation, nociceptor‐related neuropeptide immunoexpression, and fibrotic histopathology, changes associated with grip strength decline.

High force reaching task induces widespread inflammation, increased spinal cord neurochemicals and neuropathic pain.

Repetitive strain injuries (RSI), which include several musculoskeletal disorders and nerve compression injuries, are associated with performance of repetitive and forceful tasks. In this study, we examined in young, adult Sprague-Dawley rats, the effects of performing a voluntary, moderate repetition, high force (MRHF; nine reaches/min; 60% maximum pulling force) task for 12 weeks on motor behavior and nerve function, inflammatory responses in forearm musculoskeletal and nerve tissues and serum, and neurochemical immunoexpression in cervical spinal cord dorsal horns. We observed no change in reach rate, but reduced voluntary participation and grip strength in week 12, and increased cutaneous sensitivity in weeks 6 and 12, the latter indicative of mechanical allodynia. Nerve conduction velocity (NCV) decreased 15% in the median nerve in week 12, indicative of low-grade nerve compression. ED-1 cells increased in distal radius and ulna in week 12, and in the median nerve and forearm muscles and tendons in weeks 6 and 12. Cytokines IL-1alpha, IL-1beta, TNF-alpha, and IL-10 increased in distal forearm bones in week 12, while IL-6 increased in tendon in week 12. However, serum analysis revealed only increased TNF-alpha in week 6 and macrophage inflammatory protein 3a (MIP3a) in weeks 6 and 12. Lastly, Substance P and neurokinin-1 were both increased in weeks 6 and 12 in the dorsal horns of cervical spinal cord segments. These results show that a high force, but moderate repetition task, induced declines in motor and nerve function as well as peripheral and systemic inflammatory responses (albeit the latter was mild). The peripheral inflammatory responses were associated with signs of central sensitization (mechanical allodynia and increased neurochemicals in spinal cord dorsal horns).

Repetitive, Negligible Force Reaching in Rats Induces Pathological Overloading of Upper Extremity Bones

Work‐related repetitive motion disorders are costly. Immunohistochemical changes in bones resulting from repetitive reaching and grasping in 17 rats were examined. After 3–6 weeks, numbers of ED1+ macrophages and osteoclasts increased at periosteal surfaces of sites of muscle and interosseous membrane attachment and metaphyses of reach and nonreach forelimbs. These findings indicate pathological overloading leading to inflammation and subsequent bone resorption.

Peripheral neuritis and increased spinal cord neurochemicals are induced in a model of repetitive motion injury with low force and repetition exposure

Performance of high repetition tasks with or without force is associated with peripheral tissue inflammation, decreased nerve function and motor dysfunction. Here, we examined whether a low repetition task with negligible force (LRNF) produces fewer tissue and behavioral pathologies than previously observed with high repetition tasks using our rat model of repetitive motion injury (RMI). Thirty-seven rats were randomized into control or LRNF groups, the latter reaching and grasping a 45 mg food pellet at a rate of 3 reaches/min. This task was performed in 4, 0.5 5 h sessions with 1.5 5 h rest periods for 3 days/week for up to 12 weeks. Examination of distal median nerve, forelimb flexor tendons and bones for ED1-positive cells (macrophages and osteoclasts) revealed increases in nerve and bone in week 12. The nerve also contained increased TNF-alpha expressing cells in week 12. Examination of spinal cord dorsal horns revealed increased immunoexpression of Substance P in week 8 and neurokinin-1 in weeks 8 and 12 in the superficial lamina. Motor behavioral analyses showed no changes in reach rate across weeks, slightly reduced task duration (a measurement of voluntary task participation) in week 12, but significantly increased extra arm movement reversals during reaching in week 8. These extra movement reversals were corrections for missed food pellets during a reach. Thus, performance of even a low repetition, negligible force upper extremity task for 3 months can induce mild peripheral tissue inflammation, neurochemical increases in spinal cord dorsal horns, and declines in fine motor control.

Impact of prenatal ischemia on behavior, cognitive abilities and neuroanatomy in adult rats with white matter damage

Early brain damage, such as white matter damage (WMD), resulting from perinatal hypoxia-ischemia in preterm and low birth weight infants represents a high risk factor for mortality and chronic disabilities, including sensory, motor, behavioral and cognitive disorders. In previous studies, we developed a model of WMD based on prenatal ischemia (PI), induced by unilateral ligation of uterine artery at E17 in pregnant rats. We have shown that PI reproduced some of the main deficits observed in preterm infants, such as white and gray matter damage, myelination deficits, locomotor, sensorimotor, and short-term memory impairments, as well as related musculoskeletal and neuroanatomical histopathologies [1-3]. Here, we determined the deleterious impact of PI on several behavioral and cognitive abilities in adult rats, as well as on the neuroanatomical substratum in various related brain areas. Adult PI rats exhibited spontaneous exploratory and motor hyperactivity, deficits in information encoding, and deficits in short- and long-term object memory tasks, but no impairments in spatial learning or working memory in watermaze tasks. These results were in accordance with white matter injury and damage in the medial and lateral entorhinal cortices, as detected by axonal degeneration, astrogliosis and neuronal density. Although there was astrogliosis and axonal degeneration in the fornix, hippocampus and cingulate cortex, neuronal density in the hippocampus and cingulate cortex was not affected by PI. Levels of spontaneous hyperactivity, deficits in object memory tasks, neuronal density in the medial and lateral entorhinal cortices, and astrogliosis in the fornix correlated with birth weight in PI rats. Thus, this rodent model of WMD based on PI appears to recapitulate the main neurobehavioral and neuroanatomical human deficits often observed in preterm children with a perinatal history of ischemia.

Performance of Repetitive Tasks Induces Decreased Grip Strength and Increased Fibrogenic Proteins in Skeletal Muscle: Role of Force and Inflammation

Background This study elucidates exposure-response relationships between performance of repetitive tasks, grip strength declines, and fibrogenic-related protein changes in muscles, and their link to inflammation. Specifically, we examined forearm flexor digitorum muscles for changes in connective tissue growth factor (CTGF; a matrix protein associated with fibrosis), collagen type I (Col1; a matrix component), and transforming growth factor beta 1 (TGFB1; an upstream modulator of CTGF and collagen), in rats performing one of two repetitive tasks, with or without anti-inflammatory drugs. Methodology/Results To examine the roles of force versus repetition, rats performed either a high repetition negligible force food retrieval task (HRNF), or a high repetition high force handle-pulling task (HRHF), for up to 9 weeks, with results compared to trained only (TR-NF or TR-HF) and normal control rats. Grip strength declined with both tasks, with the greatest declines in 9-week HRHF rats. Quantitative PCR (qPCR) analyses of HRNF muscles showed increased expression of Col1 in weeks 3–9, and CTGF in weeks 6 and 9. Immunohistochemistry confirmed PCR results, and also showed greater increases of CTGF and collagen matrix in 9-week HRHF rats than 9-week HRNF rats. ELISA, and immunohistochemistry revealed greater increases of TGFB1 in TR-HF and 6-week HRHF, compared to 6-week HRNF rats. To examine the role of inflammation, results from 6-week HRHF rats were compared to rats receiving ibuprofen or anti-TNF-α treatment in HRHF weeks 4–6. Both treatments attenuated HRHF-induced increases in CTGF and fibrosis by 6 weeks of task performance. Ibuprofen attenuated TGFB1 increases and grip strength declines, matching our prior results with anti-TNFα. Conclusions/Significance Performance of highly repetitive tasks was associated with force-dependent declines in grip strength and increased fibrogenic-related proteins in flexor digitorum muscles. These changes were attenuated, at least short-term, by anti-inflammatory treatments.