Early movement restriction leads to enduring disorders in muscle and locomotion.

Motor control and body representation in the central nervous system (CNS) as well as musculoskeletal architecture and physiology are shaped during development by sensorimotor experience and feedback, but the emergence of locomotor disorders during maturation and their persistence over time remain a matter of debate in the absence of brain damage. By using transient immobilization of the hind limbs, we investigated the enduring impact of postnatal sensorimotor restriction (SMR) on gait and posture on treadmill, age-related changes in locomotion, musculoskeletal histopathology and Hoffmann reflex in adult rats without brain damage. SMR degrades most gait parameters and induces overextended knees and ankles, leading to digitigrade locomotion that resembles equinus. Based on variations in gait parameters, SMR appears to alter age-dependent plasticity of treadmill locomotion. SMR also leads to small but significantly decreased tibial bone length, chondromalacia, degenerative changes in the knee joint, gastrocnemius myofiber atrophy and muscle hyperreflexia, suggestive of spasticity. We showed that reduced and atypical patterns of motor outputs, and somatosensory inputs and feedback to the immature CNS, even in the absence of perinatal brain damage, play a pivotal role in the emergence of movement disorders and musculoskeletal pathologies, and in their persistence over time. Understanding how atypical sensorimotor development likely contributes to these degradations may guide effective rehabilitation treatments in children with either acquired (ie, with brain damage) or developmental (ie, without brain injury) motor disabilities.

Prolonged high force high repetition pulling induces osteocyte apoptosis and trabecular bone loss in distal radius, while low force high repetition pulling induces bone anabolism.

We have an operant rat model of upper extremity reaching and grasping in which we examined the impact of performing a high force high repetition (High-ForceHR) versus a low force low repetition (Low-ForceHR) task for 18weeks on the radius and ulna, compared to age-matched controls. High-ForceHR rats performed at 4 reaches/min and 50% of their maximum voluntary pulling force for 2h/day, 3days/week. Low-ForceHR rats performed at 6% maximum voluntary pulling force. High-ForceHR rats showed decreased trabecular bone volume in the distal metaphyseal radius, decreased anabolic indices in this same bone region (e.g., decreased osteoblasts and bone formation rate), and increased catabolic indices (e.g., microcracks, increased osteocyte apoptosis, secreted sclerostin, RANKL, and osteoclast numbers), compared to controls. Distal metaphyseal trabeculae in the ulna of High-ForceHR rats showed a non-significant decrease in bone volume, some catabolic indices (e.g., decreased trabecular numbers) yet also some anabolic indices (e.g., increased osteoblasts and trabecular thickness). In contrast, the mid-diaphyseal region of High-ForceHR rats' radial and ulnar bones showed few to no microarchitecture differences and no changes in apoptosis, sclerostin or RANKL levels, compared to controls. In further contrast, Low-ForceHR rats showed increased trabecular bone volume in the radius in the distal metaphysis and increased cortical bone area its mid-diaphysis. These changes were accompanied by increased anabolic indices, no microcracks or osteocyte apoptosis, and decreased RANKL in each region, compared to controls. Ulnar bones of Low-ForceHR rats also showed increased anabolic indices, although fewer than in the adjacent radius. Thus, prolonged performance of an upper extremity reaching and grasping task is loading-, region-, and bone-dependent, with high force loads at high repetition rates inducing region-specific increases in bone degradative changes that were most prominent in distal radial trabeculae, while low force task loads at high repetition rates induced adaptive bone responses.

Evidence of vagus nerve sprouting to innervate the urinary bladder and clitoris in a canine model of lower motoneuron lesioned bladder.

AIMS: Complete spinal cord injury does not block perceptual responses or inferior solitary nucleus activation after genital self-stimulation, even though the vagus is not thought to innervate pelvic structures. We tested if vagus nerve endings sprout after bladder decentralization to innervate genitourinary structures in canines with decentralized bladders. METHODS: Four reinnervation surgeries were performed in female hounds: bilateral genitofemoral nerve transfer to pelvic nerve with vesicostomy (GNF-V) or without (GFN-NV); and left femoral nerve transfer (FNT-V and FNT-NV). After 8 months, retrograde dyes were injected into genitourinary structures. Three weeks later, at euthanasia, reinnervation was evaluated as increased detrusor pressure induced by functional electrical stimulation (FES). Controls included un-operated, sham-operated, and decentralized animals. RESULTS: Increased detrusor pressure was seen in 8/12 GFNT-V, 4/5 GFNT-NV, 5/5 FNT-V, and 4/5 FNT-NV animals after FES, but not decentralized controls. Lumbar cord segments contained cells labeled from the bladder in all nerve transfer animals with FES-induced increased detrusor pressure. Nodose ganglia cells labeled from the bladder were observed in 5/7 nerve transfer animals (1/2 GNT-NV; 4/5 FNT-V), and from the clitoris were in 6/7 nerve transfer animals (2/2 GFNT-NV; 4/5 FNT-V). Dorsal motor nucleus vagus cells labeled from the bladder were observed in 3/5 nerve transfer animals (1/2 GFNT-NV; 2/3 FNT-V), and from the clitoris in 4/5 nerve transfer animals (1/2 GFNT-NV; 3/3 FNT-V). Controls lacked this labeling. CONCLUSIONS: Evidence of vagal nerve sprouting to the bladder and clitoris was observed in canines with lower motoneuron lesioned bladders. Neurourol. Urodynam. 36:91-97, 2017. © 2015 Wiley Periodicals, Inc.

Prenatal ischemia deteriorates white matter, brain organization, and function: implications for prematurity and cerebral palsy.

Cerebral palsy (CP) describes a group of neurodevelopmental disorders of posture and movement that are frequently associated with sensory, behavioral, and cognitive impairments. The clinical picture of CP has changed with improved neonatal care over the past few decades, resulting in higher survival rates of infants born very preterm. Children born preterm seem particularly vulnerable to perinatal hypoxia-ischemia insults at birth. Animal models of CP are crucial for elucidating underlying mechanisms and for development of strategies of neuroprotection and remediation. Most animal models of CP are based on hypoxia-ischemia around the time of birth. In this review, we focus on alterations of brain organization and functions, especially sensorimotor changes, induced by prenatal ischemia in rodents and rabbits, and relate these alterations to neurodevelopmental disorders found in preterm children. We also discuss recent literature that addresses the relationship between neural and myelin plasticity, as well as possible contributions of white matter injury to the emergence of brain dysfunctions induced by prenatal ischemia.

Prolonged performance of a high repetition low force task induces bone adaptation in young adult rats, but loss in mature rats.

We have shown that prolonged repetitive reaching and grasping tasks lead to exposure-dependent changes in bone microarchitecture and inflammatory cytokines in young adult rats. Since aging mammals show increased tissue inflammatory cytokines, we sought here to determine if aging, combined with prolonged performance of a repetitive upper extremity task, enhances bone loss. We examined the radius, forearm flexor muscles, and serum from 16 mature (14-18 months of age) and 14 young adult (2.5-6.5 months of age) female rats after performance of a high repetition low force (HRLF) reaching and grasping task for 12 weeks. Young adult HRLF rats showed enhanced radial bone growth (e.g., increased trabecular bone volume, osteoblast numbers, bone formation rate, and mid-diaphyseal periosteal perimeter), compared to age-matched controls. Mature HRLF rats showed several indices of radial bone loss (e.g., decreased trabecular bone volume, and increased cortical bone thinning, porosity, resorptive spaces and woven bone formation), increased osteoclast numbers and inflammatory cytokines, compared to age-matched controls and young adult HRLF rats. Mature rats weighed more yet had lower maximum reflexive grip strength, than young adult rats, although each age group was able to pull at the required reach rate (4 reaches/min) and required submaximal pulling force (30 force-grams) for a food reward. Serum estrogen levels and flexor digitorum muscle size were similar in each age group. Thus, mature rats had increased bone degradative changes than in young adult rats performing the same repetitive task for 12 weeks, with increased inflammatory cytokine responses and osteoclast activity as possible causes.

Ergonomic task reduction prevents bone osteopenia in a rat model of upper extremity overuse.

We evaluated the effectiveness of ergonomic workload reduction of switching rats from a high repetition high force (HRHF) lever pulling task to a reduced force and reach rate task for preventing task-induced osteopenic changes in distal forelimb bones. Distal radius and ulna trabecular structure was examined in young adult rats performing one of three handle-pulling tasks for 12 wk: (1) HRHF, (2) low repetition low force (LRLF); or (3) HRHF for 4 wk and than LRLF thereafter (HRHF-to-LRLF). Results were compared to age-matched controls rats. Distal forelimb bones of 12-wk HRHF rats showed increased trabecular resorption and decreased volume, as control rats. HRHF-to-LRLF rats had similar trabecular bone quality as control rats; and decreased bone resorption (decreased trabecular bone volume and serum CTX1), increased bone formation (increased mineral apposition, bone formation rate, and serum osteocalcin), and decreased osteoclasts and inflammatory cytokines, than HRHF rats. Thus, an ergonomic intervention of HRHF-to-LRLF prevented loss of trabecular bone volume occurring with prolonged performance of a repetitive upper extremity task. These findings support the idea of reduced workload as an effective approach to management of work-related musculoskeletal disorders, and begin to define reach rate and load level boundaries for such interventions.

Increased CCN2, substance P and tissue fibrosis are associated with sensorimotor declines in a rat model of repetitive overuse injury.

Key clinical features of cumulative trauma disorders include pain, muscle weakness, and tissue fibrosis, although the etiology is still under investigation. Here, we characterized the temporal pattern of altered sensorimotor behaviors and inflammatory and fibrogenic processes occurring in forearm muscles and serum of young adult, female rats performing an operant, high repetition high force (HRHF) reaching and grasping task for 6, 12, or 18 weeks. Palmar mechanical sensitivity, cold temperature avoidance and spontaneous behavioral changes increased, while grip strength declined, in 18-week HRHF rats, compared to controls. Flexor digitorum muscles had increased MCP-1 levels after training and increased TNFalpha in 6-week HRHF rats. Serum had increased IL-1beta, IL-10 and IP-10 after training. Yet both muscle and serum inflammation resolved by week 18. In contrast, IFNγ increased at week 18 in both muscle and serum. Given the anti-fibrotic role of IFNγ, and to identify a mechanism for the continued grip strength losses and behavioral sensitivities, we evaluated the fibrogenic proteins CCN2, collagen type I and TGFB1, as well as the nociceptive/fibrogenic peptide substance P. Each increased in and around flexor digitorum muscles and extracellular matrix in the mid-forearm, and in nerves of the forepaw at 18 weeks. CCN2 was also increased in serum at week 18. At a time when inflammation had subsided, increases in fibrogenic proteins correlated with sensorimotor declines. Thus, muscle and nerve fibrosis may be critical components of chronic work-related musculoskeletal disorders. CCN2 and substance P may serve as potential targets for therapeutic intervention, and CCN2 as a serum biomarker of fibrosis progression.

Bladder reinnervation using a primarily motor donor nerve (femoral nerve branches) is functionally superior to using a primarily sensory donor nerve (genitofemoral nerve).

PURPOSE: We determined whether transfer of a primarily motor nerve (femoral) to the anterior vesicle branch of the pelvic nerve would allow for more effective bladder reinnervation than transfer of a primarily sensory nerve (genitofemoral). MATERIALS AND METHODS: A total of 41 female mongrel dogs underwent bladder decentralization and then bilateral nerve transfer, or served as sham operated or unoperated controls. Decentralization was achieved by bilateral transection of all sacral roots that induced bladder contraction upon electrical stimulation. Retrograde neuronal labeling dye was injected in the bladder 3 weeks before sacrifice. RESULTS: Increased detrusor pressure after direct stimulation of the transferred nerve, lumbar spinal cord or spinal root was observed in 12 of 17 dogs with genitofemoral nerve transfer and in 9 of 10 with femoral nerve transfer (mean ± SEM 7.6 ± 1.4 and 11.7 ± 3.1 cm H2O, respectively). Mean detrusor pressure after direct electrical stimulation of transferred femoral nerves was statistically significantly greater than after stimulation of transferred genitofemoral nerves. Retrograde labeled neurons from the bladder observed in upper lumbar cord segments after genitofemoral and femoral nerve transfer confirmed bladder reinnervation, as did labeled axons at the nerve transfer site. CONCLUSIONS: While transfer of a mixed sensory and motor nerve (genitofemoral) or a primarily motor nerve (femoral) can reinnervate the bladder, using the primarily motor nerve provided greater return of nerve evoked detrusor contraction. This surgical approach may be useful to achieve bladder emptying in patients with lower motor spinal cord injury.

The interaction of force and repetition on musculoskeletal and neural tissue responses and sensorimotor behavior in a rat model of work-related musculoskeletal disorders.

BACKGROUND: We examined the relationship of musculoskeletal risk factors underlying force and repetition on tissue responses in an operant rat model of repetitive reaching and pulling, and if force x repetition interactions were present, indicative of a fatigue failure process. We examined exposure-dependent changes in biochemical, morphological and sensorimotor responses occurring with repeated performance of a handle-pulling task for 12 weeks at one of four repetition and force levels: 1) low repetition with low force, 2) high repetition with low force, 3) low repetition with high force, and 4) high repetition with high force (HRHF). METHODS: Rats underwent initial training for 4-6 weeks, and then performed one of the tasks for 12 weeks, 2 hours/day, 3 days/week. Reflexive grip strength and sensitivity to touch were assayed as functional outcomes. Flexor digitorum muscles and tendons, forelimb bones, and serum were assayed using ELISA for indicators of inflammation, tissue stress and repair, and bone turnover. Histomorphometry was used to assay macrophage infiltration of tissues, spinal cord substance P changes, and tissue adaptative or degradative changes. MicroCT was used to assay bones for changes in bone quality. RESULTS: Several force x repetition interactions were observed for: muscle IL-1alpha and bone IL-1beta; serum TNFalpha, IL-1alpha, and IL-1beta; muscle HSP72, a tissue stress and repair protein; histomorphological evidence of tendon and cartilage degradation; serum biomarkers of bone degradation (CTXI) and bone formation (osteocalcin); and morphological evidence of bone adaptation versus resorption. In most cases, performance of the HRHF task induced the greatest tissue degenerative changes, while performance of moderate level tasks induced bone adaptation and a suggestion of muscle adaptation. Both high force tasks induced median nerve macrophage infiltration, spinal cord sensitization (increased substance P), grip strength declines and forepaw mechanical allodynia by task week 12. CONCLUSIONS: Although not consistent in all tissues, we found several significant interactions between the critical musculoskeletal risk factors of force and repetition, consistent with a fatigue failure process in musculoskeletal tissues. Prolonged performance of HRHF tasks exhibited significantly increased risk for musculoskeletal disorders, while performance of moderate level tasks exhibited adaptation to task demands.

Mild musculoskeletal and locomotor alterations in adult rats with white matter injury following prenatal ischemia.

Early brain injury including white matter damage (WMD) appears strongly correlated to perinatal hypoxia-ischemia and adverse neurological outcomes in preterm survivors. Indeed, WMD has been widely associated with subtle to major motor disturbances, sensory, behavioral and cognitive impairments in preterm infants who afterward develop cerebral palsy (CP). Prenatal ischemia (PI) has been shown to reproduce the main features of WMD observed in preterm infants. The present study was aimed at determining in adult rats the impact of PI on brain axons, musculoskeletal histology and locomotor activity. PI was induced by unilateral intrauterine artery ligation at E17 in pregnant rats. We found axonal degeneration and reactive astrogliosis in several white matter regions of adult PI rats. We found mild myopathic and secondary joint changes, including increased variability in myofiber size in several hind limb muscles, decreased myofibers numbers but increased Pax 7 cells and myofiber size in the gastrocnemius, and mild knee and ankle chondromalacia. Although treadmill locomotion appeared normal, several kinematic parameters, such as stride length, amplitude, velocity and leg joint angles were altered in adult PI rats compared to shams. Using intra- and inter-group variability of kinematic parameters, PI seemed to impair the maturation of locomotion on the treadmill. In addition, PI rats exhibited spontaneous hyperactivity in open-field test. Musculoskeletal changes appeared concomitant with mild impairments in gait and posture. Our rodent model of WMD based on PI reproduces the mild motor deficits and musculoskeletal changes observed in many preterm infants with a perinatal history of hypoxia-ischemia, and contributes towards a better understanding of the interplay between brain injury, musculoskeletal histopathology and gait disturbances encountered subsequently.