Manual Therapy With Rest as a Treatment for Established Inflammation and Fibrosis in a Rat Model of Repetitive Strain Injury.

Background: Repetitive strain injuries caused by repetitive occupational work are difficult to prevent for multiple reasons. Therefore, we examined the effectiveness of manual therapy (MT) with rest to treat the inflammation and fibrosis that develops through the performance of a repetitive task. We hypothesized that this treatment would reduce task-induced sensorimotor declines and neuromuscular inflammation. Methods: Twenty-nine female Sprague-Dawley rats performed a reaching and lever-pulling task for 14weeks. All ceased performing the task at 14weeks. Ten were euthanized at this timepoint (TASK). Nine received manual therapy to their upper extremities while resting 7weeks (MTR); 10 were assigned to rest alone (REST). Ten additional food restricted rats were included that neither performed the task nor received manual therapy (FRC). Results: Confirming previous experiments, TASK rats showed behavioral changes (forepaw mechanical hypersensitivity, reduced grip strength, lowered forelimb/forepaw agility, and noxious cold temperature sensitivity), reduced median nerve conduction velocity (NCV), and pathological tissue changes (myelin degradation, increased median nerve and muscle inflammation, and collagen production). Manual therapy with rest (MTR) ameliorated cold sensitivity seen in REST rats, enhanced muscle interleukin 10 (IL-10) more than in REST rats, lead to improvement in most other measures, compared to TASK rats. REST rats showed improved grip strength, lowered nerve inflammation and degraded myelin, and lowered muscle tumor necrosis factor alpha (TNFα) and collagen I levels, compared to TASK rats, yet maintained lowered forelimb/forepaw agility and NCV, and increased neural fibrosis. Conclusion: In our model of repetitive motion disorder, manual therapy during rest had modest effects on behavioral, histological, and physiological measures, compared to rest alone. These findings stand in contrast to the robust preventive effects of manual therapy in this same model.

Blocking CTGF/CCN2 reverses neural fibrosis and sensorimotor declines in a rat model of overuse-induced median mononeuropathy.

Encapsulation of median nerves is a hallmark of overuse-induced median mononeuropathy and contributes to functional declines. We tested if an antibody against CTGF/CCN2 (termed FG-3019 or Pamrevlumab) reduces established neural fibrosis and sensorimotor declines in a clinically relevant rodent model of overuse in which median mononeuropathy develops. Young adult female rats performed a high repetition high force (HRHF) lever-pulling task for 18 weeks. Rats were then euthanised at 18 weeks (HRHF untreated), or rested and systemically treated for 6 weeks with either an anti-CCN2 monoclonal antibody (HRHF-Rest/FG-3019) or IgG (HRHF-Rest/IgG), with results compared with nontask control rats. Neuropathology was evident in HRHF-untreated and HRHF-Rest/IgG rats as increased perineural collagen deposition and degraded myelin basic protein (dMBP) in median nerves, and increased substance P in lower cervical dorsal root ganglia (DRG), compared with controls. Both groups showed functional declines, specifically, decreased sensory conduction velocity in median nerves, noxious cold temperature hypersensitivity, and grip strength declines, compared with controls. There were also increases of ATF3-immunopositive nuclei in ventral horn neurons in HRHF-untreated rats, compared with controls (which showed none). FG-3019-treated rats showed no increase above control levels of perineural collagen or dMBP in median nerves, Substance P in lower cervical DRGs, or ATF3-immunopositive nuclei in ventral horns, and similar median nerve conduction velocities and thermal sensitivity, compared with controls. We hypothesize that neural fibrotic processes underpin the sensorimotor declines by compressing or impeding median nerves during movement, and that inhibiting fibrosis using an anti-CCN2 treatment reverses these effects.

Bladder reinnervation by somatic nerve transfer to pelvic nerve vesical branches does not reinnervate the urethra.

AIMS: We sought to determine whether somatic lumbar nerve transfer to the pelvic nerve's anterior vesical branch after sacral decentralization for detrusor muscle reinnervation also leads to aberrant innervation of the bladder outlet. METHODS: Twenty-six female mongrel hound dogs underwent transection of sacral dorsal and ventral spinal roots (ie, sacral decentralization). Immediately afterward, 12 received genitofemoral nerve transfer and 9 received femoral nerve branch transfer. Five were left sacrally decentralized. Controls included 3 sham-operated and 6 unoperated. Eight months postsurgery, the bladder and urethra were injected with retrograde tracing dyes cystoscopically. After 3 weeks, detrusor and urethral pressures were assayed electrophysiologically immediately before euthanasia and characterization of neural reinnervation. RESULTS: Electrical stimulation of spinal cords or roots did not lead to increased urethral sphincter pressure in nerve transfer animals, compared with decentralized animals, confirming a lack of functional reinnervation of the bladder outlet. In contrast, mean detrusor pressure increased after lumbar cord/root stimulation. In sham/unoperated animals, urethral and bladder dye injections resulted in labeled neurons in sacral level neural structures (dorsal root ganglia [DRG], sympathetic trunk ganglia [STG], and spinal cord ventral horns); labeling absent in decentralized animals. Urethral dye injections did not result in labeling in lumbar or sacral level neural structures in either nerve transfer group while bladder dye injections lead to increased labeled neurons in lumbar level DRG, STG, and ventral horns, compared to sacrally decentralized animals. CONCLUSION: Pelvic nerve transfer for bladder reinnervation does not impact urethral sphincter innervation.

Nerve transfer for restoration of lower motor neuron-lesioned bladder and urethra function: establishment of a canine model and interim pilot study results.

OBJECTIVE: Previous patient surveys have shown that patients with spinal cord or cauda equina injuries prioritize recovery of bladder function. The authors sought to determine if nerve transfer after long-term decentralization restores bladder and sphincter function in canines. METHODS: Twenty-four female canines were included in this study. Transection of sacral roots and hypogastric nerves (S Dec) was performed in 6 animals, and 7 animals underwent this procedure with additional transection of the L7 dorsal roots (L7d+S Dec). Twelve months later, 3 L7d+S Dec animals underwent obturator-to-pelvic nerve and sciatic-to-pudendal nerve transfers (L7d+S Dec+Reinn). Eleven animals served as controls. Squat-and-void behaviors were tracked before and after decentralization, after reinnervation, and following awake bladder-filling procedures. Bladders were cystoscopically injected with Fluoro-Gold 3 weeks before euthanasia. Immediately before euthanasia, transferred nerves were stimulated to evaluate motor function. Dorsal root ganglia were assessed for retrogradely labeled neurons. RESULTS: Transection of only sacral roots failed to reduce squat-and-void postures; L7 dorsal root transection was necessary for significant reduction. Three L7d+S Dec animals showing loss of squat-and-void postures post-decentralization were chosen for reinnervation and recovered these postures 4-6 months after reinnervation. Each showed obturator nerve stimulation-induced bladder contractions and sciatic nerve stimulation-induced anal sphincter contractions immediately prior to euthanasia. One showed sciatic nerve stimulation-induced external urethral sphincter contractions and voluntarily voided twice following nonanesthetized bladder filling. Reinnervation was confirmed by increased labeled cells in L2 and the L4-6 dorsal root ganglia (source of obturator nerve in canines) of L7d+S Dec+Reinn animals, compared with controls. CONCLUSIONS: New neuronal pathways created by nerve transfer can restore bladder sensation and motor function in lower motor neuron-lesioned canines even 12 months after decentralization.

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.