Search

BACKGROUND: To prospectively evaluate ultrasound backscatter coefficients (BSCs) of the supraspinatus and infraspinatus muscles and compare with Goutallier classification on magnetic resonance imaging (MRI). METHODS: Fifty-six participants had shoulder MRI exams and ultrasound exams of the supraspinatus and infraspinatus muscles. Goutallier MRI grades were determined and BSCs were measured. Group means were compared and the strength of relationships between the measures were determined. Using binarized Goutallier groups (0-2 versus 3-4), areas under the receiver operating characteristic curves (AUROCs) were calculated. The nearest integer cutoff value was determined using Youdens index. RESULTS: BSC values were significantly different among most Goutallier grades for the supraspinatus and infraspinatus muscles (both p

BackgroundWe investigated the relationship of two commonly used quantitative ultrasound (QUS) parameters, speed of sound (SoS) and attenuation coefficient (α), with water and macromolecular contents of bovine cortical bone strips as measured with ultrashort echo time (UTE) magnetic resonance imaging (MRI).MethodsSoS and α were measured in 36 bovine cortical bone strips utilizing a single-element transducer with nominal 5 MHz center frequency based on the time of flight principles after accommodating for reflection losses. Specimens were then scanned using UTE MRI to measure total, bound, and pore water proton density (TWPD, BWPD, and PWPD) as well as macromolecular proton fraction and macromolecular transverse relaxation time (T2-MM). Specimens were also scanned using microcomputed tomography (μCT) at 9-μm isometric voxel size to measure bone mineral density (BMD), porosity, and pore size. The elastic modulus (E) of each specimen was measured using a 4-point bending test.Resultsα demonstrated significant positive Spearman correlations with E (R = 0.69) and BMD (R = 0.44) while showing significant negative correlations with porosity (R = -0.41), T2-MM (R = -0.47), TWPD (R = -0.68), BWPD (R = -0.67), and PWPD (R = -0.45).ConclusionsThe negative correlation between α and T2-MM is likely indicating the relationship between QUS and collagen matrix organization. The higher correlations of α with BWPD than with PWPD may indicate that water organized in finer structure (bound to matrix) provides lower acoustic impedance than water in larger pores, which is yet to be investigated thoroughly.Relevance statementThis study highlights the importance of future investigations exploring the relationship between QUS measures and all major components of the bone, including the collagenous matrix and water. Investigating the full potential of QUS and its validation facilitates a more affordable and accessible tool for bone health monitoring in clinics.Key points• Ultrasound attenuation demonstrated significant positive correlations with bone mechanics and mineral density. • Ultrasound attenuation demonstrated significant negative correlations with porosity and bone water contents. • This study highlights the importance of future investigations exploring the relationship between QUS measures and all major components of the bone.

In this study, we evaluated the utility of using high-frequency ultrasound to non-invasively track the degenerative process in a rat model of peripheral nerve injury. Primary analyses explored spatial and temporal changes in quantitative backscatter coefficient (BSC) spectrum-based outcomes and B-mode textural outcomes, using gray level co-occurrence matrices (GLCMs), during the progressive transition from acute to chronic injury. As secondary analyses, correlations among GLCM and BSC spectrum-based parameters were evaluated, and immunohistochemistry were used to suggest a structural basis for ultrasound outcomes. Both mean BSC spectrum-based and mean GLCM-based measures exhibited significant spatial differences across presurgical and 1-month/2-month time points, distal stumps enclosed proximity to the injury site being particularly affected. The two sets of parameters sensitively detected peripheral nerve degeneration at 1-month and 2-month post-injury, with area under the receiver operating charactersitic curve > 0.8 for most parameters. The results also indicated that the many BSC spectrum-based and GLCM-based parameters significantly correlate with each other, and suggested a common structural basis for a diverse set of quantitative ultrasound parameters. The findings of this study suggest that BSC spectrum-based and GLCM-based analysis are promising non-invasive techniques for diagnosing peripheral nerve degeneration.

Ultrasound (US) is an important imaging tool for skeletal muscle analysis. The advantages of US include point-of-care access, real-time imaging, cost-effectiveness, and absence of ionizing radiation. However, US can be highly dependent on the operator and/or US system, and a portion of the potentially useful information carried by raw sonographic data is discarded in image formation for routine qualitative US. Quantitative ultrasound (QUS) methods provide analysis of the raw or post-processed data, revealing additional information about normal tissue structure and disease status. There are four QUS categories that can be used on muscle and are important to review. First, quantitative data derived from B-mode images can help determine the macrostructural anatomy and microstructural morphology of muscle tissues. Second, US elastography can provide information about muscle elasticity or stiffness through strain elastography or shear wave elastography (SWE). Strain elastography measures the induced tissue strain caused either by internal or external compression by tracking tissue displacement with detectable speckle in B-mode images of the examined tissue. SWE measures the speed of induced shear waves traveling through the tissue to estimate the tissue elasticity. These shear waves may be produced using external mechanical vibrations or internal "push pulse" ultrasound stimuli. Third, raw radiofrequency signal analyses provide estimates of fundamental tissue parameters, such as the speed of sound, attenuation coefficient, and backscatter coefficient, which correspond to information about muscle tissue microstructure and composition. Lastly, envelope statistical analyses apply various probability distributions to estimate the number density of scatterers and quantify coherent to incoherent signals, thus providing information about microstructural properties of muscle tissue. This review will examine these QUS techniques, published results on QUS evaluation of skeletal muscles, and the strengths and limitations of QUS in skeletal muscle analysis.

AimThis review article describes quantitative ultrasound (QUS) techniques and summarizes their strengths and limitations when applied to peripheral nerves.MethodsA systematic review was conducted on publications after 1990 in Google Scholar, Scopus, and PubMed databases. The search terms "peripheral nerve", "quantitative ultrasound", and "elastography ultrasound" were used to identify studies related to this investigation.ResultsBased on this literature review, QUS investigations performed on peripheral nerves can be categorized into three main groups: (1) B-mode echogenicity measurements, which are affected by a variety of post-processing algorithms applied during image formation and in subsequent B-mode images; (2) ultrasound (US) elastography, which examines tissue stiffness or elasticity through modalities such as strain ultrasonography or shear wave elastography (SWE). With strain ultrasonography, induced tissue strain, caused by internal or external compression stimuli that distort the tissue, is measured by tracking detectable speckles in the B-mode images. In SWE, the propagation speed of shear waves, generated by externally applied mechanical vibrations or internal US "push pulse" stimuli, is measured to estimate tissue elasticity; (3) the characterization of raw backscattered ultrasound radiofrequency (RF) signals, which provide fundamental ultrasonic tissue parameters, such as the acoustic attenuation and backscattered coefficients, that reflect tissue composition and microstructural properties.ConclusionsQUS techniques allow the objective evaluation of peripheral nerves and reduce operator- or system-associated biases that can influence qualitative B-mode imaging. The application of QUS techniques to peripheral nerves, including their strengths and limitations, were described and discussed in this review to enhance clinical translation.

Mild traumatic brain injury (mTBI), a condition in which brain function is transiently disrupted by a mechanical force, is a major risk factor for developing Alzheimer's disease (AD) and other neurodegenerative conditions. In this commentary, we summarize recent findings in human neurons derived from induced pluripotent stem cells, detailing early neuronal events following mild injury that may seed future neurodegeneration. In particular, we discuss interlinked relationships between mTBI and several biological pathways hypothesized to underlie AD progression, including amyloidogenic cleavage of amyloid precursor protein (APP), impairment of axonal transport, and the development of APP-associated axonal swellings. We also describe the implications of these findings for future mechanistic and translational studies.

BackgroundPeripheral nerve damage can have debilitating consequences. Rabbit sciatic nerve transection models allow the effective evaluation of surgical repair strategies for large nerve gaps. Despite advantages in size, ease of handling, and functional utility, rabbits can suffer from a number of side effects that affect animal welfare and the quality of scientific inquiry. Such side-effects, which include pressure ulcers and traumatic damage to the foot, are primarily a consequence of insensitivity of the distal hindlimb following sciatic nerve injury. In this study, we present a number of methodologies for identifying, treating, and preventing unintended adverse effects in rabbit sciatic nerve injury models.ResultsFirst, we categorize pressure ulcers according to their severity and describe the deployment of a padded bandaging technique to enable ulcer healing. We also introduce a proactive bandaging approach to reduce the likelihood of pressure ulcer formation. Second, we define phenotypes that distinguish between foot injuries resulting from self-mutilation (autotomy) from those caused by incidental traumatic injury secondary to sensori-motor damage. Finally, we detail an effective strategy to reduce the usage of Elizabethan collars; through a gradual weaning protocol, their usefulness in preventing autotomy is retained, while their propensity to impede rabbit grooming and cause abrasion-injury to the neck region is minimized.ConclusionsWe suggest that application of these methods offer a practical and systematic approach to avoid adverse side effects associated with rabbit sciatic nerve damage, enabling improved animal welfare and scientific outcomes in a powerful nerve injury model.

PurposeTo develop a deep learning-based method for knee menisci segmentation in 3D ultrashort echo time (UTE) cones MR imaging, and to automatically determine MR relaxation times, namely the T1, T1ρ , and T2∗ parameters, which can be used to assess knee osteoarthritis (OA).MethodsWhole knee joint imaging was performed using 3D UTE cones sequences to collect data from 61 human subjects. Regions of interest (ROIs) were outlined by 2 experienced radiologists based on subtracted T1ρ -weighted MR images. Transfer learning was applied to develop 2D attention U-Net convolutional neural networks for the menisci segmentation based on each radiologist's ROIs separately. Dice scores were calculated to assess segmentation performance. Next, the T1, T1ρ , T2∗ relaxations, and ROI areas were determined for the manual and automatic segmentations, then compared.ResultsThe models developed using ROIs provided by 2 radiologists achieved high Dice scores of 0.860 and 0.833, while the radiologists' manual segmentations achieved a Dice score of 0.820. Linear correlation coefficients for the T1, T1ρ , and T2∗ relaxations calculated using the automatic and manual segmentations ranged between 0.90 and 0.97, and there were no associated differences between the estimated average meniscal relaxation parameters. The deep learning models achieved segmentation performance equivalent to the inter-observer variability of 2 radiologists.ConclusionThe proposed deep learning-based approach can be used to efficiently generate automatic segmentations and determine meniscal relaxations times. The method has the potential to help radiologists with the assessment of meniscal diseases, such as OA.

Proper function of the female pelvic floor requires intact pelvic floor muscles (PFMs). The prevalence of pelvic floor disorders (PFDs) increases substantially with age, in part due to clinically identified deterioration of PFM function with age. However, the etiology of this decline remains largely unknown. We previously demonstrated that PFMs undergo age-related fibrotic changes. This study sought to determine whether aging also impacts PFMs' passive mechanical properties that are largely determined by the intramuscular extracellular matrix. Biopsies from younger (≤52y) and older (>52y) female cadaveric donors were procured from PFMs, specifically coccygeus (C) and two portions of the levator ani - iliococcygeus (IC) and pubovisceralis (PV), and the appendicular muscles - obturator internus (OI) and vastus lateralis (VL). Muscle bundles were subjected to a passive loading protocol, and stress-sarcomere length (Ls) relationships calculated. Muscle stiffness was compared between groups using 2-way ANOVA and Sidak pairwise comparisons, α

Pelvic floor disorders negatively impact millions of women worldwide. Although there is a strong epidemiological association with childbirth, the mechanisms leading to the dysfunction of the integral constituents of the female pelvic floor, including pelvic floor skeletal muscles, are not well understood. This is in part due to the constraints associated with directly probing these muscles, which are located deep in the pelvis. Thus, experimental models and non-invasive techniques are essential for advancing knowledge of various phenotypes of pelvic floor muscle injury and pathogenesis of muscle dysfunction, as well as developing minimally invasive approaches for the delivery of novel therapeutics. The most widely used animal model for pelvic floor disorders is the rat. However, the radiological anatomy of rat pelvic floor muscles has not been described. To remedy this gap, the current study provides the first detailed description of the female rat pelvic floor muscles' radiological appearance on MR and ultrasound images, validated by correlation with gross anatomy and histology. We also demonstrate that ultrasound guidance can be used to target rat pelvic floor muscles for possible interventional therapies.

Peripheral nerves are a composite tissue consisting of neurovascular elements packaged within a well-organized extracellular matrix. Their composition, size, and anatomy render nerves a challenging medical imaging target. In contrast to morphological MRI, which represents the predominant approach to nerve imaging, quantitative MRI sequences can provide information regarding tissue composition. Here, we applied standard clinical Carr-Purcell-Meiboom-Gill (CPMG) and experimental three-dimensional (3D) ultrashort echo time (UTE) Cones sequences for quantitative nerve imaging including T2 measurement with single-component analysis, T2 * measurement with single-component and bi-component analyses, and magnetization transfer ratio (MTR) analysis. We demonstrated the feasibility and the high quality of single-component T2 *, bi-component T2 *, and MTR approaches to analyze nerves imaged with clinically deployed 3D UTE Cones pulse sequences. For 24 single fascicles from eight nerves, we measured a mean single-component T2 * of 22.6 ±8.9 ms, and a short T2 * component (STC) with a mean T2 * of 1.7 ±1.0 ms and a mean fraction of (6.74 ±4.31)% in bi-component analysis. For eight whole nerves, we measured a mean single-component T2 * of 16.7 ±2.2 ms, and an STC with a mean T2 * of 3.0 ±1.0 ms and a mean fraction of (15.56 ±7.07)% in bi-component analysis. For nine fascicles from three healthy nerves, we measured a mean MTR of (25.2 ±1.9)% for single fascicles and a mean MTR of (23.6 ±0.9)% for whole nerves. No statistically significant correlation was observed between any MRI parameter and routine histological outcomes, perhaps due to the small sample size and lack of apparent sample pathology. Overall, we have successfully demonstrated the feasibility of measuring quantitative MR outcomes ex vivo, which might reflect features of nerve structure and macromolecular content. These methods should be validated comprehensively on a larger and more diverse set of nerve samples, towards the interpretation of in vivo outcomes. These approaches have new and broad implications for the management of nerve disease, injury, and repair.

Paraneurial adhesions have been implicated in the pathological progression of entrapment neuropathies. Surgical decompression of adhesions is often performed, with the intent of restoring nerve kinematics. The normal counterpart of adhesions, native paraneurium, is also thought to influence nerve deformation and mobility. However, influences of native or abnormal paraneurial structures on nerve kinematics have not been investigated. We measured regional strains in rat sciatic nerves before and immediately after decompression of native paraneurial tissue, and before and after decompression of abnormal paraneurial adhesions, which formed within 6 weeks of the initial decompression. Strain was significantly higher in the distal-femoral than in the mid-femoral region of the nerve before either decompression. Decompression of native and abnormal paraneurial tissue removed this regional strain difference. Paraneurial tissues appear to play a major role in distributing peripheral nerve strain. Normal nerve strain distributions may be reconstituted following decompression, even in the presence of paraneurial adhesions.

Atrophy is thought to be a primary mode of muscle loss in neuromuscular injuries. The differential effects of central and peripheral injuries on atrophy and degeneration/regeneration in skeletal muscle tissue have not been well described. This study investigated skeletal muscle atrophy and degeneration/regeneration in an animal model of traumatic brain injury (TBI). Eight 8-month-old wild-type C57BL6 mice underwent either a sham craniotomy or TBI targeting the motor cortex. Atrophy (fiber area; FA) and degeneration/regeneration (centralized nuclei proportions; CN) of the soleus and tibialis anterior (TA) muscles were measured 2 months post-injury. Injured soleus FAs were smaller than sham soleus (p = 0.02) and injured TA (p

Pannexins belong to a family of ATP-release channels expressed in almost all cell types. An increasing body of literature on pannexins suggests that these channels play dual and sometimes contradictory roles, contributing to normal cell function, as well as to the pathological progression of disease. In this review, we summarize our understanding of pannexin "protective" and "harmful" functions in inflammation, regeneration and mechanical signaling. We also suggest a possible basis for pannexin's dual roles, related to extracellular ATP and K+ levels and the activation of various types of P2 receptors that are associated with pannexin. Finally, we speculate upon therapeutic strategies related to pannexin using eyes, lacrimal glands, and peripheral nerves as examples of interesting therapeutic targets.

While excessive tensile strain can be detrimental to nerve function, strain can be a positive regulator of neuronal outgrowth. We used an in vivo rat model of sciatic nerve strain to investigate signaling mechanisms underlying peripheral nerve response to deformation. Nerves were deformed by 11% and did not demonstrate deficits in compound action potential latency or amplitude during or after 6 h of strain. As revealed by Western blotting, application of strain resulted in significant upregulation of mammalian target of rapamycin (mTOR) and S6 signaling in nerves, increased myelin basic protein (MBP) and β-actin levels, and increased phosphorylation of neurofilament subunit H (NF-H) compared with unstrained (sham) contralateral nerves (P < 0.05 for all comparisons, paired two-tailed t-test). Strain did not alter neuron-specific β3-tubulin or overall nerve tubulin levels compared with unstrained controls. Systemic rapamycin treatment, thought to selectively target mTOR complex 1 (mTORC1), suppressed mTOR/S6 signaling, reduced levels of MBP and overall tubulin, and decreased NF-H phosphorylation in nerves strained for 6 h, revealing a role for mTOR in increasing MBP expression and NF-H phosphorylation, and maintaining tubulin levels. Consistent with stretch-induced increases in MBP, immunolabeling revealed increased S6 signaling in Schwann cells of stretched nerves compared with unstretched nerves. In addition, application of strain to cultured adult dorsal root ganglion neurons showed an increase in axonal protein synthesis based on a puromycin incorporation assay, suggesting that neuronal translational pathways also respond to strain. This work has important implications for understanding mechanisms underlying nerve response to strain during development and regeneration.NEW & NOTEWORTHY Peripheral nerves experience tensile strain (stretch) during development and movement. Excessive strain impairs neuronal function, but moderate strains are accommodated by nerves and can promote neuronal growth; mechanisms underlying these phenomena are not well understood. We demonstrated that levels of several structural proteins increase following physiological levels of nerve strain and that expression of a subset of these proteins is regulated by mTOR. Our work has important implications for understanding nerve development and strain-based regenerative strategies.

Regeneration is a process that restores structure and function of tissues damaged by injury or disease. In mammals complete regeneration is often unsuccessful, while most of the low phyla animals can re-grow many parts of their body after amputation. Cephalopod molluscs, and in particular Octopus vulgaris, are well known for their capacity to regenerate their arms and other body parts, including central and peripheral nervous system. To better understand the mechanism of recovery following nerve injury in this species we investigated the process of axon regrowth and nerve regeneration after complete transection of the Octopus pallial nerves. This injury induces scar formation and activates the proliferation of hemocytes which invade the lesion site. Hemocytes appear involved in debris removal and seem to produce factors that foster axon re-growth. Connective tissue is involved in driving regenerating fibers in a single direction, outlining for them a well-defined pathway. Injured axons are able to quickly re-grow thus to restoring structure and function.

Nerves in the mouth of the rorqual whale can double in length during feeding, without incurring damage. Several clever structural features underlie this amazing phenomenon. Such neuroprotective architectural strategies may be conserved, to a lesser extreme, across the organismal spectrum.

The pannexin family of channels consists of three members-pannexin-1 (Panx1), pannexin-2 (Panx2), and pannexin-3 (Panx3) that enable the exchange of metabolites and signaling molecules between intracellular and extracellular compartments. Pannexin-mediated release of intracellular ATP into the extracellular space has been tied to a number of cellular activities, primarily through the activity of type P2 purinergic receptors. Previous work indicates that the opening of Panx1 channels and activation of purinergic receptors by extracellular ATP may cause inflammation and apoptosis. In the CNS (central nervous system) and PNS (peripheral nervous system), coupled pannexin, and P2 functions have been linked to peripheral sensitization (pain) pathways. Purinergic pathways are also essential for other critical processes in the PNS, including myelination and neurite outgrowth. However, whether such pathways are pannexin-dependent remains to be determined. In this study, we use a Panx1 knockout mouse model and pharmacological inhibitors of the Panx1 and the ATP-mediated signaling pathway to fill gaps in our understanding of Panx1 localization in peripheral nerves, roles for Panx1 in axonal outgrowth and myelination, and neurite extension. Our data show that Panx1 is localized to axonal, myelin, and vascular compartments of the peripheral nerves. Knockout of Panx1 gene significantly increased axonal caliber in vivo and axonal growth rate in cultured dorsal root ganglia (DRG) neurons. Furthermore, genetic knockout of Panx1 or inhibition of components of purinergic signaling, by treatment with probenecid and apyrase, resulted in denser axonal outgrowth from cultured DRG explants compared to untreated wild-types. Our findings suggest that Panx1 regulates axonal growth in the peripheral nervous system.

Lower motor neuron (LMN) damage results in denervation of the associated muscle targets and is a significant yet under-appreciated component of spinal cord injury (SCI). Denervated muscle undergoes a progressive degeneration and fibro-fatty infiltration that eventually renders the muscle non-viable unless reinnervated within a limited time window. The distal nerve deprived of axons also undergoes degeneration and fibrosis making it less receptive to axons. In this review, we describe the LMN injury associated with SCI and its clinical consequences. The process of degeneration of the muscle and nerve is broken down into the primary components of the neuromuscular circuit and reviewed, including the nerve and Schwann cells, the neuromuscular junction, and the muscle. Finally, we discuss three promising strategies to reverse denervation atrophy. These include providing surrogate axons from local sources; introducing stem cell-derived spinal motor neurons into the nerve to provide the missing axons; and finally, instituting a training program of high-energy electrical stimulation to directly rehabilitate these muscles. Successful interventions for denervation atrophy would significantly expand reconstructive options for cervical SCI and could be transformative for the predominantly LMN injuries of the conus medullaris and cauda equina. [ABSTRACT FROM AUTHOR]

PurposeSimple decompression and anterior subcutaneous transposition are effective surgical interventions for cubital tunnel syndrome and yield similarly favorable outcomes. However, a substantial proportion of patients demonstrate unsatisfactory outcomes for reasons that remain unclear. We compared effects of decompression and transposition on regional ulnar nerve strain to better understand the biomechanical impacts of each strategy.MethodsPatients diagnosed with cubital tunnel syndrome and scheduled for anterior subcutaneous transposition surgery were enrolled. Simple decompression, circumferential decompression, and anterior transposition of the ulnar nerve were performed during the course of the transposition procedure. Regional ulnar nerve strain around the elbow was measured for each surgical intervention based on 4 wrist and elbow joint configurations.ResultsWith elbow extension at 180°, both circumferential decompression and anterior transposition resulted in approximately 68% higher nerve strains than simple decompression. Conversely, with elbow flexion, simple decompression resulted in higher average strains than anterior transposition. Limited regional differences in strain were observed for any surgical intervention with elbow extension. However, with elbow flexion, strains were higher in distal and central regions compared with the proximal region within all surgical groups, and proximal region strain was higher after simple decompression compared with anterior transposition.ConclusionsAs predicted by the altered anatomic course, anterior transposition results in lower ulnar nerve strains than simple decompression during elbow flexion and higher nerve strains during elbow extension. Irrespective of anatomic course, circumferential release of paraneurial tissues may also influence nerve strain. Nerve strain varies regionally and is influenced by surgery and joint configuration.Clinical relevanceOur data provide insight into how surgery resolves and redistributes traction on the ulnar nerve. These findings may help inform which surgical procedure to perform for a specific patient, guide rehabilitation protocols, and suggest regions of anatomic concern during index and revision surgery.

Axons in the peripheral nervous system respond to injury by activating retrograde injury signaling (RIS) pathways, which promote local axonal protein synthesis (LPS) and neuronal regeneration. RIS is also initiated following injury of neurons in the central nervous system (CNS). However, regulation of the localization of axonal mRNA required for LPS is not well understood. We used a hippocampal explant system to probe the regulation of axonal levels of RIS-associated transcripts following axonal injury. Axonal levels of importin β1 and RanBP1 were elevated biphasically at 1 and 24 hrs after axotomy. Transcript levels for β-actin, a prototypic axonally synthesized protein, were similarly elevated. Our data suggest differential regulation of axonal transcripts. At 1 hr after injury, deployment of actinomycin revealed that RanBP1, but not importin β1, requires de novo mRNA synthesis. At 24 hrs after injury, use of importazole revealed that the second wave of increased axonal mRNA levels required importin β-mediated nuclear import. We also observed increased importin β1 axonal protein levels at 1 and 6 hrs after injury. RanBP1 levels and vimentin levels fluctuated but were unchanged at 3 and 6 hrs after injury. This study revealed temporally complex regulation of axonal transcript levels, and it has implications for understanding neuronal response to injury in the CNS.

Rotator cuff (RC) disease is an extremely common condition associated with shoulder pain, reduced functional capacities, and impaired quality of life. It primarily involves alterations in tendon health and mechanical properties that can ultimately lead to tendon failure. RC tendon tears induce progressive muscle changes that have a negative impact on surgical reparability of the RC tendons and clinical outcomes. At the same time, a significant base of clinical data suggests a relatively weak relationship between RC integrity and clinical presentation, emphasizing the multifactorial aspects of RC disease. This review aims to summarize the potential contribution of peripheral, spinal, and supraspinal neural factors that may (1) exacerbate structural and functional muscle changes induced by tendon tear, (2) compromise the reversal of these changes during surgery and rehabilitation, (3) contribute to pain generation and persistence of pain, (4) impair shoulder function through reduced proprioception, kinematics, and muscle recruitment, and (5) help explain interindividual differences and response to treatment. Given the current clinical and scientific interest in peripheral nerve injury in the context of RC disease and surgery, we carefully reviewed this body of literature with a particular emphasis on suprascapular neuropathy that has generated a large number of studies in the past decade. Within this process, we highlight the gaps in current knowledge and suggest research avenues for scientists and clinicians.

Local synthesis of proteins within the Schwann cell periphery is extremely important for efficient process extension and myelination, when cells undergo dramatic changes in polarity and geometry. Still, it is unclear how ribosomal distributions are developed and maintained within Schwann cell projections to sustain local translation. In this multi-disciplinary study, we expressed a plasmid encoding a fluorescently labeled ribosomal subunit (L4-GFP) in cultured primary rat Schwann cells. This enabled the generation of high-resolution, quantitative data on ribosomal distributions and trafficking dynamics within Schwann cells during early stages of myelination, induced by ascorbic acid treatment. Ribosomes were distributed throughout Schwann cell projections, with ~2-3 bright clusters along each projection. Clusters emerged within 1 day of culture and were maintained throughout early stages of myelination. Three days after induction of myelination, net ribosomal movement remained anterograde (directed away from the Schwann cell body), but ribosomal velocity decreased to about half the levels of the untreated group. Statistical and modeling analysis provided additional insight into key factors underlying ribosomal trafficking. Multiple regression analysis indicated that net transport at early time points was dependent on anterograde velocity, but shifted to dependence on anterograde duration at later time points. A simple, data-driven rate kinetics model suggested that the observed decrease in net ribosomal movement was primarily dictated by an increased conversion of anterograde particles to stationary particles, rather than changes in other directional parameters. These results reveal the strength of a combined experimental and theoretical approach in examining protein localization and transport, and provide evidence of an early establishment of ribosomal populations within Schwann cell projections with a reduction in trafficking following initiation of myelination.

Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease in which weakness, increased susceptibility to muscle injury, and inadequate repair underlie the pathology. While most attention has focused within the muscle fiber, we recently demonstrated significant alterations in the neuromuscular junction (NMJ) morphology and resulting neuromuscular transmission failure (NTF) 24 h after injury in mdx mice (murine model for DMD). Here we determine the contribution of NMJ morphology and NTF to the recovery of muscle contractile function post-injury. NMJ morphology and NTF rates were assessed day 0 (immediately after injury) and days 1, 7, 14 and 21 after quadriceps injury. Eccentric injury of the quadriceps resulted in a significant loss of maximal torque in both WT (39 ± 6 %) and mdx (76 ± 8 %) with a full recovery in WT by day 7 and in mdx by day 21. Post-injury alterations in NMJ morphology and NTF were found only in mdx, were limited to days 0 and 1, and were independent of changes in MuSK or AChR expression. Such early changes at the NMJ after injury are consistent with mechanical disruption rather than newly forming NMJs. Furthermore, we show that the dense microtubule network that underlies the NMJ is significantly reduced and disorganized in mdx compared to WT. These structural changes at the NMJ may play a role in the increased NMJ disruption and the exaggerated loss of nerve-evoked muscle force seen after injury to dystrophic muscles.

Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease in which weakness, increased susceptibility to muscle injury, and inadequate repair appear to underlie the pathology. While most attention has focused within the muscle fiber, we recently demonstrated in mdx mice (murine model for DMD) significant morphologic alterations at the motor endplate of the neuromuscular junction (NMJ) and corresponding NMJ transmission failure after injury. Here we extend these initial observations at the motor endplate to gain insight into the pre- vs. postsynaptic morphology, as well as the subsynaptic nuclei in healthy (WT) vs. mdx mice. We quantified the discontinuity and branching of the terminal nerve in adult mice. We report mdx- and age-dependent changes for discontinuity and an increase in branching when compared to WT. To examine mdx- and age-dependent changes in the relative localization of pre- and postsynaptic structures, we calculated NMJ occupancy, defined as the ratio of the footprint occupied by presynaptic vesicles vs. that of the underlying motor endplate. The normally congruent coupling between presynaptic and postsynaptic morphology was altered in mdx mice, independent of age. Finally we found an almost two-fold increase in the number of nuclei and an increase in density (nuclei/area) underlying the NMJ. These outcomes suggest substantial remodeling of the NMJ during dystrophic progression. This remodeling reflects plasticity in both pre- and postsynaptic contributors to NMJ structure, and thus perhaps also NM transmission and muscle function.

BackgroundNerve cuff electrodes are commonly and successfully used for stimulating peripheral nerves. On the other hand, they occasionally induce functional and morphological changes following chronic implantation, for reasons not always clear. We hypothesize that restriction of nerve mobility due to cuff implantation may alter nerve conduction.MethodsWe quantified acute changes in nerve-muscle electrophysiology, using electromyography, and nerve kinematics in anesthetized Sprague Dawley rat sciatic nerves during controlled hindlimb joint movement. We compared electrophysiological and biomechanical response in uncuffed nerves and those secured within a cuff electrode using analysis of variance (ANOVA) and regression analysis.ResultsTethering resulting from cuff implantation resulted in altered nerve strain and a complex biomechanical environment during joint movement. Coincident with biomechanical changes, electromyography revealed significantly increased variability in the response of conduction latency and amplitude in cuffed, but not free, nerves following joint movement.ConclusionOur findings emphasize the importance of the mechanical interface between peripheral nerves and their devices on neurophysiological performance. This work has implications for nerve device design, implantation, and prediction of long-term efficacy.