Endplate Region Research Articles

COMPARISON OF VERTEBRAL AND INTERVERTEBRAL DISC STRAINS IN AXIAL COMPRESSION AND FLEXION, AND THE EFFECT OF DISC DEGENERATION

IntroductionVertebral compression fractures are the most common type of osteoporotic fracture. Though 89% of clinical fractures occur anteriorly, it is challenging to replicate these ex vivo with the underlying intervertebral discs (IVDs) present. Furthermore, the role of disc degeneration in this mechanism is poorly understood. Understanding how disc morphology alters vertebral strain distributions may lead to the utilisation of IVD metrics in fracture prediction, or inform surgical decision-making regarding instrumentation type and placement.AimTo determine the effect of disc degeneration on the vertebral trabecular bone strain distributions in axial compression and flexion loading.MethodsEight cadaveric thoracolumbar segments (T11-L3) were prepared (N=4 axial compression, N=4 flexion). µCT-based digital volume correlation was used to quantify trabecular strains. A bespoke loading device fixed specimens at the resultant displacement when loaded to 50N and 800N. Flexion was achieved by adding 6° wedges. Disc degeneration was quantified with Pfirrmann grading and T2 relaxation times.ResultsAnterior axial strains were 80.9±39% higher than the posterior region in flexion (p<0.01), the ratio of which was correlated with T2 relaxation time (R2=0.80, p<0.05). In flexion, the central-to-peripheral axial strain ratio in the endplate region was significantly higher when the underlying IVDs were non-degenerated relative to degenerated (+38.1±12%, p<0.05). No significant differences were observed in axial compression.ConclusionDisc degeneration is a stronger determinant of the trabecular strain distribution when flexion is applied. Load transfer through non-degenerate IVDs under flexion appears to be more centralised, suggesting that disc degeneration predisposes flexion-type compression fractures by shifting high strains anteriorly.Conflicts of interestThe authors declare none.Sources of fundingThis work was funded by the Engineering & Physical Sciences Research Council (EP/V029452/1), and Back-to-Back.

From Modic to Disc Endplate Bone Marrow Complex - The Natural Course and Clinical Implication of Vertebral Endplate Changes.

Review article. A review of literature on the epidemiology, natural course, pathobiology and clinical implications of vertebral endplate changes. A literature search was performed using the Cochrane Database of Systematic Reviews, EMBASE, and PubMed. Studies published over the last 10 years were analysed. The searches were performed using Medical Subject Headings terms, and the subheadings used were "Vertebral endplate changes", "Modic changes", "Disc Endplate Bone Marrow complex". The disc, endplate (EP), and bone marrow region of the spine constitute a unified morphological and functional unit, with isolated degeneration of any one structure being uncommon. Disc degeneration causes endplate defects, which result in direct communication and a constant cross-talk between the disc and the vertebral body. This may result in a persistent inflammatory state of the vertebral bone marrow, serving as a major pain generator. This review article focuses on vertebral endplate changes and how the current understanding has progressed from the Modic classification to the Disc Endplate Bone Marrow complex classification. It provides a clear portrayal of the natural course of these alterations and their clinical implications in low back pain. In light of the heightened interest and current prominence of vertebral endplate changes within the spine community, we must progress beyond the Modic changes to achieve a comprehensive understanding. The DEBM complex classification will play a major part in disc degeneration research and clinical care, representing a considerable advancement in our understanding of the vertebral endplate changes over the classical Modic changes.

Vertebral Endplate Changes: Insights Into Its Natural Course and Clinical Implications in Low Back Pain

Abstract This study presents the literature review on vertebral endplate (EP) changes, which are frequently observed in patients with chronic low back pain (LBP). The disc, EP, and bone marrow region of the spine form a single anatomical and functional interdependent unit; isolated degeneration of any one structure is rare. The cartilaginous EP supported by a bony EP is responsible for anatomical integrity and controls diffusion, the only source of nutrition to the disc. A break in the EP establishes disc-bone marrow contact leading to possible severe autoimmune inflammation and also neovascularization and destruction of the disc. Conversely, degeneration, herniation, or infection of the disc will end in the destruction of both EPs as well as involve the subchondral bone. It is then logical that this region must be considered together as a whole. To consider any one of them in isolation can lead to the error of overlooking changes in the other structures of the disc EP bone marrow complex. Modic changes are discussed extensively in the literature from various angles of being a separate clinical phenotype, having a controversial etiology with the possibility of subclinical infection and treatment with antibiotics, having poor outcomes, and having higher complication rates after surgery. This review article highlights our understanding of vertebral EP changes and progression from Modic classification to disc EP bone marrow complex classification with more clearer depiction of its natural course and clinical implication in LBP.

Mrgprb2-mediated mast cell activation exacerbates Modic changes by regulating immune niches

Modic changes are radiographic features associated with microfracture, low-virulence organism infection and chronic inflammation with inflammatory cell infiltration in the vertebral endplate region. Mast cells, as innate immune cells similar to macrophages, are present in painful degenerated intervertebral discs. However, the involvement and mechanisms of mast cells in the development of Modic changes remain unclear. Herein, we found increased mast cell infiltration in samples from patients with Modic changes and in mouse models of Modic changes. To clarify the role of mast cells in the progression of Modic changes, we used mast cell-deficient (KITW-SH/W-SH) mice to construct a model of Modic changes and found that the severity of Modic changes in KITW-SH/W-SH mice was significantly lower than that in WT mice. These findings were further supported by the use of a mast cell-specific activator (compound 48/80) and a stabilizer (cromolyn). Furthermore, we found that mast cells were not activated via the classic IgE pathway in the Modic change models and that Mrgprb2 is the specific receptor for mast cell activation reported in recent studies. Then, we utilized Mrgprb2 knockout mice to demonstrate that Mrgprb2 knockout inhibited mast cell activation and thus reduced the degree of Modic changes. Transcriptomic sequencing revealed aberrant PI3K-AKT and MAPK pathway activation in the Mrgprb2-deficient mast cells. Additionally, Mrgpbrb2-activated mast cells regulate immune niches by recruiting macrophages, promoting M1 polarization and reducing M2 polarization, thereby promoting the progression of Modic changes. These findings suggest that mast cells may serve as a novel therapeutic target for addressing Modic changes.

Induction of cervical disc degeneration and discogenic pain by low concentration Propionibacterium acnes infection: an in vivo animal study

BackgroundAlthough cervical intervertebral disc (IVD) degeneration is closely associated with neck pain, its cause remains unclear. In this study, an animal model of cervical disc degeneration and discogenic neck pain induced by a low concentration of Propionibacterium acnes (P. acnes-L) is investigated to explore the possible mechanisms of cervical discogenic pain.MethodsCervical IVD degeneration and discitis was induced in 8-week-old male rats in C3–C6 IVDs through the anterior intervertebral puncture with intradiscal injections of low and high concentrations of P. acnes (P. acnes-L, n = 20 and P. acnes-H, n = 15) or Staphylococcus aureus (S. aureus, n = 15), compared to control (injection with PBS, n = 20). The structural changes in the cervical IVD using micro-CT, histological evaluation, and gene expression assays after MRI scans at 2 and 6 weeks post-modeling. The P. acnes-L induced IVD degeneration model was assessed for cervical spine MRI, histological degeneration, pain-like behaviors (guarding behavior and forepaw von Frey), nerve fiber growth in the IVD endplate region, and DRG TNF-α and CGRP.ResultsIVD injection with P. acnes-L induced IVD degeneration with decreased IVD height and MRI T2 values. IVD injection with P. acnes-H and S. aureus both lead to discitis-like changes on T2-weighted MRI, trabecular bone remodeling on micro-CT, and osseous fusion after damage in the cartilage endplate adjacent to the injected IVD. Eventually, rats in the P. acnes-L group exhibited significant nociceptive hypersensitivity, nerve fiber ingrowth was observed in the IVD endplate region, inflammatory activity in the DRG was significantly increased compared to the control group, and the expression of the pain neurotransmitter CGRP was significantly upregulated.ConclusionP. acnes-L was validated to induce cervical IVD degeneration and discogenic pain phenotype, while P. acnes-H induced was identified to resemble septic discitis comparable to those caused by S. aureus infection.

Indentation mechanics and native collagen content in the cartilaginous endplate: A comparison between porcine cervical and human lumbar spines

This study characterized the regional indentation mechanics and native collagen content in cartilaginous endplates (CEPs) from the porcine cervical spine, young human lumbar spine, and aged human lumbar spine. Seventeen endplates were included in this study: six porcine cervical, nine young human lumbar, and two aged human lumbar. Width and depth measurements were obtained using a digital caliper and used to size-normalize and identify the central, anterior, posterior, and lateral regions. Regional microindentation tests were performed using a serial robot, where surface locations were loaded/unloaded at 0.1 mm/s and held at a constant 10 N force for 30 s. Loading stiffness and creep displacement were obtained from force-displacement data. Immunofluorescence staining for type I and type II collagen was subsequently performed on sagittal sections of all endplate regions. 255 images were obtained from which fluorescence intensity, sub-surface void area, and cartilage thickness were measured. CEPs from the young human lumbar spine were, on average, 27% more compliant, 0.891 mm thicker, had a lower fluorescence intensity for native collagen proteins within the cartilage (−58%) and subchondral bone (−24%), and had a sub-surface void area that was 19.7 times greater than porcine cervical CEPs. Compared to aged human lumbar CEPs, young human lumbar CEPs were 57% stiffer, 0.568 mm thicker, had a higher fluorescence intensity for native collagen proteins within the cartilage (+30%) and subchondral bone (+46%), and had a sub-surface void area that was 10.6 times smaller. Although not a perfect mechanical and structural surrogate, porcine cervical CEPs provided initial conditions that may be more representative of the young and healthy human lumbar spine compared to aged human cadaveric specimens. The indentation properties presented may have further applications to finite element models of the human lumbar spine.

The disc-endplate-bone-marrow complex classification: progress in our understanding of Modic vertebral endplate changes and their clinical relevance

Background contextThe disc, endplate (EP), and bone marrow region of the spine form a single anatomical and functional interdependent unit; isolated degeneration of any one structure is rare. Modic changes (MC), however, are restricted to the subchondral bone alone and based on only T1 and T2 sequences of MRI. This results in poor reliability in differentiating fat from edema and hence may give a false impression of disease inactivity. PurposeTo study the changes in disc, endplate, and bone marrow as a whole in degeneration and propose a classification based on the activity status of this complex with the addition of STIR MRI sequences. Study designObservational cohort. Patient samplePatients with isolated brain, cervical, or thoracic spine injury and patients with low back pain (LBP) who underwent MRI formed the control and study groups, respectively. Outcome measuresDemographic data, the prevalence of MC and disc-endplate-bone marrow classification (DEBC) changes, EPs undergoing reclassification based on DEBC, and comparison of the prevalence of MC, DEBC, H+modifier and DEBC with H+concordance between control and LBP group. The study determined the risk of LBP patients undergoing surgery as well as the incidence of postoperative infection based on DEBC changes. Significance was calculated by binomial test and chi-square test with the effect size of 0.3 to 0.5. Prevalence and association of outcome were calculated by Altman's odds ratio with the 95% CI and the scoring of z statistics. Logistic expression was plotted for independent variables associated with each class of both Modic and DEBC against dependent variables surgery and nonsurgery. MethodsLumbar segments in both groups were assessed for MC types. The DEBC classification was developed with the addition of STIR images and studying the interdependent complex as a whole: type-A: acute inflammation; type-B: chronic persistence; type-C: latent and type-D: inactive. Modifier H+ was added if there was disc herniation. The classification was compared with MC and correlated to clinical outcomes. ResultsA total of 3,560 EPs of 445 controls and 8,680 EPs in 1,085 patients with LBP were assessed. Four nonMC, 560 MC-II, and 22 MC-III EPs were found to have previously undetected edema in STIR (n=542) or hyperintensity in discs (n=44) needing reclassification. The formerly undescribed type-B of DEBC, representing a chronic persistent activity state was the most common (51.8%) type. The difference between the control and LBP of H+(12% vs 28.8%) and its co-occurrence with DEBC type 1.1% vs 23.3%) was significant (p<.0001). The odds ratio for the need for surgery was highest (OR=5.2) when H+ and DEBC type change co-occurred. Postoperative deep infection (as determined by CDC criteria) was 0.47% in nonDEBC, compared with 2.4% in patients with DEBC (p=.002), with maximum occurrence in type-B. ConclusionClassification based on the classic MC was found to need a reclassification in 586 EPs showing the shortcomings of results of previous studies. Considering the DEBC allowed better classification and better predictability for the need for surgical intervention and incidence of postoperative infection rate than MC.

Anatomical analysis of the motor endplate zones of the suprascapular nerve to the infraspinatus muscle and its clinical significance in managing pain disorder.

Myofascial pain syndrome caused by myofascial trigger points is a musculoskeletal disorder commonly encountered in clinical practice. The infraspinatus muscle is the region most frequently involved in the myofascial pain syndrome in the scapular region. The characteristics of the myofascial trigger points are that they can be found constantly in the motor endplate zone. However, localizing myofascial trigger points within the motor endplate zone and establishing an accurate injection site of the infraspinatus muscle has been challenging because the anatomical position of the motor endplate zone of the infraspinatus muscle is yet to be described. Therefore, this cadaveric study aimed to scrutinize the motor endplate zone of the infraspinatus muscle, propose potential myofascial trigger points within the muscle, and recommend therapeutic injection sites. Twenty specimens of the infraspinatus muscle for nerve staining and 10 fresh frozen cadavers for evaluation of the injection were used in this study. The number of nerve branches penetrating the infraspinatus muscle and their entry locations were analyzed and photographed. Modified Sihler's staining was performed to examine the motor endplate regions of the infraspinatus muscle. The nerve entry points were mostly observed in the center of the muscle belly. The motor endplate was distributed equally throughout the infraspinatus muscle, but the motor endplate zone was primarily identified in the B area, which is approximately 20-40% proximal to the infraspinatus muscle. The second-most common occurrence of the motor endplate zone was observed in the center of the muscle. These detailed anatomical data would be very helpful in predicting potential pain sites and establishing safe and effective injection treatment using botulinum neurotoxin, steroids, or lidocaine to alleviate the pain disorder of the infraspinatus muscle.

A Tunable Calcium Phosphate Coating to Drive in vivo Osseointegration of Composite Engineered Tissues

Varying degrees of hydroxyapatite (HA) surface functionalization have been implicated as the primary driver of differential osteogenesis observed in infiltrating cells. The ability to reliably create spatially controlled areas of mineralization in composite engineered tissues is of growing interest in the field, and the use of HA-functionalized biomaterials may provide a robust solution to this challenge. In this study, we successfully fabricated polycaprolactone salt-leached scaffolds with two levels of a biomimetic calcium phosphate coating to examine their effects on MSC osteogenesis. Longer duration coating in simulated body fluid (SBF) led to increased HA crystal nucleation within scaffold interiors as well as more robust HA crystal formation on scaffold surfaces. Ultimately, the increased surface stiffness of scaffolds coated in SBF for 7 days in comparison to scaffolds coated in SBF for 1 day led to more robust osteogenesis of MSCs in vitro without the assistance of osteogenic signaling molecules. This study also demonstrated that the use of SBF-based HA coatings can promote higher levels of osteogenesis in vivo. Finally, when incorporated as the endplate region of a larger tissue-engineered intervertebral disc replacement, HA coating did not induce mineralization in or promote cell migration out of neighboring biomaterials. Overall, these results verified tunable biomimetic HA coatings as a promising biomaterial modification to promote discrete regions of mineralization within composite engineered tissues.

Modelling of spinal injury during aircraft seat ejection loads

The primary aim of the present work is to calculate the ejection forces on the spine lumbar vertebra (L1-L5) using Finite element modeling. The critical time of ejection was calculated based on mathematical modelling using ejection parameters such as tail height, aircraft velocity, and aircraft length. The Finite element analysis at a different level of G-Forces was performed with appropriate boundary conditions to simulate seat ejection and stress on the vertebral body is analyzed. The model was validated at the Functional spinal unit level and a multi-level model based on published literature. It was found that the anterior side of the L1 Vertebrae experiences the maximum stress, which justifies the common anterior wedge compression fracture. More stress was distributed on the superior region of endplates than that at the inferior region throughout the lumbar vertebra although the difference in the stress value between the superior and inferior region decreases from L1 to L5. In all the cases cortical bone experiences the maximum stress followed by the endplate and the stress value obtained for Intervertebral Disc(IVD) is found to be 90% lesser than the endplate, which means the initial failure may occur at the vertebral body followed by endplate.

Neoepitope fragments as biomarkers for different phenotypes of intervertebral disc degeneration.

BackgroundDuring the intervertebral disc (IVD) degeneration process, initial degenerative events occur at the extracellular matrix level, with the appearance of neoepitope peptides formed by the cleavage of aggrecan and collagen. This study aims to elucidate the spatial and temporal alterations of aggrecan and collagen neoepitope level during IVD degeneration.MethodsBovine caudal IVDs were cultured under four different conditions to mimic different degenerative situations. Samples cultured after 1‐ or 8‐days were collected for analysis. Human IVD samples were obtained from patients diagnosed with lumbar disc herniation (LDH) or adolescent idiopathic scoliosis (AIS). After immunohistochemical (IHC) staining of Aggrecanase Cleaved C‐terminus Aggrecan Neoepitope (NB100), MMP Cleaved C‐terminus Aggrecan Neoepitope (MMPCC), Collagen Type 1α1 1/4 fragment (C1α1) and Collagenase Cleaved Type I and II Collagen Neoepitope (C1,2C), staining optical density (OD)/area in extracellular matrix (OECM) and pericellular zone (OPCZ) were analyzed. Conditioned media of the bovine IVD was collected to measure protein level of inflammatory cytokines and C1,2C.ResultsFor the bovine IVD sections, the aggrecan MMPCC neoepitope was accumulated in nucleus pulposus (NP) and cartilage endplate (EP) regions following mechanical overload in the one strike model after long‐term culture; as for the TNF‐α induced degeneration, the OECM and OPCZ of collagen C1,2C neoepitope was significantly increased in the outer AF region after long‐term culture; moreover, the C1,2C was only detected in conditioned medium from TNF‐α injection + Degenerative loading group after 8 days of culture. LDH patients showed higher MMPCC OECM in NP and higher C1,2C OECM in AF region compared with AIS patients.ConclusionsIn summary, aggrecan and collagen neoepitope profiles showed degeneration induction trigger‐ and region‐specific differences in the IVD organ culture models. Different IVD degeneration types are correlated with specific neoepitope expression profiles. These neoepitopes may be helpful as biomarkers of ECM degradation in early IVD degeneration and indicators of different degeneration phenotypes.

Computed Tomography Osteoabsorptiometry Evaluation of Cervical Endplate Subchondral Bone Mineral Density.

Basic Science. Poor subchondral bone mineral density (sBMD) has been linked with subsidence of cervical interbody devices or grafts, which are traditionally placed centrally on the endplates. Considering that sBMD reflects long-term stress distributions, we hypothesize that the cervical uncovertebral joints are denser than the central endplate region. This study sought to investigate density distributions using computed tomography osteoabsorptiometry (CT-OAM). Twelve human cervical spines from C3-C7 (60 vertebrae, 120 endplates) were imaged with CT and segmented to create 3D reconstructions. The superior and inferior endplates were isolated, and the sBMD of the whole endplate, endplate center, and uncus was evaluated using CT-OAM. Density distributions were compared across the subaxial cervical spine. The uncinate region of the inferior and superior endplates was significantly denser than the central endplate across all vertebral levels (P < .01). When comparing sBMD of the whole inferior and superior endplates, the superior endplate was significantly denser than the inferior endplate (P < .0001). However, the inferior uncus was denser than the superior uncus (P = .035). When assessing sBMD by vertebral level, peak densities were observed at C4 and C5, while C7 was, on average, significantly less dense than all other vertebrae. The subchondral bone of the cervical uncovertebral joints is significantly denser than the central endplates. While the superior endplate in its entirety is denser than the inferior endplate, the inverse was true for the uncovertebral joints. This study serves as a basis for future investigations of new implant designs and their implications on subsidence.

Regional distribution of computed tomography attenuation across the lumbar endplate.

The vertebral endplate forms a structural boundary between intervertebral disc and the trabecular bone of the vertebral body. As a mechanical interface between the stiff bone and resilient disc, the endplate is the weakest portion of the vertebral-disc complex and is predisposed to mechanical failure. However, the literature concerning the bone mineral density (BMD) distribution within the spinal endplate is comparatively sparse. The objective of this study is to investigate the three-dimensional (3D) distribution of computed tomography (CT) attenuation across the lumbosacral endplate measured in Hounsfield Units (HU). A total of 308 endplates from 28 cadaveric fresh-frozen lumbosacral spines were used in this study. Each spine was CT-scanned and the resulting DICOM data was used to obtain HU values of the bone endplate. Each individual endplate surface was subdivided into five clinically-relevant topographic zones. Attenuation was analyzed by spinal levels, sites (superior or inferior endplate) and endplate region. The highest HU values were found at the S1 endplate. Comparisons between the superior and inferior endplates showed the HU values in inferior endplates were significantly higher than those in the superior endplates within the same vertebra and the HU values in endplates cranial to the disc were significantly higher than those in the endplates caudal to the disc within the same disc. Attenuation in the peripheral region was significantly higher than in the central region by 32.5%. Regional comparison within the peripheral region showed the HU values in the posterior region were significantly higher than those in the anterior region and the HU values in the left region were significantly higher than those in the right region. This study provided detailed data on the regional HU distribution across the lumbosacral endplate, which can be useful to understand causes of some endplate lesions, such as fracture, and also to design interbody instrumentation.

Treatment of Degenerative Disc Disease associated with Modic changes, with ozone therapy. A new therapeutic proposal.

Introduction.&#x0D; Modic Changes (MCs) represent signal changes in the vertebral endplate and subchondral bone region visualized on T1 and T2 weighted magnetic resonance images (MRI). Three types of MCs It have been identified (Types 1 to 3). Modic changes are commonly associated with low-back pain (LBP). &#x0D; In the last few years scientific papers have shown that one of the causes of MCs (fundamentally, the MCs type 1) is the infection caused by an anaerobic bacterium of very low virulence: Propionibacterium acnes (P. acnes). This bacterium resides on the human skin, oral cavity, intestinal tract, and external ear canal as normal flora. As a consequence of tooth brushing and endodontic-therapy, could invade the blood stream leading to transient bacteremia. The authors propose a treatment which consists of Amoxicillin-clavulanate (500 mg/125 mg) three times a day, at 8-hour intervals, for 90 days/100 days.&#x0D; Objectives.&#x0D; Ozone therapy could be the gold standard therapy for MC1 because ozone is a powerful anti-microbial, anti-inflammatory and analgesic agent, which regulates oxidative stress, immune system and oxygen metabolism. &#x0D; Materials and Methods &#x0D; Patients with LBP lasting 6 months or more and MC1 confirmed by MRI of lumbar spine L3/L4 or L4/L5 or L5/S1 and who responded with 5 or more points on the VAS scale were treated with three intradiscal sessions of ozone therapy and ten paravertebral sessions. &#x0D; Results.&#x0D; Patients who were treated with ozone therapy according to our treatment proposal showed a substantial improvement on VAS comparing the beginning and the end of the treatment. They show a significant difference in pain, and general condition. However, these results were not reflected on ODI scale, neither on the MRI but we could notice certain improvements.

"Time window" effect of Yoda1-evoked Piezo1 channel activity during mouse skeletal muscle differentiation.

AimMechanosensitive Piezo1 ion channels emerged recently as important contributors to various vital functions including modulation of the blood supply to skeletal muscles. The specific Piezo1 channel agonist Yoda1 was shown to regulate the tone of blood vessels similarly to physical exercise. However, the direct role of Piezo1 channels in muscle function has been little studied so far. We therefore investigated the action of Yoda1 on the functional state of skeletal muscle precursors (satellite cells and myotubes) and on adult muscle fibres.MethodsImmunostaining, electrophysiological intracellular recordings and Ca2+ imaging experiments were performed to localize and assess the effect of the chemical activation of Piezo1 channels with Yoda1, on myogenic precursors, adult myofibres and at the adult neuromuscular junction.ResultsPiezo1 channels were detected by immunostaining in satellite cells (SCs) and myotubes as well as in adult myofibres. In the skeletal muscle precursors, Yoda1 treatment stimulated the differentiation and cell fusion rather than the proliferation of SCs. Moreover, in myotubes, Yoda1 induced significant [Ca2+] i transients, without detectable [Ca2+] i response in adult myofibres. Furthermore, although expression of Piezo1 channels was detected around the muscle endplate region, Yoda1 application did not alter either the nerve‐evoked or spontaneous synaptic activity or muscle contractions in adult myofibres.ConclusionOur data indicate that the chemical activation of Piezo1 channels specifically enhances the differentiation of skeletal muscle precursors, suggesting a possible new strategy to promote muscle regeneration.

Development of a standardized histopathology scoring system for human intervertebral disc degeneration: an Orthopaedic Research Society Spine Section Initiative.

BackgroundHistopathological analysis of intervertebral disc (IVD) tissues is a critical domain of back pain research. Identification, description, and classification of attributes that distinguish abnormal tissues form a basis for probing disease mechanisms and conceiving novel therapies. Unfortunately, lack of standardized methods and nomenclature can limit comparisons of results across studies and prevent organizing information into a clear representation of the hierarchical, spatial, and temporal patterns of IVD degeneration. Thus, the following Orthopaedic Research Society (ORS) Spine Section Initiative aimed to develop a standardized histopathology scoring scheme for human IVD degeneration.MethodsGuided by a working group of experts, this prospective process entailed a series of stages that consisted of reviewing and assessing past grading schemes, surveying IVD researchers globally on current practice and recommendations for a new grading system, utilizing expert opinion a taxonomy of histological grading was developed, and validation performed.ResultsA standardized taxonomy was developed, which showed excellent intra‐rater reliability for scoring nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous end plate (CEP) regions (interclass correlation [ICC] > .89). The ability to reliably detect subtle changes varied by IVD region, being poorest in the NP (ICC: .89‐.95) where changes at the cellular level were important, vs the AF (ICC: .93‐.98), CEP (ICC: .97‐.98), and boney end plate (ICC: .96‐.99) where matrix and structural changes varied more dramatically with degeneration.ConclusionsThe proposed grading system incorporates more comprehensive descriptions of degenerative features for all the IVD sub‐tissues than prior criteria. While there was excellent reliability, our results reinforce the need for improved training, particularly for novice raters. Future evaluation of the proposed system in real‐world settings (eg, at the microscope) will be needed to further refine criteria and more fully evaluate utility. This improved taxonomy could aid in the understanding of IVD degeneration phenotypes and their association with back pain.

Neuropathologic Findings in Chronic Kidney Disease (CKD)

Studying the neuropathologic autopsy findings in subjects with chronic kidney disease (CKD) or chronic renal failure (CRF) is difficult for several reasons: etiology of the CKD may be heterogeneous, affected patients may have one or more major co-morbidities that themselves can cause significant neurologic disease, and agonal events may result in significant findings that were of minimal significance earlier in a patient's life. We studied the constellation of neuropathologic abnormalities in 40 autopsy brains originating from subjects of ages 34-95 years (no children in the study). The most common pathologic change was that of ischemic infarcts (cystic, lacunar and/or microinfarcts), which were seen in over half of subjects. These were associated with both large artery atherosclerosis and arteriolosclerosis (A/S), the latter finding being present in 29/40 subjects. Charcot-Bouchard microaneurysms were present in the brains of three subjects, in one case associated with severe amyloid angiopathy. Microvascular calcinosis (medial sclerosis in the case of arterioles) was seen in the basal ganglia (n=8) and/or endplate region of the hippocampus (n=7) and occasional ischemic infarcts in one brain showed severe calcification. Sequelae of cerebrovascular disease (especially A/S or microvascular disease) are a common neuropathologic substrate for neurologic disability and brain lesions in this complex group of patients. Regulation of calcium metabolism within brain microvessel walls may be worthy of further research in both human brain specimens and animal models.

Multiphoton imaging and Raman spectroscopy of the bovine vertebral endplate.

The interface between the intervertebral disc and the vertebral body is important to the discs' biomechanics and physiology, and is widely implicated in its pathology. This study aimed to explore biochemically and structurally the bony endplate, cartilage endplate and intervertebral disc, below the nucleus and below the annulus in healthy bovine tails. Multiphoton imaging and spontaneous Raman spectroscopy were employed. Raman spectroscopy provided relative quantification of mineral and matrix components across the vertebral endplate and its adjacent areas with microscopic spatial resolution. Microscopy utilising second-harmonic generation (SHG) and two-photon fluorescence (TPF) allowed for the structural identification of distinct endplate regions. The cartilage endplate was revealed as structurally distinct from both the bone and disc, supporting its biomechanical function as a transition zone between the soft and hard tissue components. The collagen fibres were continuous across the tidemark which defines the interface between the mineralised and non-mineralised regions of the endplate. Raman spectroscopy revealed gradients in phosphate and carbonate content through the depth of the endplate and also differences beneath the nucleus and annulus consistent with a higher rate of remodelling under the annulus.

Texture analysis in the classification of T2 -weighted magnetic resonance images in persons with and without low back pain.

Magnetic resonance imaging findings often do not distinguish between people with and without low back pain (LBP). However, there are still a large number of people who undergo magnetic resonance imaging to help determine the etiology of their back pain. Texture analysis shows promise for the classification of tissues that look similar, and machine learning can minimize the number of comparisons. This study aimed to determine if texture features from lumbar spine magnetic resonance imaging differ between people with and without LBP. In total, 14 participants with chronic LBP were matched for age, weight, and gender with 14 healthy volunteers. A custom texture analysis software was used to construct a gray-levelco-occurrence matrix with one to four pixels offset in 0° direction for the discand superior and inferior endplate regions. The Random Forests Algorithm was used to select the most promising classifiers. The linear mixed-effect model analysis was used to compare groups (pain vs. pain-free) at each level controlling for age. The Random Forest Algorithm recommended focusing on intervertebral discs and endplate zones at L4-5 and L5-S1. Differences were observed between groups for L5-S1 superior endplate contrast, homogeneity, and energy (p = .02). Differences were observed for L5-S1 disc contrast and homogeneity (p < .01), as well as for the inferior endplates contrast, homogeneity, and energy (p < .03). Magnetic resonance imaging textural features may have potential in identifying structures that may be the target of further investigations about the reasons for LBP.

Modulation of neuromuscular transmission using transcutaneous direct currents: An exploratory study

To assess the in vivo long-lasting effects on neuromuscular transmission using transcutaneous stimulation with anodal and cathodal direct currents applied over the end-plate region (epDCS). An active DCS electrode was placed over the end-plate region of both abductor pollicis brevis and first dorsal interosseous muscles, with a reference electrode located on the forearm. Cathodal or anodal currents were applied (2.5mA during 15min). Repetitive nerve stimulation of the median and ulnar nerves at the wrist was performed before and after DCS: protocol A - 500 stimuli at 3Hz; protocol B - 30 stimuli at 30Hz. For both muscles, we measured changes in amplitude and area between the first and 4th compound muscle action potential (CMAP) and between the first and 500th CMAP (protocol A); and the change in amplitude and area between the first and 30th CMAP (protocol B). Anodal current did not change any measurement. Using cathodal epDCS and median nerve testing, there was a larger increase in CMAP amplitude (p=0.046) and a smaller decrease in area (p=0.008) between the first and 30th response (protocol B). Using cathodal epDCS and ulnar nerve testing, there was a possible significant smaller amplitude decrease of the CMAP measured, between the first and fourth response (protocol A). Cathodal transcutaneous direct currents over the end-plate may modulate end-plate function by increasing the release of quanta of acetylcholine (Ach) and/or the number of Ach receptors available. Future studies should address this topic.