Lumbar foraminal stenosis was associated with back pain and leg pain: epidemiological evidence from a population-based cohort.

OBJECTIVES: To determine the characteristics of lumbar foraminal stenosis (LFS) on magnetic resonance (MR) images and their association with back pain and radiating leg pain in a population-based sample of Chinese subjects. METHODS: This study was an extension of the Hangzhou Lumbar Spine Study, a cross-sectional study focusing on back pain and lumbar spine MR imaging findings. Questionnaire data, including demographics, lifestyle, occupational exposures, back pain and radiating leg pain were included. On lumbar spine MR images, disc degeneration was assessed using Pfirrmann grade and Modic changes were evaluated. Using Lee's scale, the L3-S1 intervertebral foramina were evaluated, with grade 2-3 representing substantial LFS and grade 0-1 no LFS. Characteristics of LFS were noted, and associations of LFS with back pain and radiating leg pain were examined. RESULTS: Among the 644 study subjects, 141 (21.9%) had at least one LFS, and its occurrence was associated with greater age (OR = 1.93 for each 10 years, p < 0.001). Substantial LFS was associated with the presence of back pain (OR = 1.92, p = 0.001) and the intensity of the worst back pain (Coef = 8.30, p < 0.001) over the past 12 months, and disabling back pain during their lifetime (OR = 2.25, p < 0.001). Substantial LFS was also associated with leg pain (OR = 14.27, p < 0.001), with a sensitivity of 75.7% for the presence of radiating leg pain and a specificity of 81.4%. CONCLUSION: Substantial LFS on MR images was a common age-related degenerative phenotype in adults, and appears to be an independent risk factor for back pain and leg pain.

Biphasic release of betamethasone from an injectable HA hydrogel implant for alleviating lumbar disc herniation induced sciatica.

Epidural steroid injection (ESI) is a common therapeutic approach for managing sciatica caused by lumbar disc herniation (LDH). However, the short duration of therapeutic efficacy and the need for repeated injections pose challenges in LDH treatment. The development of a controlled delivery system capable of prolonging the effectiveness of ESI and reducing the frequency of injections, is highly significant in LDH clinical practice. In this study, we utilized a thiol-ene click chemistry to create a series of injectable hyaluronic acid (HA) based release systems loaded with diphasic betamethasone, including betamethasone dipropionate (BD) and betamethasone 21-phosphate disodium (BP) (BD/BP@HA). BD/BP@HA hydrogel implants demonstrated biocompatibility and biodegradability to matched neuronal tissues, avoiding artificial compression following injection. The sustained release of betamethasone from BD/BP@HA hydrogels effectively inhibited both acute and chronic neuroinflammation by suppressing the nuclear factor kappa-B (NF-κB) pathway. In a mouse model of LDH, the epidural administration of BD/BP@HA efficiently alleviated LDH-induced sciatica for at least 10 days by inhibiting the activation of macrophages and microglia in dorsal root ganglion and spinal dorsal horn, respectively. The newly developed HA hydrogels represent a valuable platform for achieving sustained drug release. Additionally, we provide a simple paradigm for fabricating BD/BP@HA for epidural injection, demonstrating greater and sustained efficiency in alleviating LDH-induced sciatica compared to traditional ESI and displaying potentials for clinical translation. This system has the potential to revolutionize drug delivery for co-delivery of both soluble and insoluble drugs, thereby making a significant impact in the pharmaceutical industry. STATEMENT OF SIGNIFICANCE: Lumbar disc herniation (LDH) is a common degenerative disorder leading to sciatica and spine surgery. Although epidural steroid injection (ESI) is routinely used to alleviate sciatica, the efficacy is short and repeated injections are required. There remains challenging to prolong the efficacy of ESI. Herein, an injectable hyaluronic acid (HA) hydrogel implant by crosslinking acrylated-modified HA (HA-A) with thiol-modified HA (HA-SH) was designed to achieve a biphasic release of betamethasone. The hydrogel showed biocompatibility and biodegradability to match neuronal tissues. Notably, compared to traditional ESI, the hydrogel better alleviated sciatica in vivo by synergistically inhibiting the neuroinflammation in central and peripheral nervous systems. We anticipate the injectable HA hydrogel implant has the potential for clinical translation in treating LDH-induced sciatica.

Referred pain: characteristics, possible mechanisms, and clinical management.

Purpose of this review: Referred pain is a common but less understood symptom that originates from somatic tissues. A comprehensive recognition of referred pain is important for clinicians when dealing with it. The purpose of this study is to summarize the current understanding of referred pain, including its pathogenesis, characteristics, diagnosis, and treatment. Recent findings: Referred pain arises not only from pathologies primarily involving local tissue but also from lesions in distant structures. Central sensitization of convergent neurons and peripheral reflexes of dichotomizing afferent fibers are two theories proposed to explain the pathological mechanism of referred pain. Because syndromes related to referred pain of different origins overlap each other, it is challenging to define referred pain and identify its originating lesions. Although various approaches have been used in the diagnosis and treatment of referred pain, including conservative treatment, blockade, radiofrequency, and surgery, management of referred pain remains a clinical challenge. Summary: Unlike radicular pain and neuropathic pain, referred pain is a less studied area, despite being common in clinics. Referred pain can derive from various spinal structures, and blockage helps identify the primary pathology. Due to the heterogeneity of referred pain, treatment outcomes remain uncertain. Further studies are needed to improve our understanding of referred pain.

Sensory innervation of the lumbar 5/6 intervertebral disk in mice.

Introduction: Over the years, most back pain-related biological studies focused on the pathogenesis of disk degeneration. It is known that nerve distributions at the outer layer of the annulus fibrosus (AF) may be an important contributor to back pain symptoms. However, the types and origins of sensory nerve terminals in the mouse lumbar disks have not been widely studied. Using disk microinjection and nerve retrograde tracing methods, the current study aimed to characterize the nerve types and neuropathway of the lumbar 5/6 (L5/6) disk in mice. Methods: Using an anterior peritoneal approach, the L5/6 disk of adult C57BL/6 mice (males, 8-12 weeks) disk microinjection was performed. Fluorogold (FG) was injected into the L5/6 disk using the Hamilton syringe with a homemade glass needle driven by a pressure microinjector. The lumbar spine and bilateral thoracic 13 (Th13) to L6 DRGs were harvested at 10 days after injection. The number of FG+ neurons among different levels was counted and analyzed. Different nerve markers, including anti-neurofilament 160/200 (NF160/200), anti-calcitonin gene-related peptide (CGRP), anti-parvalbumin (PV), and anti-tyrosine hydroxylase (TH), were used to identify different types of nerve terminals in AF and their origins in DRG neurons. Results: There were at least three types of nerve terminals at the outer layer of L5/6 AF in mice, including NF160/200+ (indicating Aß fibers), CGRP+ (Aδ and C fibers), and PV+ (proprioceptive fibers). No TH+ fibers (sympathetic nerve fibers and some C-low threshold mechanoreceptors) were noticed in either. Using retrograde tracing methods, we found that nerve terminals in the L5/6 disk were multi-segmentally from Th13-L6 DRGs, with L1 and L5 predominately. An immunofluorescence analysis revealed that FG+ neurons in DRGs were co-localized with NF160/200, CGRP, and PV, but not TH. Conclusion: Intervertebral disks were innervated by multiple types of nerve fibers in mice, including Aß, Aδ, C, and proprioceptive fibers. No sympathetic nerve fibers were found in AF. The nerve network of the L5/6 disk in mice was multi-segmentally innervated by the Th13-L6 DRGs (mainly L1 and L5 DRGs). Our results may serve as a reference for preclinical studies of discogenic pain in mice.

Microglia and macrophages contribute to the development and maintenance of sciatica in lumbar disc herniation.

ABSTRACT: Lumbar disc herniation (LDH) is a major cause of sciatica. Emerging evidence indicated that inflammation induced by the herniated nucleus pulposus (NP) tissues plays a major role in the pathogenesis of sciatica. However, the underlying mechanisms are still elusive. Although microglia and macrophages have been implicated in nerve injury-induced neuropathic pain, their roles in LDH-induced sciatica largely remain unknown. This study successfully established and modified a mouse model of LDH. We found that nerve root compression using degenerated NP tissues can initiate remarkable and persistent sciatica, with increased and prolonged macrophage infiltration in dorsal root ganglia (DRG) and significant activation of microglia in the spinal dorsal horn. Instead, compression of the nerve root with nondegenerated NP tissues only led to transient sciatica, with transient infiltration and activation of macrophages and microglia. Moreover, continuous treatment of PLX5622, a specific colony-stimulating factor 1 receptor antagonist, ablated both macrophages and microglia, which effectively alleviated LDH-induced sciatica. However, mechanical allodynia reoccurred along with the repopulation of macrophages and microglia after the withdrawal of PLX5622. Using RNA sequencing analysis, the current study depicted transcriptional profile changes of DRG after LDH and identified several macrophage-related potential target candidates. Our results suggested that microglia and macrophages may play an essential role in the development and maintenance of LDH-induced sciatica. Targeting microglia and macrophages may be a promising treatment for chronic LDH-induced sciatica.

mTOR-neuropeptide Y signaling sensitizes nociceptors to drive neuropathic pain.

Neuropathic pain is a refractory condition that involves de novo protein synthesis in the nociceptive pathway. The mTOR is a master regulator of protein translation; however, mechanisms underlying its role in neuropathic pain remain elusive. Using the spared nerve injury-induced neuropathic pain model, we found that mTOR was preferentially activated in large-diameter dorsal root ganglion (DRG) neurons and spinal microglia. However, selective ablation of mTOR in DRG neurons, rather than microglia, alleviated acute neuropathic pain in mice. We show that injury-induced mTOR activation promoted the transcriptional induction of neuropeptide Y (Npy), likely via signal transducer and activator of transcription 3 phosphorylation. NPY further acted primarily on Y2 receptors (Y2R) to enhance neuronal excitability. Peripheral replenishment of NPY reversed pain alleviation upon mTOR removal, whereas Y2R antagonists prevented pain restoration. Our findings reveal an unexpected link between mTOR and NPY/Y2R in promoting nociceptor sensitization and neuropathic pain.

Reconstruction of the Hypothalamo-Neurohypophysial System and Functional Dissection of Magnocellular Oxytocin Neurons in the Brain.

The hypothalamo-neurohypophysial system (HNS), comprising hypothalamic magnocellular neuroendocrine cells (MNCs) and the neurohypophysis, plays a pivotal role in regulating reproduction and fluid homeostasis by releasing oxytocin and vasopressin into the bloodstream. However, its structure and contribution to the central actions of oxytocin and vasopressin remain incompletely understood. Using viral tracing and whole-brain imaging, we reconstruct the three-dimensional architecture of the HNS and observe collaterals of MNCs within the brain. By dual viral tracing, we further uncover that subsets of MNCs collaterally project to multiple extrahypothalamic regions. Selective activation of magnocellular oxytocin neurons promote peripheral oxytocin release and facilitate central oxytocin-mediated social interactions, whereas inhibition of these neurons elicit opposing effects. Our work reveals the previously unrecognized complexity of the HNS and provides structural and functional evidence for MNCs in coordinating both peripheral and central oxytocin-mediated actions, which will shed light on the mechanistic understanding of oxytocin-related psychiatric diseases.

mTOR-mediated metabolic reprogramming shapes distinct microglia functions in response to lipopolysaccharide and ATP.

Microglia constantly survey the brain microenvironment and rapidly adopt different phenotypes in response to environmental stimuli. Such dynamic functions require a unique metabolism and bioenergetics. However, little is known about the basic metabolism of microglia and how metabolic changes regulate microglia function. Here, we uncover that microglia activation is accompanied by extensive transcriptional changes in glucose and lipid metabolism-related genes. Using metabolic flux assays, we found that LPS, a prototype of the pathogen-associated molecular patterns (PAMPs), significantly enhanced glycolysis but suppressed oxidative phosphorylation (OXPHOS) in primary cultured microglia. By contrast, ATP, a known damage-associated molecular pattern (DAMPs) that triggers sterile activation of microglia, boosted both glycolysis and OXPHOS. Importantly, both LPS and ATP activated the mechanistic target of rapamycin (mTOR) pathway and enhanced the intracellular reactive oxygen species (ROS). Inhibition of mTOR activity suppressed glycolysis and ROS production in both conditions but exerted different effects on OXPHOS: it attenuated the ATP-induced elevation of OXPHOS, yet had no impact on the LPS-induced suppression of OXPHOS. Further, inhibition of mTOR or glycolysis decreased production of LPS-induced proinflammatory cytokines and ATP-induced tumor necrosis factor-α (TNF-α) and brain derived neurotrophic factor (BDNF) in microglia. Our study reveals a critical role for mTOR in the regulation of metabolic programming of microglia to shape their distinct functions under different states and shed light on the potential application of targeting metabolism to interfere with microglia-mediated neuroinflammation in multiple disorders.

Lumbar vertebral endplate defects on magnetic resonance images: prevalence, distribution patterns, and associations with back pain.

BACKGROUND CONTEXT: Although the roles of Modic Changes (MCs) and disc degeneration in back pain remain controversial, clues from cadaveric studies suggest that lumbar vertebral endplate lesions may be important in back pain. Endplate lesions can be detected on magnetic resonance (MR) images as various endplate defects, including focal, corner, and erosive defects. Yet, the clinical significance of such endplate defects remains unknown. PURPOSE: To determine the prevalence and distribution patterns of lumbar vertebral endplate defects and their associations with back pain in a population-based sample. STUDY DESIGN: Cross-sectional study. PATIENT SAMPLE: Subjects were randomly selected from a typical community in Hangzhou Eastern China, regardless of back pain status. OUTCOME MEASURES: Each subject underwent a structured interview and lumbar MR imaging. Back pain history, including today, over the past 4 weeks, 12 months, and lifetime, were acquired. Endplate defects, MCs, and disc degeneration were evaluated on MRIs. Age, gender and body mass index (kg/m2), as well as lifetime exposures, including smoking history, riding in motorized vehicles and associated vibration, and occupational physical demands were assessed. METHODS: Descriptive statistics were used to depict prevalence and distribution patterns of endplate defects in the lumbar spine. Logistic regressions were used to examine associations of endplate defects with back pain. The research grant was obtained from the National Natural Science Foundation of China (115,000 USD), Key Platform Project of the Health Department of Zhejiang Province (14,000 USD), Technology Program of Traditional Chinese Medicine Department of Zhejiang Province (21,000 USD), and 2015 Qianjiang Talent Program of Zhejiang Province (7,000 USD) toward this work. There is no conflict to disclose. RESULTS: There were 478 subjects (53.3±14.4 years, range 20-88 years) studied. Endplate defects presented in 301 (63.0%) subjects and 842 (16.0%) endplates. The presence of endplate defects, but not MCs and disc degeneration, was associated with lifetime back pain (odds ratio=1.64, p=.026) in multivariate analyses. Focal and erosive endplate defects were associated with lifetime back pain history (odds ratio=1.74-2.23, p<.05 for both), whereas all three types of defects were associated with intensity of worst back pain over the past 12 months (Coef=5.84-7.19, p<.05 for all). CONCLUSIONS: Endplate defects are common findings on lumbar MRIs in adults. Specific types of endplate defects were associated with back pain history. Endplate defects may be an independent risk factor for back pain.

Implication of microglia activation and CSF-1/CSF-1Rpathway in lumbar disc degeneration-related back pain.

Back pain is common and costly. Although lumbar disc degeneration has long been regarded as a major contributor to back pain, how disc degeneration leads to back pain remains unclear. Recent studies observed microglia activation in the spinal cord after disc degeneration, suggesting activated microglia may be involved in discogenic back pain. To determine whether microglia activation participates in disc degeneration-induced back pain, we used a modified disc puncture-induced degeneration-related back pain mouse model to examine the changes in spinal microglia and investigate the potential link between microglia activation and discogenic back pain. In this study, 46 CX3CR1GFP/+ male mice were used in experimental and sham groups. A modified posterolateral retroperitoneal approach was used to expose the L3/L4 disc to induce the needle puncture in the experimental group. Behavioral tests, including grip force and physical function, were used to measure back pain at pre- and postsurgery. The L3 dorsal root ganglions and lumbar spinal cord were obtained at postoperative weeks 1 to 4 followed by immunofluorescence with different antibodies. Micrographs were obtained by confocal microscopy, and morphometric measurements of microglia were analyzed using Imaris. The punctured disc underwent progressive degeneration and mice with disc degeneration showed impaired grip force and physical function. Compared to the control mice, the number of microglia in the lumbar spinal cord was significantly increased in the disc-punctured animals. Moreover, accumulated microglia exhibited larger soma size and lesser ramification in the disc-injured mice. Immunofluorescence demonstrated colony-stimulating factor 1, a cytokine that promotes microglia repopulation, was significantly increased in L3 dorsal root ganglions, whereas its receptor colony-stimulating factor 1 receptor was upregulated on microglia in the disc-injured mice. In summary, lumbar disc puncture caused progressive disc degeneration which induced microglia activation and back pain in mice. Increased colony-stimulating factor 1/colony-stimulating factor 1 receptor signaling is involved in the disc degeneration-induced microglia activation and back pain.

Methodology and cohort profile for the Hangzhou Lumbar Spine Study: a study focusing on back health in a Chinese population.

Back pain is a worldwide health problem, adding a tremendous burden to modern societies. However, little information on back health is available in China, even though a quarter of the world's population is Chinese. To enhance knowledge in this area, we designed and initiated the Hangzhou Lumbar Spine Study, which is a cross-sectional study of a general sample of mainland Chinese with focusing on disc degeneration, Modic changes, endplate lesions, and back pain. The study consists of a structured questionnaire to measure back pain history and lifetime exposure to suspected risk factors, magnetic resonance imaging of the lumbar spine, bone mineral density study of the spine and hip, and DNA sample analysis. Here we briefly introduce the study methodology, report the test-retest reliability of the questionnaire, and describe the cohort profile to date. Since May 2014, 301 randomly selected subjects (male/female, 122/179; mean age, 51.0 years; range, 20-87 years) have been recruited. Tests-retests of the questionnaire, completed by 40 participants, revealed good reliability. To our knowledge, the Hangzhou Lumbar Spine Study is the first population-based epidemiological study conducted to characterize lumbar spinal phenotypes and back pain, their interaction, and their associations with lifetime environmental exposure, in mainland Chinese. Epidemiological information obtained from a reliable questionnaire, magnetic resonance (MR) imaging data, dual energy X-ray absorptiometry (DXA) measurements, and DNA analysis may serve as a valuable reference for future studies on back health, particularly for mainland Chinese.

A Novel Method to Image Macropinocytosis in Vivo.

Here we described an experimental protocol for in vivo imaging of macropinocytosis and subsequent intracellular events. By microinjection, we delivered fluorescence dextrans together with or without ATPγS into transparent Drosophila melanogaster embryos. Using a confocal microscope for live imaging, we monitored the generation of dextran-positive macropinosomes and subsequent intracellular events. Our protocol provides a continent and reliable way for investigating macropinocytosis and its underlying mechanisms, especially when combined with genetic strategies.

Langerhans cell histiocytosis at L5 vertebra treated with en bloc vertebral resection: a case report.

BACKGROUND: Langerhans cell histiocytosis (LCH) in adult lumbar spine is extremely rare, and optimal treatments remain unclear. In literature, only a few cases of lumbar spine LCH were treated using surgery but en bloc vertebral resection has not been used. CASE PRESENTATION: A 50-year-old man presented with unbearable radiating pain at his right leg. Radiological studies revealed a solitary osteolytic lesion, which was moderately enhanced on contrast MR imaging and hyper-metabolic on PET/CT, at the right L5 vertebral body and arch. In biopsy, Langerhans cells were observed, but findings were insufficient to establish a diagnosis of LCH. A modified L5 en bloc vertebral resection via anterior and posterior approaches was performed to remove the right 2/3 portion of the L5 vertebra. The left 1/3 vertebral body and left pedicle of L5, which were not affected, were kept in situ to allow short instrumentation and reconstruction. His leg pain disappeared after the surgery, and a precise diagnosis of LCH was established after a throughout histological study of the removed vertebra. The patient further accepted 1 cycle of low-dose radiotherapy postoperatively. At 18-month follow-up, the lumbosacral spine was fused and no local reoccurrence was noticed. CONCLUSIONS: For lumbar spine LCH, surgery should be considered if there are neurological symptoms or histological diagnosis is indefinite in biopsy. En bloc vertebral resection can be used to alleviate neurological symptoms and prevent local reoccurrence.

Modic Changes in the Lumbar Spine are Common Aging-related Degenerative Findings that Parallel With Disk Degeneration.

STUDY DESIGN: This is a cross-sectional study. OBJECTIVE: To determine the prevalence and distribution patterns of Modic changes (MCs) in the lumbar spine and their associations with disk degeneration in mainland Chinese using a sample of general population. SUMMARY OF BACKGROUND DATA: Previous studies reported that the prevalence of MCs in Hong Kong Chinese was much lower than in other populations. Moreover, their associations with disk degeneration need further study. MATERIALS AND METHODS: The study sample consisted of 442 subjects (53.6±14.9 y; range, 20-88 y) randomly selected from a typical Chinese community. Lumbar spines were imaged using a 3.0 T magnetic resonance scanner. Eleven endplates (L1-S1) in the lumbar spine were evaluated for the presence of MCs, type, location, and size to determine MCs prevalence and distribution patterns. Disk degeneration was graded using a Pfirrmann scale. RESULTS: MCs were present in 209 (47.3%) subjects and 593 (12.2%) endplates. Among these endplates, 84.1% (499) were type II, 9.1% (54) were type I, and 6.4% (38) were mixed MCs. Approximately 2/3 MCs were present in the lower lumbar spine and 44.9% of MCs were at the L5/S1 disk level. Most MCs (73.9%) involved both endplates of a disk. Greater age [odds ratio (OR)=2.44 for each 10-year increase, P<0.001] and body mass index (OR=1.07, P=0.016) were associated with the presence of MCs, as was adjacent disk degeneration (OR=6.00, P<0.001), controlling for age and other covariates. Greater age, body mass index, and adjacent disk degeneration were also associated with greater MCs size. CONCLUSIONS: MCs are common in mainland Chinese, with type II predominating. MCs mainly present in the lower lumbar region and tend to occur in pairs. MCs were strongly associated with age and disk degeneration, suggesting MCs may be aging-related degenerative findings that parallel disk degeneration. LEVEL OF EVIDENCE: Level II.

Vertebral Augmentation can Induce Early Signs of Degeneration in the Adjacent Intervertebral Disc: Evidence from a Rabbit Model.

STUDY DESIGN: An experimental study. OBJECTIVE: The aim of this study was to determine the effect of polymethylmethacrylate (PMMA) augmentation on the adjacent disc. SUMMARY OF BACKGROUND DATA: Vertebral augmentation with PMMA reportedly may predispose the adjacent vertebra to fracture. The influence of PMMA augmentation on the adjacent disc, however, remains unclear. METHODS: Using a retroperitoneal approach, PMMA augmentation was performed for 23 rabbits. For each animal, at least one vertebra was augmented with 0.2 to 0.3 mL PMMA. The disc adjacent to the augmented vertebra and a proximal control disc were studied using magnetic resonance (MR) imaging, histological and molecular level evaluation at 1, 3, and 6 months postoperatively. Marrow contact channels in the endplate were quantified in histological slices and number of invalid channels (those without erythrocytes inside) was rated. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was performed to determine disc cell apoptosis. RESULTS: On MR images, the signal and height of the adjacent disc did not change 6 months after vertebral augmentation. Histological scores of the adjacent disc increased over time, particularly for the nucleus pulposus. The adjacent disc had greater nucleus degeneration score than the control disc at 3 months (5.7 vs. 4.5, P < 0.01) and 6 months (6.9 vs. 4.4, P < 0.001). There were more invalid marrow contact channels in the endplate of augmented vertebra than the control (43.3% vs. 11.1%, P < 0.01). mRNA of ADAMTS-5, MMP-13, HIF-1α, and caspase-3 were significantly upregulated in the adjacent disc at 3 and 6 months (P < 0.05 for all). In addition, there were more TUNEL-positive cells in the adjacent disc than in the control disc (43.4% vs. 24.0%, P < 0.05) at 6 months postoperatively. CONCLUSION: Vertebral augmentation can induce early degenerative signs in the adjacent disc, which may be due to impaired nutrient supply to the disc. LEVEL OF EVIDENCE: N/A.