Sijia Zhang

Riluzole effects on behavioral sensitivity and the development of axonal damage and spinal modifications that occur after painful nerve root compression

OBJECT Cervical radiculopathy is often attributed to cervical nerve root injury, which induces extensive degeneration and reduced axonal flow in primary afferents. Riluzole inhibits neuro-excitotoxicity in animal models of neural injury. The authors undertook this study to evaluate the antinociceptive and neuroprotective properties of riluzole in a rat model of painful nerve root compression. METHODS A single dose of riluzole (3 mg/kg) was administered intraperitoneally at Day 1 after a painful nerve root injury. Mechanical allodynia and thermal hyperalgesia were evaluated for 7 days after injury. At Day 7, the spinal cord at the C-7 level and the adjacent nerve roots were harvested from a subgroup of rats for immunohistochemical evaluation. Nerve roots were labeled for NF200, CGRP, and IB4 to assess the morphology of myelinated, peptidergic, and nonpeptidergic axons, respectively. Spinal cord sections were labeled for the neuropeptide CGRP and the glutamate transporter GLT-1 to evaluate their expression in the dorsal horn. In a separate group of rats, electrophysiological recordings were made in the dorsal horn. Evoked action potentials were identified by recording extracellular potentials while applying mechanical stimuli to the forepaw. RESULTS Even though riluzole was administered after the onset of behavioral sensitivity at Day 1, its administration resulted in immediate resolution of mechanical allodynia and thermal hyperalgesia (p < 0.045), and these effects were maintained for the study duration. At Day 7, axons labeled for NF200, CGRP, and IB4 in the compressed roots of animals that received riluzole treatment exhibited fewer axonal swellings than those from untreated animals. Riluzole also mitigated changes in the spinal distribution of CGRP and GLT-1 expression that is induced by a painful root compression, returning the spinal expression of both to sham levels. Riluzole also reduced neuronal excitability in the dorsal horn that normally develops by Day 7. The frequency of neuronal firing significantly increased (p < 0.045) after painful root compression, but riluzole treatment maintained neuronal firing at sham levels. CONCLUSIONS These findings suggest that early administration of riluzole is sufficient to mitigate nerve root-mediated pain by preventing development of neuronal dysfunction in the nerve root and the spinal cord.

Collagen Organization in Facet Capsular Ligaments Varies with Spinal Region and with Ligament Deformation

The spinal facet capsular ligament (FCL) is primarily comprised of heterogeneous arrangements of collagen fibers. This complex fibrous structure and its evolution under loading play a critical role in determining the mechanical behavior of the FCL. A lack of analytical tools to characterize the spatial anisotropy and heterogeneity of the FCLs microstructure has limited the current understanding of its structure-function relationships. Here, the collagen organization was characterized using spatial correlation analysis of the FCLs optically obtained fiber orientation field. FCLs from the cervical and lumbar spinal regions were characterized in terms of their structure, as was the reorganization of collagen in stretched cervical FCLs. Higher degrees of intra- and intersample heterogeneity were found in cervical FCLs than in lumbar specimens. In the cervical FCLs, heterogeneity was manifested in the form of curvy patterns formed by collections of collagen fibers or fiber bundles. Tensile stretch, a common injury mechanism for the cervical FCL, significantly increased the spatial correlation length in the stretch direction, indicating an elongation of the observed structural features. Finally, an affine estimation for the change of correlation length under loading was performed which gave predictions very similar to the actual values. These findings provide structural insights for multiscale mechanical analyses of the FCLs from various spinal regions and also suggest methods for quantitative characterization of complex tissue patterns.

The Physiological Basis of Cervical Facet-Mediated Persistent Pain: Basic Science and Clinical Challenges

Synopsis Chronic neck pain is a common condition and a primary clinical symptom of whiplash and other spinal injuries. Loading-induced neck injuries produce abnormal kinematics between the vertebrae, with the potential to injure facet joints and the afferent fibers that innervate the specific joint tissues, including the capsular ligament. Mechanoreceptive and nociceptive afferents that innervate the facet have their peripheral terminals in the capsule, cell bodies in the dorsal root ganglia, and terminal processes in the spinal cord. As such, biomechanical loading of these afferents can initiate nociceptive signaling in the peripheral and central nervous systems. Their activation depends on the local mechanical environment of the joint and encodes the neural processes that initiate pain and lead to its persistence. This commentary reviews the complex anatomical, biomechanical, and physiological consequences of facet-mediated whiplash injury and pain. The clinical presentation of facet-mediated pain is complex in its sensory and emotional components. Yet, human studies are limited in their ability to elucidate the physiological mechanisms by which abnormal facet loading leads to pain. Over the past decade, however, in vivo models of cervical facet injury that reproduce clinical pain symptoms have been developed and used to define the complicated and multifaceted electrophysiological, inflammatory, and nociceptive signaling cascades that are involved in the pathophysiology of whiplash facet pain. Integrating the whiplash-like mechanics in vivo and in vitro allows transmission of pathophysiological mechanisms across scales, with the hope of informing clinical management. Yet, despite these advances, many challenges remain. This commentary further describes and highlights such challenges. J Orthop Sports Phys Ther 2017;47(7):450-461. Epub 16 Jun 2017. doi:10.2519/jospt.2017.7255.

The Interface of Mechanics and Nociception in Joint Pathophysiology: Insights From the Facet and Temporomandibular Joints

Chronic joint pain is a widespread problem that frequently occurs with aging and trauma. Pain occurs most often in synovial joints, the bodys load bearing joints. The mechanical and molecular mechanisms contributing to synovial joint pain are reviewed using two examples, the cervical spinal facet joints and the temporomandibular joint (TMJ). Although much work has focused on the macroscale mechanics of joints in health and disease, the combined influence of tissue mechanics, molecular processes, and nociception in joint pain has only recently become a focus. Trauma and repeated loading can induce structural and biochemical changes in joints, altering their microenvironment and modifying the biomechanics of their constitutive tissues, which themselves are innervated. Peripheral pain sensors can become activated in response to changes in the joint microenvironment and relay pain signals to the spinal cord and brain where pain is processed and perceived. In some cases, pain circuitry is permanently changed, which may be a potential mechanism for sustained joint pain. However, it is most likely that alterations in both the joint microenvironment and the central nervous system (CNS) contribute to chronic pain. As such, the challenge of treating joint pain and degeneration is temporally and spatially complicated. This review summarizes anatomy, physiology, and pathophysiology of these joints and the sensory pain relays. Pain pathways are postulated to be sensitized by many factors, including degeneration and biochemical priming, with effects on thresholds for mechanical injury and/or dysfunction. Initiators of joint pain are discussed in the context of clinical challenges including the diagnosis and treatment of pain.

Tissue loading and microstructure regulate the deformation of embedded nerve fibres: Predictions from single-scale and multiscale simulations

Excessive deformation of nerve fibres (axons) in the spinal facet capsular ligaments (FCLs) can be a cause of pain. The axons are embedded in the fibrous extracellular matrix (ECM) of FCLs, so understanding how local fibre organization and micromechanics modulate their mechanical behaviour is essential. We constructed a computational discrete-fibre model of an axon embedded in a collagen fibre network attached to the axon by distinct fibre–axon connections. This model was used to relate the axonal deformation to the fibre alignment and collagen volume concentration of the surrounding network during transverse, axial and shear deformations. Our results showed that fibre alignment affects axonal deformation only during transverse and axial loading, but higher collagen volume concentration results in larger overall axonal strains for all loading cases. Furthermore, axial loading leads to the largest stretch of axonal microtubules and induces the largest forces on axons surface in most cases. Comparison between this model and a multiscale continuum model for a representative case showed that although both models predicted similar averaged axonal strains, strain was more heterogeneous in the discrete-fibre model.

Stretch-induced network reconfiguration of collagen fibres in the human facet capsular ligament

Biomaterials can display complex spatial patterns of cellular responses to external forces. Revealing and predicting the role of these patterns in material failure require an understanding of the statistical dependencies between spatially distributed changes in a cells local biomechanical environment, including altered collagen fibre kinematics in the extracellular matrix. Here, we develop and apply a novel extension of network science methods to investigate how excessive tensile stretch of the human cervical facet capsular ligament (FCL), a common source of chronic neck pain, affects the local reorganization of collagen fibres. We define collagen alignment networks based on similarity in fibre alignment angles measured by quantitative polarized light imaging. We quantify the reorganization of these networks following macroscopic loading by describing the dynamic reconfiguration of network communities, regions of the material that display similar fibre alignment angles. Alterations in community structure occur smoothly over time, indicating coordinated adaptation of fibres to loading. Moreover, flexibility, a measure of network reconfiguration, tracks the loss of FCLs mechanical integrity at the onset of anomalous realignment (AR) and regions of AR display altered community structure. These findings use novel network-based techniques to explain abnormal collagen fibre reorganization, a dynamic and coordinated multivariate process underlying tissue failure.

Multiscale mechanics of the cervical facet capsular ligament, with particular emphasis on anomalous fiber realignment prior to tissue failure

The facet capsular ligaments encapsulate the bilateral spinal facet joints and are common sources of painful injury due to afferent innervation. These ligaments exhibit architectural complexity, which is suspected to contribute to the experimentally observed lack of co-localization between macroscopic strain and microstructural tissue damage. The heterogeneous and multiscale nature of this ligament, combined with challenges in experimentally measuring its microscale mechanics, hinders the ability to understand sensory mechanisms under normal or injurious loading. Therefore, image-based, subject-specific, multiscale finite-element models were constructed to predict the mechanical responses of the human cervical facet capsular ligament under uniaxial tensile stretch. The models precisely simulated the force–displacement responses for all samples (

Template Abaqus input file from Tissue loading and microstructure regulate the deformation of embedded nerve fibres: predictions from single-scale and multiscale simulations

\textit{R}^{2}=0.99\pm 0.01