Winkelstein, Beth A

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2003 - 2009102010 - 20111
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  • Publication
    Mechanical thresholds for initiation and persistence of pain following nerve root injury: mechanical and chemical contributions at injury
    (2004-04-01) Winkelstein, Beth A; DeLeo, Joyce A.
    There is much evidence supporting the hypothesis that magnitude of nerve root mechanical injury affects the nature of the physiological responses which can contribute to pain in lumbar radiculopathy. Specifically, injury magnitude has been shown to modulate behavioral hypersensitivity responses in animal models of radiculopathy. However, no study has determined the mechanical deformation thresholds for initiation and maintenance of the behavioral sensitivity in these models. Therefore, it was the purpose of this study to quantify the effects of mechanical and chemical contributions at injury on behavioral outcomes and to determine mechanical thresholds for pain onset and persistence. Male Holtzman rats received either a silk or chromic gut ligation of the L5 nerve roots, a sham exposure of the nerve roots, or a chromic exposure in which no mechanical deformation was applied but chromic gut material was placed on the roots. Using image analysis, nerve root radial strains were estimated at the time of injury. Behavioral hypersensitivity was assessed by measuring mechanical allodynia continuously throughout the study. Chromic gut ligations produced allodynia responses for nerve root strains at two-thirds of the magnitudes of those strains which produced the corresponding behaviors for silk ligation. Thresholds for nerve root compression producing the onset (8.4%) and persistence of pain (17.4-22.2%) were determined for silk ligation in this lumbar radiculopathy model. Such mechanical thresholds for behavioral sensitivity in a painful radiculopathy model begin to provide biomechanical data which may have utility in broader experimental and computational models for relating injury biomechanics and physiologic responses of pain.
  • Publication
    Vector Correlation Technique for Pixel-wise Detection of Collagen Fiber Realignment During Injurious Tensile Loading
    (2009-09-16) Quinn, Kyle P.; Winkelstein, Beth A
    Excessive soft tissue loading can produce adverse structural and physiological changes in the absence of any visible tissue rupture. However, image-based analysis techniques to assess microstructural changes during loading without any visible rupture remain undeveloped. Quantitative polarized light imaging (QPLI) can generate spatial maps of collagen fiber alignment during loading with high temporal resolution and can provide a useful technique to measure microstructural responses. While collagen fibers normally realign in the direction that tissue is loaded, rapid, atypical fiber realignment during loading may be associated with the response of a local collagenous network to fiber failure. A vector correlation technique was developed to detect this atypical fiber realignment using QPLI and mechanical data collected from human facet capsular ligaments (n=16) loaded until visible rupture. Initial detection of anomalous realignment coincided with a measurable decrease in the tissue stiffness in every specimen and occurred at significantly lower strains than those at visible rupture (ρ < 0.004), suggesting this technique may be sensitive to a loss of microstructural integrity. The spatial location of anomalous realignment was significantly associated with regions where visible rupture developed (ρ < 0.001). This analysis technique provides a foundation to identify regional differences in soft tissue injury tolerances and relevant mechanical thresholds.
  • Publication
    Cervical facet capsular ligament yield defines the threshold for injury and persistent joint-mediated cervical pain
    (2006-12-01) Quinn, Kyle P; Winkelstein, Beth A
    The cervical facet joint has been identified as a source of neck pain, and its capsular ligament is a likely candidate for injury during whiplash. Many studies have shown that the mechanical properties of ligaments can be altered by subfailure injury. However, the subfailure mechanical response of the facet capsular ligament has not been well defined, particularly in the context of physiology and pain. Therefore, the goal of this study was to quantify the structural mechanics of the cervical facet capsule and define the threshold for altered structural responses in this ligament during distraction. Tensile failure tests were preformed using isolated C6/C7 rat facet capsular ligaments (n=8); gross ligament failure, the occurrence of minor ruptures and ligament yield were measured. Gross failure occurred at 2.45±0.60 N and 0.92±0.17 mm. However, the yield point occurred at 1.68±0.56 N and 0.57±0.08 mm, which was significantly less than gross failure (p<0.001 for both measurements). Maximum principal strain in the capsule at yield was 80±24%. Energy to yield was 14.3±3.4% of the total energy for a complete tear of the ligament. Ligament yield point occurred at a distraction magnitude in which pain symptoms begin to appear in vivo in the rat. These mechanical findings provide insight into the relationship between gross structural failure and painful loading for the facet capsular ligament, which has not been previously defined for such neck injuries. Findings also present a framework for more in-depth methods to define the threshold for persistent pain and could enable extrapolation to the human response.
  • Publication
    Schwann Cell Proliferation and Macrophage Infiltration Are Evident at Day 14 after Painful Cervical Nerve Root Compression in the Rat
    (2011-12-09) Chang, Yu-Wen; Winkelstein, Beth A
    Although it is known that different types of nerve root insults can produce radicular pain, it is not known whether the neuronal and Schwann cell pathologies in the nerve root vary between inflammation-induced nerve root injury and traumatic compression. This study examined the extent of Wallerian degeneration and associated cellular repair processes in the nerve root in the context of mechanical hyperalgesia resulting from different modes of painful nerve root injury. The C7 dorsal nerve root underwent a transient 10 gram-force compression (10g), inflammation-induced irritation by chromic gut exposure (Cg), or a combination of those stimuli (10g + Cg). Fourteen days after injury when hyperalgesia remained, immunohistochemical analysis revealed upregulation of substance P, robust macrophage infiltration, myelin degeneration and debris removal, and a significant increase in the number of myelinating Schwann cells (Krox20-positive) in the compressed roots (10g, 10g + Cg). Cg alone also produced hyperalgesia, despite being associated with intact myelin. Unilateral exposure to chromic material induced bilateral increases in macrophages and Krox20-positive Schwann cells in the nerve roots, and substance P expression in the dorsal root ganglion (DRG) neurons. Results suggest that despite similar sensitivity, the extent of infiltrating macrophages and repopulated Schwann cells varies for pain from mechanical and/or chemical nerve root injury. Although these different cellular mechanisms may explain pain, they may also only reflect varying injury etiologies.
  • Publication
    Chemical and mechanical nerve root insults induce differential behavioral sensitivity and glial activation that are enhanced in combination
    (2007-08-28) Rothman, Sarah M; Winkelstein, Beth A
    Both chemical irritation and mechanical compression affect radicular pain from disc herniation. However, relative effects of these insults on pain symptoms are unclear. This study investigated chemical and mechanical contributions for painful cervical nerve root injury. Accordingly, the C7 nerve root separately underwent chromic gut exposure, 10gf compression, or their combination. Mechanical allodynia was assessed, and glial reactivity in the C7 spinal cord tissue was assayed at days 1 and 7 by immunohistochemistry using GFAP and OX-42 as markers of astrocytes and microglia, respectively. Both chromic gut irritation and 10gf compression produced ipsilateral increases in allodynia over sham (p<0.048); combining the two insults significantly (p<0.027) increased ipsilateral allodynia compared to either insult alone. Behavioral hypersensitivity was also produced in the contralateral forepaw for all injuries, but only the combined insult was significantly increased over sham (p<0.031). Astrocytic activation was significantly increased over normal (p<0.001) in the ipsilateral dorsal horn at 1 day after either compression or the combined injury. By day 7, GFAP-reactivity was further increased for the combined injury compared to day 1 (p<0.001). In contrast, spinal OX-42 staining was generally variable, with only mild activation at day 1. By day 7 after the combined injury, there were significant (p<0.003) bilateral increases in OX-42 staining over normal. Spinal astrocytic and microglial reactivity follow different patterns after chemical root irritation, compression, and a combined insult. The combination of transient compression and chemical irritation produces sustained bilateral hypersensitivity, sustained ipsilateral spinal astrocytic activation and late onset bilateral spinal microglial activation.
  • Publication
    Tensile Cervical Facet Capsule Ligament Mechanics: Failure and Subfailure Responses in the Rat
    (2006-02-01) Lee, Kathryn E; Franklin, Andrew N; Davis, Martin B; Winkelstein, Beth A
    Clinical, epidemiological, and biomechanical studies suggest the involvement of the cervical facet joint in neck pain. Mechanical studies have suggested the facet capsular ligament to be at risk for subfailure tensile injury during whiplash kinematics of the neck. Ligament mechanical properties can be altered by subfailure injury and such loading can induce cellular damage. However, at present, there is no clear understanding of the physiologic context of subfailure facet capsular ligament injury and mechanical implications for whiplash-related pain. Therefore, this study aimed to define a relationship between mechanical properties at failure and a subfailure condition associated with pain for tension in the rat cervical facet capsular ligament. Tensile failure studies of the C6/C7 rat cervical facet capsular ligament were performed using a customized vertebral distraction device. Force and displacement at failure were measured and stiffness and energy to failure were calculated. Vertebral motions and ligament deformations were tracked and maximum principal strains and their directions were calculated. Mean tensile force at failure (2.96±0.69 N) was significantly greater (p<0.005) than force at subfailure (1.17±0.48 N). Mean ligament stiffness to failure was 0.75±0.27 N/mm. Maximum principal strain at failure (41.3±20.0%) was significantly higher (p=0.003) than the corresponding subfailure value (23.1±9.3%). This study determined that failure and a subfailure painful condition were significantly different in ligament mechanics and findings provide preliminary insight into the relationship between mechanics and pain physiology for this ligament. Together with existing studies, these findings offer additional considerations for defining mechanical thresholds for painful injuries.
  • Publication
    Structural Changes in the Cervical Facet Capsular Ligament: Potential Contributions to Pain Following Subfailure Loading
    (2007-10-01) Quinn, Kyle P; Lee, Kathryn E; Ahaghotu, Chukwunyere C; Winkelstein, Beth A
    While studies have demonstrated the cervical facet capsule is at risk for tensile injury during whiplash, the relationship between joint loading, changes in the capsule’s structure, and pain is not yet fully characterized. Complementary approaches were employed to investigate the capsule’s structure-function relationship in the context of painful joint loading. Isolated C6/C7 facet joints (n=8) underwent tensile mechanical loading, and measures of structural modification were compared for two distraction magnitudes: 300 μm (PV) and 700 μm (SV). In a matched in vivo study, C6/C7 facet joints (n=4) were harvested after the same SV distraction and the tissue was sectioned to analyze collagen fiber organization using polarized light microscopy. Laxity following SV distraction (7.30±3.01%) was significantly greater (p<0.001) than that produced following PV distraction (0.99±0.44%). Also, SV distractions produced significantly higher maximum principal strain (p<0.001) in the capsule and resulted in significantly greater decreases in stiffness (p=0.002) when compared to PV distraction. After SV distraction in vivo, mean angular deviation of the fiber direction (16.8±2.6º) was significantly increased (p=0.004) relative to naive samples in the lateral region of the capsule, indicating collagen fiber disorganization. These findings demonstrate that certain subfailure loading conditions are associated with altered joint mechanics and collagen fiber disorganization and imply ligament damage. Substructural damage in the capsule has the potential to both directly modulate nerve fiber signaling and produce sustained physiologic modifications that may initiate persistent pain.
  • Publication
    Transient Cervical Nerve Root Compression Modulates Pain: Load Thresholds for Allodynia and Sustained Changes in Spinal Neuropeptide Expression
    (2007-10-30) Hubbard, Raymond D; Chen, Zen; Winkelstein, Beth A
    Nerve root compression produces chronic pain and altered spinal neuropeptide expression. This study utilized controlled transient loading in a rat model of painful cervical nerve root compression to investigate the dependence of mechanical allodynia on load magnitude. Injury loads (0–110 mN) were applied quasistatically using a customized loading device, and load thresholds to produce maintained mechanical allodynia were defined. Bilateral spinal expression of substance P (SP) and calcitonin gene-related peptide (CGRP) was assessed 7 days following compression using immunohistochemistry to determine relationships between these neuropeptides and compression load. A three-segment change point model was implemented to model allodynia responses and their relationship to load. Load thresholds were defined at which ipsilateral and contralateral allodynia were produced and sustained. The threshold for increased allodynia was lowest for acute (day 1) ipsilateral responses (26.29 mN), while thresholds for allodynia on day 7 were similar for the ipsilateral (38.16 mN) and contralateral forepaw (38.26 mN). CGRP, but not SP, significantly decreased with load; the thresholds for ipsilateral and contralateral CGRP decreases corresponded to 19.52 and 24.03 mN, respectively. These thresholds suggest bilateral allodynia may be mediated by spinal mechanisms, and that these mechanisms depend on the magnitude of load.
  • Publication
    Rigid model-based 3D segmentation of the bones of joints in MR and CT images for motion analysis
    (2008-08-01) Udupa, Jayaram K; Liu, Jiamin; Odhner, Dewey; Saha, Punam K; Hirsch, Bruce E; Winkelstein, Beth A; Seigler, Sorin; Simon, Scott
    There are several medical application areas that require the segmentation and separation of the component bones of joints in a sequence of images of the joint acquired under various loading conditions, our own target area being joint motion analysis. This is a challenging problem due to the proximity of bones at the joint, partial volume effects, and other imaging modality-specific factors that confound boundary contrast. In this article, a two-step model-based segmentation strategy is proposed that utilizes the unique context of the current application wherein the shape of each individual bone is preserved in all scans of a particular joint while the spatial arrangement of the bones alters significantly among bones and scans. In the first step, a rigid deterministic model of the bone is generated from a segmentation of the bone in the image corresponding to one position of the joint by using the live wire method. Subsequently, in other images of the same joint, this model is used to search for the same bone by minimizing an energy function that utilizes both boundary - and region-based information. An evaluation of the method by utilizing a total of 60 data sets on MR and CT images of the ankle complex and cervical spine indicates that the segmentations agree very closely with the live wire segmentations, yielding true positive and false positive volume fractions in the range 89%–97% and 0.2%–0.7%. The method requires 1–2 minutes of operator time and 6–7 min of computer time per data set, which makes it significantly more efficient than live wire - the method currently available for the task that can be used routinely.
  • Publication
    A novel rodent neck pain model of facet-mediated behavioral hypersensitivity: implications for persistent pain and whiplash injury
    (2004-08-01) Lee, Kathryn E.; Thinnes, John H.; Gokhin, David S.; Winkelstein, Beth A
    Clinical, epidemiological, and biomechanical studies suggest involvement of cervical facet joint injuries in neck pain. While bony motions can cause injurious tensile facet joint loading, it remains speculative whether such injuries initiate pain. There is currently a paucity of data explicitly investigating the relationship between facet mechanics and pain physiology. A rodent model of tensile facet joint injury has been developed using a customized loading device to apply 2 separate tensile deformations (low, high; n=5 each) across the C6/C7 joint, or sham (n=6) with device attachment only. Microforceps were rigidly coupled to the vertebrae for distraction and joint motions tracked in vivo. Forepaw mechanical allodynia was measured postoperatively for 7 days as an indicator of behavioral sensitivity. Joint strains for high (33.6±3.1%) were significantly elevated (p<0.005) over low (11.1±2.3%). Digitization errors (0.17±0.20%) in locating bony markers were small compared to measured strains. Allodynia was significantly elevated for high over low and sham for all postoperative days. However, allodynia for low injury was not different than sham. A greater than three-fold increase in total allodynia resulted for high compared to low, corresponding to the three-fold difference in injury strain. Findings demonstrate tensile facet joint loading produces behavioral sensitivity that varies in magnitude according to injury severity. These results suggest that a facet joint tensile strain threshold may exist above which pain symptoms result. Continued investigation into the relationship between injury mechanics and nociceptive physiology will strengthen insight into painful facet injury mechanisms.