Associations between serum biomarkers and pain and pain-related function in older adults with low back pain: a pilot study.

OBJECTIVES: To examine the relationship between serum biomarkers and self-reported pain intensity and pain-related function, in addition to the contribution of magnetic resonance imaging (MRI) findings of lumbar spine degenerative changes, in older adults with chronic low back pain. DESIGN: Single-center cross-sectional cohort study. SETTING: Academic medical center. PARTICIPANTS: Individuals aged 60 and older with axial low back pain without radiculopathy or previously diagnosed osteoarthritis of the knee or hip or pain outside the low back that is more severe than the back pain (n = 43). MEASUREMENTS: To examine pain-related impairment, pain was measured on a pain thermometer and the McGill Pain Questionnaire Short Form was administered. To examine pain-related function or activity limitation, the Roland Morris Disability Questionnaire, Short Physical Performance Battery (SPPB), and repetitive trunk rotation were used. Single plasma samples were obtained before and after physical performance tests and analyzed for inflammatory markers (E-selectin and regulated on activation, normal T cell expressed and secreted (RANTES)), inhibitors of catabolic enzymes (tissue inhibitor of metalloproteinases-1 (TIMP-1)), markers of matrix turnover (C- telopeptide of type II collagen (CTX-II) and aggrecan chondroitin sulfate 846 (CS846)), and stress biomarkers (neuropeptide Y (NPY)). Conventional nongadolinium lumbar MRI was performed and analyzed quantitatively and clinically. RESULTS: Composite MRI measurements did not show significant correlation with pain or pain-related function. Basal levels and changes in serum biomarkers in response to activity, particularly NPY and RANTES, demonstrated associations with pain and pain-related function in addition to the explanatory power of MRI-based results. CONCLUSION: Serum biomarkers may be a metric for assessment of active disease in older adults, in whom imaging changes are ubiquitous. In addition, changing levels of biomarkers in response to activity suggests that they may be useful as metrics to measure treatment responses in future studies and may reflect potential targets for use in designing personalized treatment for older adults with low back pain.

Correlation of pain with objective quantification of magnetic resonance images in older adults with chronic low back pain.

STUDY DESIGN: Cross sectional study. OBJECTIVE: The goal of this study is to identify relationships between objectively measured and subjectively scored parameters and reported pain. SUMMARY OF BACKGROUND DATA: Studies have demonstrated the unreliability of magnetic resonance imaging (MRI)-based parameters to identify pathological pain generators of chronic low back pain, but they were based on visual inspection and subjective assessment of lumbar disc features. Advancements in computer image analysis provide objective measurements of lumbar disc features. METHODS: Two radiologists evaluated 39 axial and sagittal T1- and T2-weighted MR images of patients with chronic axial low back pain (age, >65 yr) and graded 4 subjective lumbar disc parameters (T2 signal intensity, nucleus shape, Modic changes, and osteophyte formation) whose sum is the cumulative MRI score. Objective parameter, MRI index, was calculated as the product of the measured lumbar disc area and total disc MRI signal intensity. Discs were sorted from least to the most degenerated relative to each parameter. Pearson correlation coefficient and multiple linear regression analysis were performed between the reported pain score and each parameter. RESULTS: The most and least degenerated discs in each patient, as assessed by MRI index, had the highest negative and positive correlation coefficient and regression weight contribution, respectively. All subjective parameters had low correlation coefficients and regression goodness of fit. CONCLUSION: Although limited by small sample size, the objective parameter, MRI index, can be a potential imaging biomarker used to identify possible pain generators. This study presents a potential new application of MR imaging in identifying pain generators of patients with chronic low back pain.

Injection of human umbilical tissue-derived cells into the nucleus pulposus alters the course of intervertebral disc degeneration in vivo.

BACKGROUND CONTEXT: Patients often present to spine clinic with evidence of intervertebral disc degeneration (IDD). If conservative management fails, a safe and effective injection directly into the disc might be preferable to the risks and morbidity of surgery. PURPOSE: To determine whether injecting human umbilical tissue-derived cells (hUTC) into the nucleus pulposus (NP) might improve the course of IDD. DESIGN: Prospective, randomized, blinded placebo-controlled in vivo study. PATIENT SAMPLE: Skeletally mature New Zealand white rabbits. OUTCOME MEASURES: Degree of IDD based on magnetic resonance imaging (MRI), biomechanics, and histology. METHODS: Thirty skeletally mature New Zealand white rabbits were used in a previously validated rabbit annulotomy model for IDD. Discs L2-L3, L3-L4, and L4-L5 were surgically exposed and punctured to induce degeneration and then 3 weeks later the same discs were injected with hUTC with or without a hydrogel carrier. Serial MRIs obtained at 0, 3, 6, and 12 weeks were analyzed for evidence of degeneration qualitatively and quantitatively via NP area and MRI Index. The rabbits were sacrificed at 12 weeks and discs L4-L5 were analyzed histologically. The L3-L4 discs were fixed to a robotic arm and subjected to uniaxial compression, and viscoelastic displacement curves were generated. RESULTS: Qualitatively, the MRIs demonstrated no evidence of degeneration in the control group over the course of 12 weeks. The punctured group yielded MRIs with the evidence of disc height loss and darkening, suggestive of degeneration. The three treatment groups (cells alone, carrier alone, or cells+carrier) generated MRIs with less qualitative evidence of degeneration than the punctured group. MRI Index and area for the cell and the cell+carrier groups were significantly distinct from the punctured group at 12 weeks. The carrier group generated MRI data that fell between control and punctured values but failed to reach a statistically significant difference from the punctured values. There were no statistically significant MRI differences among the three treatment groups. The treated groups also demonstrated viscoelastic properties that were distinct from the control and punctured values, with the cell curve more similar to the punctured curve and the carrier curve and carrier+cells curve more similar to the control curve (although no creep differences achieved statistical significance). There was some histological evidence of improved cellularity and disc architecture in the treated discs compared with the punctured discs. CONCLUSIONS: Treatment of degenerating rabbit intervertebral discs with hUTC in a hydrogel carrier solution might help restore the MRI, histological, and biomechanical properties toward those of nondegenerated controls. Treatment with cells in saline or a hydrogel carrier devoid of cells also might help restore some imaging, architectural, and physical properties to the degenerating disc. These data support the potential use of therapeutic cells in the treatment of disc degeneration.

Glucosamine supplementation demonstrates a negative effect on intervertebral disc matrix in an animal model of disc degeneration.

STUDY DESIGN: Laboratory based controlled in vivo study. OBJECTIVE: To determine the in vivo effects of oral glucosamine sulfate on intervertebral disc degeneration. SUMMARY OF BACKGROUND DATA: Although glucosamine has demonstrated beneficial effect in articular cartilage, clinical benefit is uncertain. A Centers for Disease Control report from 2009 reported that many patients are using glucosamine supplementation for low back pain, without significant evidence to support its use. Because disc degeneration is a major contributor of low back pain, we explored the effects of glucosamine on disc matrix homeostasis in an animal model of disc degeneration. METHODS: Eighteen skeletally mature New Zealand White rabbits were divided into 4 groups: control, annular puncture, glucosamine, and annular puncture + glucosamine. Glucosamine treated rabbits received daily oral supplementation with 107 mg/d (weight based equivalent to human 1500 mg/d). Annular puncture surgery involved puncturing the annulus fibrosus of 3 lumbar discs with a 16-gauge needle to induce degeneration. Serial magnetic resonance images were obtained at 0, 4, 8, 12, and 20 weeks. Discs were harvested at 20 weeks for determination of glycosaminoglycan content, relative gene expression measured by real time polymerase chain reaction, and histological analyses. RESULTS: The magnetic resonance imaging index and nucleus pulposus area of injured discs of glucosamine treated animals with annular puncture was found to be lower than that of degenerated discs from rabbits not supplemented with glucosamine. Consistent with this, decreased glycosaminoglycan was demonstrated in glucosamine fed animals, as determined by both histological and glycosaminoglycan content. Gene expression was consistent with a detrimental effect on matrix. CONCLUSION: These data demonstrate that the net effect on matrix in an animal model in vivo, as measured by gene expression, magnetic resonance imaging, histology, and total proteoglycan is antianabolic. This raises concern about this commonly used supplement, and future research is needed to establish the clinical relevance of these findings.

Injection of AAV2-BMP2 and AAV2-TIMP1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model.

BACKGROUND CONTEXT: Intervertebral disc degeneration (IDD) is a common cause of back pain. Patients who fail conservative management may face the morbidity of surgery. Alternative treatment modalities could have a significant impact on disease progression and patients' quality of life. PURPOSE: To determine if the injection of a virus vector carrying a therapeutic gene directly into the nucleus pulposus improves the course of IDD. STUDY DESIGN: Prospective randomized controlled animal study. METHODS: Thirty-four skeletally mature New Zealand white rabbits were used. In the treatment group, L2-L3, L3-L4, and L4-L5 discs were punctured in accordance with a previously validated rabbit annulotomy model for IDD and then subsequently treated with adeno-associated virus serotype 2 (AAV2) vector carrying genes for either bone morphogenetic protein 2 (BMP2) or tissue inhibitor of metalloproteinase 1 (TIMP1). A nonoperative control group, nonpunctured sham surgical group, and punctured control group were also evaluated. Serial magnetic resonance imaging (MRI) studies at 0, 6, and 12 weeks were obtained, and a validated MRI analysis program was used to quantify degeneration. The rabbits were sacrificed at 12 weeks, and L4-L5 discs were analyzed histologically. Viscoelastic properties of the L3-L4 discs were analyzed using uniaxial load-normalized displacement testing. Creep curves were mathematically modeled according to a previously validated two-phase exponential model. Serum samples obtained at 0, 6, and 12 weeks were assayed for biochemical evidence of degeneration. RESULTS: The punctured group demonstrated MRI and histologic evidence of degeneration as expected. The treatment groups demonstrated less MRI and histologic evidence of degeneration than the punctured group. The serum biochemical marker C-telopeptide of collagen type II increased rapidly in the punctured group, but the treated groups returned to control values by 12 weeks. The treatment groups demonstrated several viscoelastic properties that were distinct from control and punctured values. CONCLUSIONS: Treatment of punctured rabbit intervertebral discs with AAV2-BMP2 or AAV2-TIMP1 helps delay degenerative changes, as seen on MRI, histologic sampling, serum biochemical analysis, and biomechanical testing. Although data from animal models should be extrapolated to the human condition with caution, this study supports the potential use of gene therapy for the treatment of IDD.

In vivo analysis of cervical range of motion after 4- and 5-level subaxial cervical spine fusion.

STUDY DESIGN: A cohort study analyzing the cervical range of motion (ROM) of subjects with 4- or 5-level posterior laminectomy and fusion or anterior and posterior decompression and fusion operation. OBJECTIVE: The purpose of this study was to evaluate the effect of extending a C3-C7 fusion to C3-T1 on subject's ROM and level of disability. SUMMARY OF BACKGROUND DATA: Cadaveric studies show a reduction in the ROM of C3-C7 cervical fusion spines. In vivo, surgeons treat symptomatic cervical subaxial spine with either a C3-C7 fusion or C3-T1 fusion. While in some cases extending the fusion level to T1 is merited due to pathology, most cases are due to surgeon's preference to avoid future degeneration and reoperation of the C7-T1 junction. METHODS: This study involved 44 4-level fusion and 20 5-level fusion subjects along with 18 nonoperative controls. Operative subjects were divided according to early or late postoperative clinical visit. Subjects were asked to complete the neck disability index survey and their maximum ROM during flexion/extension, axial rotation, and lateral bending was measured using a virtual reality assisted electromagnetic tracking system. In addition, the helical axis of motion was calculated for flexion and extension motions. An analysis of variance statistical test was used to determine significant differences between study groups. RESULTS: Five- level subjects had significantly less ROM than 4-level subjects and both groups were significantly less than control group during all motions. There was no effect of postoperative time on subject's ROM. In addition, there was no difference in the center of helical axis of rotation across the 3 groups. Finally, both operative groups exhibited similar levels of mild disability as measured by the neck disability index. CONCLUSIONS: Extending the subaxial fusion from C3-C7 to include C7-T1 resulted in a significant loss of ROM, while postoperative time healing, center of rotation, and level of disability were similar across groups. This finding merits further investigation of the intersegmental motions of the cervical spine.

Influence of number of operated levels and postoperative time on active range of motion following anterior cervical decompression and fusion procedures.

STUDY DESIGN: A cohort study analyzing the cervical range of motion of subjects with anterior cervical decompression and fusion operation (ACDF). OBJECTIVE: The purpose of this study was to compare the cervical range of motion of subjects who underwent an ACDF operation to age-matched healthy nonoperative subjects. Subjects were divided according to the number of operated levels, postoperative time point, and level of disability. SUMMARY OF BACKGROUND DATA: ACDF is an operative treatment aimed at expansion of the spinal canal and relief of cord compression. In addition to alleviating pain, 2 common tools are used to measure postoperative success; cervical range of motion kinematic analysis and subjective evaluation questionnaires (Neck Disability Index [NDI]). METHODS: This study involved 25 preoperative and 110 postoperative ACDF subjects as well as 18 control volunteers with no prior history of neck complaints. ACDF subjects were divided according to the number of operated levels; 1-, 2-, 3-, and 4-levels as well as time of their clinical visit; preoperative, early, and late postoperative. Before kinematic testing, the subjects were asked to complete the NDI survey. A virtual reality assisted electromagnetic tracking was used to measure an active voluntary motion of the head relative to the torso. The subjects' maximum range of motion was calculated and compared as they executed 3 to 5 consecutive cycles of the primary motions, flexion/extension, axial rotation, and lateral bending. An analysis of variance statistical test (P < 0.01) was used to determine significant differences between study groups. RESULTS.: Subject's range of motion decreased relative to control as the number of operated levels increased. Moreover, 1- and 2-level subjects increased their range motion relative to preoperative. Finally, there was a decrease in range of motion as the subject's level of disability increased as measured by an NDI score but all subjects reported a lower score relative to preoperative time point. CONCLUSION: The active range of motion of subjects who underwent an ACDF surgery increased postoperative and was dependent on the number of operated levels. In addition, there was an improvement in the disability level after the surgery as measured by the NDI score.

Matching the oculomotor drive during head-restrained and head-unrestrained gaze shifts in monkey.

High-frequency burst neurons in the pons provide the eye velocity command (equivalently, the primary oculomotor drive) to the abducens nucleus for generation of the horizontal component of both head-restrained (HR) and head-unrestrained (HU) gaze shifts. We sought to characterize how gaze and its eye-in-head component differ when an "identical" oculomotor drive is used to produce HR and HU movements. To address this objective, the activities of pontine burst neurons were recorded during horizontal HR and HU gaze shifts. The burst profile recorded on each HU trial was compared with the burst waveform of every HR trial obtained for the same neuron. The oculomotor drive was assumed to be comparable for the pair yielding the lowest root-mean-squared error. For matched pairs of HR and HU trials, the peak eye-in-head velocity was substantially smaller in the HU condition, and the reduction was usually greater than the peak head velocity of the HU trial. A time-varying attenuation index, defined as the difference in HR and HU eye velocity waveforms divided by head velocity [alpha = (H(hr) - E(hu))/H] was computed. The index was variable at the onset of the gaze shift, but it settled at values several times greater than 1. The index then decreased gradually during the movement and stabilized at 1 around the end of gaze shift. These results imply that substantial attenuation in eye velocity occurs, at least partially, downstream of the burst neurons. We speculate on the potential roles of burst-tonic neurons in the neural integrator and various cell types in the vestibular nuclei in mediating the attenuation in eye velocity in the presence of head movements.

Effect of reversible inactivation of superior colliculus on head movements.

Because of limitations in the oculomotor range, many gaze shifts must be accomplished using coordinated movements of the eyes and head. Stimulation and recording data have implicated the primate superior colliculus (SC) in the control of these gaze shifts. The precise role of this structure in head movement control, however, is not known. The present study uses reversible inactivation to gain insight into the role of this structure in the control of head movements, including those that accompany gaze shifts and those that occur in the absence of a change in gaze. Forty-five lidocaine injections were made in two monkeys that had been trained on a series of behavioral tasks that dissociate movements of the eyes and head. Reversible inactivation resulted in clear impairments in the animals' ability to perform gaze shifts, manifested by increased reaction times, lower peak velocities, and increased durations. In contrast, comparable effects were not found for head movements (with or without gaze shifts) with the exception of a very small increase in reaction times of head movements associated with gaze shifts. Eye-head coordination was clearly affected by the injections with gaze onset occurring relatively later with respect to head onset. Following the injections, the head contributed slightly more to the gaze shift. These results suggest that head movements (with and without gaze shifts) can be controlled by pathways that do not involve SC.

Role of the primate superior colliculus in the control of head movements.

One important behavioral role for head movements is to assist in the redirection of gaze. However, primates also frequently make head movements that do not involve changes in the line of sight. Virtually nothing is known about the neural basis of these head-only movements. In the present study, single-unit extracellular activity was recorded from the superior colliculus while monkeys performed behavioral tasks that permit the temporal dissociation of gaze shifts and head movements. We sought to determine whether superior colliculus contains neurons that modulate their activity in association with head movements in the absence of gaze shifts and whether classic gaze-related burst neurons also discharge for head-only movements. For 26% of the neurons in our sample, significant changes in average firing rate could be attributed to head-only movements. Most of these increased their firing rate immediately prior to the onset of a head movement and continued to discharge at elevated frequency until the offset of the movement. Others discharged at a tonic rate when the head was stable and decreased their activity, or paused, during head movements. For many putative head cells, average firing rate was found to be predictive of head displacement. Some neurons exhibited significant changes in activity associated with gaze, eye-only, and head-only movements, although none of the gaze-related burst neurons significantly modulated its activity in association with head-only movements. These results suggest the possibility that the superior colliculus plays a role in the control of head movements independent of gaze shifts.