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.

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.

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 dis...

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.

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.