Corticospinal Motor Circuit Plasticity After Spinal Cord Injury: Harnessing Neuroplasticity to Improve Functional Outcomes.

Spinal cord injury (SCI) is a devastating condition that affects approximately 294,000 people in the USA and several millions worldwide. The corticospinal motor circuitry plays a major role in controlling skilled movements and in planning and coordinating movements in mammals and can be damaged by SCI. While axonal regeneration of injured fibers over long distances is scarce in the adult CNS, substantial spontaneous neural reorganization and plasticity in the spared corticospinal motor circuitry has been shown in experimental SCI models, associated with functional recovery. Beneficially harnessing this neuroplasticity of the corticospinal motor circuitry represents a highly promising therapeutic approach for improving locomotor outcomes after SCI. Several different strategies have been used to date for this purpose including neuromodulation (spinal cord/brain stimulation strategies and brain-machine interfaces), rehabilitative training (targeting activity-dependent plasticity), stem cells and biological scaffolds, neuroregenerative/neuroprotective pharmacotherapies, and light-based therapies like photodynamic therapy (PDT) and photobiomodulation (PMBT). This review provides an overview of the spontaneous reorganization and neuroplasticity in the corticospinal motor circuitry after SCI and summarizes the various therapeutic approaches used to beneficially harness this neuroplasticity for functional recovery after SCI in preclinical animal model and clinical human patients' studies.

Vitamin D status in cervical spondylotic myelopathy: comparison of fusion rates and patient outcome measures.

BACKGROUND: Patients undergoing elective spinal fusion have an alarming rate of vitamin D deficiency, but its impact on bone fusion and patient outcomes is unclear. We investigated the association of perioperative vitamin D levels, fusion rates, and patient-reported outcome in patients undergoing spinal fusion for cervical spondylotic myelopathy. METHODS: In this one-year, prospective, single-center observational study, serum 25-OH vitamin D levels were measured perioperatively in adult patients. Serum vitamin D levels <30 ng/mL were considered abnormal. The primary outcome measures were postoperative patient-reported outcomes (Neck Disability Index, Visual Analog Scale, EuroQol EQ-5D-3L, EQ-VAS). Secondary outcome measures were the presence of and time to solid bony fusion, controlling for Body Mass Index (BMI), age, and number of motion segments. RESULTS: Forty-one of 58 patients (71%) had laboratory-confirmed abnormal vitamin D levels. Patients with low vitamin D were younger (P<0.05) and had a higher BMI (P<0.05) than patients with adequate vitamin D, but the groups were otherwise similar. There were no differences in mean time to fusion between the two groups, but patients with low vitamin D reported more postoperative disability (P<0.05). Multivariate model analysis demonstrated an independent, significant association between normal vitamin D and lower postoperative neck disability index (P=0.05) and EQ-5D-3L (P=0.03). CONCLUSIONS: Vitamin D deficiency (<30 ng/mL) is highly prevalent in patients undergoing elective spinal fusion for cervical myelopathy. Low vitamin D levels were associated with worse patient-reported outcomes and were an independent predictor of greater disability, which suggests vitamin D supplementation may offer some benefit in these patients.

Does combined therapy of curcumin and epigallocatechin gallate have a synergistic neuroprotective effect against spinal cord injury?

Systematic inflammatory response after spinal cord injury (SCI) is one of the factors leading to lesion development and a profound degree of functional loss. Anti-inflammatory compounds, such as curcumin and epigallocatechin gallate (EGCG) are known for their neuroprotective effects. In this study, we investigated the effect of combined therapy of curcumin and EGCG in a rat model of acute SCI induced by balloon compression. Immediately after SCI, rats received curcumin, EGCG, curcumin + EGCG or saline [daily intraperitoneal doses (curcumin, 6 mg/kg; EGCG 17 mg/kg)] and weekly intramuscular doses (curcumin, 60 mg/kg; EGCG 17 mg/kg)] for 28 days. Rats were evaluated using behavioral tests (the Basso, Beattie, and Bresnahan (BBB) open-field locomotor test, flat beam test). Spinal cord tissue was analyzed using histological methods (Luxol Blue-cresyl violet staining) and immunohistochemistry (anti-glial fibrillary acidic protein, anti-growth associated protein 43). Cytokine levels (interleukin-1ß, interleukin-4, interleukin-2, interleukin-6, macrophage inflammatory protein 1-alpha, and RANTES) were measured using Luminex assay. Quantitative polymerase chain reaction was performed to determine the relative expression of genes (Sort1, Fgf2, Irf5, Mrc1, Olig2, Casp3, Gap43, Gfap, Vegf, NfκB, Cntf) related to regenerative processes in injured spinal cord. We found that all treatments displayed significant behavioral recovery, with no obvious synergistic effect after combined therapy of curcumin and ECGC. Curcumin and EGCG alone or in combination increased axonal sprouting, decreased glial scar formation, and altered the levels of macrophage inflammatory protein 1-alpha, interleukin-1ß, interleukin-4 and interleukin-6 cytokines. These results imply that although the expected synergistic response of this combined therapy was less obvious, aspects of tissue regeneration and immune responses in severe SCI were evident.

Anti-inflammatory compound curcumin and mesenchymal stem cells in the treatment of spinal cord injury in rats.

Spinal cord injury leads to a robust inflammatory response that is an unfavorable environment for stem cell implantation. In this study, we evaluated the effect of combined therapy of curcumin and mesenchymal stem cells (MSC) on behavioral recovery and tissue sparing, glial scar formation, axonal sprouting and inflammatory responses in a rat experimental model of spinal cord injury (SCI). Balloon-induced compression lesion was performed at thoracic (Th8-9) spinal level. Out of the four groups studied, two groups received curcumin on the surface of the spinal cord immediately after SCI and then once a week for 3 weeks together with an intraperitoneal daily curcumin injection for 28 days. The other two groups received saline. Seven days after SCI, human MSC were intrathecally implanted in one curcumin and one saline group. Both curcumin and curcumin combined with MSC treatment improved locomotor ability in comparison to the saline treated animals. The combined treatment group showed additional improvement in advanced locomotor performance. The combined therapy facilitated axonal sprouting, and modulated expression of pro-regenerative factors and inflammatory responses, when compared to saline and single treatments. These results demonstrate that preconditioning with curcumin, prior to the MSC implantation could have a synergic effect in the treatment of experimental SCI.

A green tea polyphenol epigallocatechin-3-gallate enhances neuroregeneration after spinal cord injury by altering levels of inflammatory cytokines.

Spinal cord injury (SCI) is a debilitating condition which is characterized by an extended secondary injury due to the presence of inflammatory local milieu. Epigallocatechin gallate (EGCG) appears to possess strong neuroprotective properties. Here, we evaluated the beneficial effect of EGCG on recovery from SCI. Male Wistar rats were given either EGCG or saline directly to the injured spinal cord and thereafter a daily IP injection. Behavior recovery was monitored by BBB, plantar, rotarod and flat-beam tests. The levels of inflammatory cytokines were determined on days 1, 3, 7, 10 and 14 after SCI. Additionally, NF-κB pathway activity was evaluated. The results demonstrated that EGCG-treated rats displayed a superior behavioral performance in a flat beam test, higher axonal sprouting and positive remodelation of glial scar. Cytokine analysis revealed a reduction in IL-6, IL2, MIP1α and RANTES levels on days 1 and 3, and an upregulation of IL-4, IL-12p70 and TNFα 1 day following SCI in EGCG-treated rats. Treatment with EGCG was effective in decreasing the nuclear translocation of subunit p65 (RelA) of the NF-κB dimer, and therefore canonical NF-κB pathway attenuation. A significant increase in the gene expression of growth factors (FGF2 and VEGF), was noted in the spinal cord of EGCG-treated rats. Further, EGCG influenced expression of M1 and M2 macrophage markers. Our results have demonstrated a therapeutic value of EGCG in SCI, as observed by better behavioral performance measured by flat beam test, modulation of inflammatory cytokines and induction of higher axonal sprouting.

Prevalence of Vitamin D Deficiency in Patients Undergoing Elective Spine Surgery: A Cross-Sectional Analysis.

OBJECTIVE: Decreased bone density secondary to osteoporosis and osteomalacia represents a significant risk factor for bony fracture and spinal instrumentation failure. We evaluated the incidence of vitamin D deficiency in patients undergoing elective spinal instrumentation to investigate which patient-level risk factors are associated with deficient vitamin D levels. METHODS: Serum 25-OH vitamin D levels were evaluated postoperatively (<72 hours) in patients undergoing elective spinal fusion from 2011 through 2012. Patients >18 years with a diagnosis of degenerative spinal spondylosis or spinal instability treated with spinal fusion were included. Risk factors for vitamin D deficiency (<20 ng/mL) were analyzed using univariate and multiple logistic regression to identify independent predictors of deficiency. RESULTS: The mean preoperative neck and Oswestry disability indexes of the 230 consecutive patients (mean, 57 ± 13.9 years) were 21.0 ± 9.8 and 22.2 ± 8.5, respectively. Mean 25-OH vitamin D level was 25.9 ± 12.4 ng/mL (range, 6-77 ng/mL). Sixty-nine (30.0%) patients had laboratory-confirmed vitamin D deficiency and 89 (38.9%) had laboratory-confirmed vitamin D insufficiency (20-30 ng/mL). The risk of vitamin D deficiency was greater in men (odds ratio [OR] 2.53; P = 0.009), patients aged 40-60 years (OR 2.45; P = 0.018), and those who had body mass index >40 (OR 7.55; P = 0.004), an existing diagnosis of diabetes (OR 3.29; P = 0.019), or no vitamin D supplementation (OR 4.96; P = 0.043). CONCLUSIONS: Vitamin D deficiency was common in patients with degenerative spondylosis undergoing spinal fusion. Middle-aged patients, men, the morbidly obese, those with a history of diabetes, and those with no history of supplementation had a higher incidence of vitamin D deficiency.

Cervical spine metastases: techniques for anterior reconstruction and stabilization.

The surgical management of cervical spine metastases continues to evolve and improve. The authors provide an overview of the various techniques for anterior reconstruction and stabilization of the subaxial cervical spine after corpectomy for spinal metastases. Vertebral body reconstruction can be accomplished using a variety of materials such as bone autograft/allograft, polymethylmethacrylate, interbody spacers, and/or cages with or without supplemental anterior cervical plating. In some instances, posterior instrumentation is needed for additional stabilization.