Agarwal, Amit; Kanekar, Sangam; Thamburaj, Krishnamurthy; Vijay, Kanupriya
Intraspinal hemorrhage is very rare and intramedullary hemorrhage, also called hematomyelia, is the rarest form of intraspinal hemorrhage, usually related to trauma. Spinal vascular malformations such intradural arteriovenous malformations are the most common cause of atraumatic hematomyelia. Other considerations include warfarin or heparin anticoagulation, bleeding disorders, spinal cord tumors. Radiation-induced hematomyelia of the cord is exceedingly rare with only one case in literature to date. We report the case of an 8 year old girl with Ewing's sarcoma of the thoracic vertebra, under radiation therapy, presenting with hematomyelia. We describe the clinical course, the findings on imaging studies and the available information in the literature. Recognition of the clinical pattern of spinal cord injury should lead clinicians to perform imaging studies to evaluate for compressive etiologies.
Li, Yu-Qing; Chen, Paul; Jain, Vipan; Reilly, Raymond M; Wong, C Shun
Using a rat spinal cord model, this study was designed to characterize radiation-induced vascular endothelial cell loss and its relationship to early blood-brain barrier disruption in the central nervous system. Adult rats were given a single dose of 0, 2, 8, 19.5, 22, 30 or 50 Gy to the cervical spinal cord. At various times up to 2 weeks after irradiation, the spinal cord was processed for histological and immunohistochemical analysis. Radiation-induced apoptosis was assessed by morphology and TdT-mediated dUTP nick end labeling combined with immunohistochemical markers for endothelial and glial cells. Image analysis was performed to determine endothelial cell and microvessel density using immunohistochemistry with endothelial markers, namely endothelial barrier antigen, glucose transporter isoform 1, laminin and zonula occludens 1. Blood-spinal cord barrier permeability was assessed using immunohistochemistry for albumin and (99m)Tc-diethylenetriamine pentaacetic acid as a vascular tracer. Endothelial cell proliferation was assessed using in vivo BrdU labeling. During the first 24 h after irradiation, apoptotic endothelial cells were observed in the rat spinal cord. The decrease in endothelial cell density at 24 h after irradiation was associated with an increase in albumin immunostaining around microvessels. The decrease in the number of endothelial cells persisted for 7 days and recovery of endothelial density was apparent by day 14. A similar pattern of blood-spinal cord barrier disruption and recovery of permeability was observed over the 2 weeks, and an increase in BrdU-labeled endothelial cells was seen at day 3. These results are consistent with an association between endothelial cell death and acute blood-spinal cord barrier disruption in the rat spinal cord after irradiation.
Spinal cord tumor Overview By Mayo Clinic Staff A spinal tumor is a growth that develops within your ... as vertebral tumors. Tumors that begin within the spinal cord itself are called spinal cord tumors. There are ...
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... Counseling About Blog Facing Disability Jeff Shannon Donate Spinal Cord Injury Map Loss of function depends on what ... control. Learn more about spinal cord injuries. A spinal cord injury affects the entire family FacingDisability is designed ...
Wong, Larry; Done, Joseph D.; Schaeffer, Anthony J.; Thumbikat, Praveen
Background The pathogenesis of chronic prostatitis/chronic pelvic pain syndrome is unknown and factors including the host’s immune response and the nervous system have been attributed to the development of CP/CPPS. We previously demonstrated that mast cells and chemokines such as CCL2 and CCL3 play an important role in mediating prostatitis. Here, we examined the role of neuroinflammation and microglia in the CNS in the development of chronic pelvic pain. Methods Experimental autoimmune prostatitis (EAP) was induced using a subcutaneous injection of rat prostate antigen. Sacral spinal cord tissue (segments S4–S5) was isolated and utilized for immunofluorescence or QRT-PCR analysis. Tactile allodynia was measured at baseline and at various points during EAP using Von Frey fibers as a function for pelvic pain. EAP mice were treated with minocycline after 30 days of prostatitis to test the efficacy of microglial inhibition on pelvic pain. Results Prostatitis induced the expansion and activation of microglia and the development of inflammation in the spinal cord as determined by increased expression levels of CCL3, IL-1β, Iba1, and ERK1/2 phosphorylation. Microglial activation in mice with prostatitis resulted in increased expression of P2X4R and elevated levels of BDNF, two molecular markers associated with chronic pain. Pharmacological inhibition of microglia alleviated pain in mice with prostatitis and resulted in decreased expression of IL-1β, P2X4R, and BDNF. Conclusion Our data shows that prostatitis leads to inflammation in the spinal cord and the activation and expansion of microglia, mechanisms that may contribute to the development and maintenance of chronic pelvic pain. PMID:25263093
Doulames, Vanessa M.; Plant, Giles W.
Cervical-level injuries account for the majority of presented spinal cord injuries (SCIs) to date. Despite the increase in survival rates due to emergency medicine improvements, overall quality of life remains poor, with patients facing variable deficits in respiratory and motor function. Therapies aiming to ameliorate symptoms and restore function, even partially, are urgently needed. Current therapeutic avenues in SCI seek to increase regenerative capacities through trophic and immunomodulatory factors, provide scaffolding to bridge the lesion site and promote regeneration of native axons, and to replace SCI-lost neurons and glia via intraspinal transplantation. Induced pluripotent stem cells (iPSCs) are a clinically viable means to accomplish this; they have no major ethical barriers, sources can be patient-matched and collected using non-invasive methods. In addition, the patient’s own cells can be used to establish a starter population capable of producing multiple cell types. To date, there is only a limited pool of research examining iPSC-derived transplants in SCI—even less research that is specific to cervical injury. The purpose of the review herein is to explore both preclinical and clinical recent advances in iPSC therapies with a detailed focus on cervical spinal cord injury. PMID:27070598
AWARD NUMBER: W81XWH-14-2-0013 TITLE: DEVELOPMENT OF AN ANIMAL MODEL OF THORACOLUMBAR BURST FRACTURE - INDUCED ACUTE SPINAL CORD INJURY...2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER DEVELOPMENT OF AN ANIMAL MODEL OF THORACOLUMBAR BURST FRACTURE -INDUCED ACUTE SPINAL CORD INJURY 5b...leads to permanent disability following traumatic spine injury. A dramatic increase in blast related spinal burst fracture has been observed in
Olby, Natasha J.; Blakemore, W. F.
Focal thrombosis was induced in the dorsal funiculus of the rat spinal cord by exposing the cord to light following intravenous injection of the photoactive dye, rose bengal. The light source was a 599 standing wave dye laser, pumped by an Innova 70 - 4 argon ion laser (Coherent Ltd, Cambridge, UK) and the light was delivered to the operative site via an optical fiber. The histological characteristics of the development and resolution of the lesion have been studied. Forty rats were examined with light and electron microscopy at various time points between 30 minutes and one month after irradiation and the lesion length was measured. Platelet aggregation, increased extracellular space in the white matter and vacuolation of the neurones and glia of the grey matter were present 30 minutes after injury. Progressive necrosis of the white and grey matter developed over the subsequent 24 hours to produce a fusiform lesion that occupied the dorsal funiculus and dorsal horns of the spinal cord at its center and tapered cranially and caudally along the dorsal columns for a total distance of seven millimeters. By one month after injury the area of necrosis had become a cyst lined by astrocytes ventrolaterally and meningeal cells dorsally. Measurements of lesion length showed a variability of 26%. This model of spinal cord trauma produces a lesion that is sufficiently reproducible to be suitable for performing studies aimed at tissue preservation and repair.
Huie, J. Russell
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family of signaling molecules. Since its discovery over three decades ago, BDNF has been identified as an important regulator of neuronal development, synaptic transmission, and cellular and synaptic plasticity and has been shown to function in the formation and maintenance of certain forms of memory. Neural plasticity that underlies learning and memory in the hippocampus shares distinct characteristics with spinal cord nociceptive plasticity. Research examining the role BDNF plays in spinal nociception and pain overwhelmingly suggests that BDNF promotes pronociceptive effects. BDNF induces synaptic facilitation and engages central sensitization-like mechanisms. Also, peripheral injury-induced neuropathic pain is often accompanied with increased spinal expression of BDNF. Research has extended to examine how spinal cord injury (SCI) influences BDNF plasticity and the effects BDNF has on sensory and motor functions after SCI. Functional recovery and adaptive plasticity after SCI are typically associated with upregulation of BDNF. Although neuropathic pain is a common consequence of SCI, the relation between BDNF and pain after SCI remains elusive. This article reviews recent literature and discusses the diverse actions of BDNF. We also highlight similarities and differences in BDNF-induced nociceptive plasticity in naïve and SCI conditions. PMID:27721996
... care for people with spinal cord injuries and aggressive treatment and rehabilitation can minimize damage to the ... care for people with spinal cord injuries and aggressive treatment and rehabilitation can minimize damage to the ...
... your body and your brain. A spinal cord injury disrupts the signals. Spinal cord injuries usually begin with a blow that fractures or ... bone disks that make up your spine. Most injuries don't cut through your spinal cord. Instead, ...
... the movement of the spinal cord within the spinal column. Attachments may occur congenitally at the base of ... or may be due to narrowing of the spinal column (stenosis) with age. Tethering may also develop after ...
Yun, Hyun-Sik; Sun, Hyung-Seok; Seon, Hyo-Jeong; Han, Jae-Young; Choi, In-Sung
A 49-year-old man received prolotherapy in the upper cervical region at a local medical clinic. Immediately after the procedure, he felt a sensation resembling an electric shock in his right upper and lower extremities, and continuously complained of numbness and discomfort in the right hemibody. He visited our clinic a week later. Upon physical examination, there were no significant abnormal findings. The visual analog scale was 60 points. T2-weight magnetic resonance images of the cervical spine showed a 0.7 cm sized bright oval spot on the right side of the spinal cord at the level of C4-C5 disc, suggesting spinal cord injury. There were no definite electrodiagnostic abnormalities. Digital infrared thermal images showed moderately decreased surface temperature on lateral aspect of the right forearm and dorsum of the right hand compared with the other side. Considering that very rare complications like spinal cord injury may develop after prolotherapy, we suggest that special interventions such as prolotherapy be performed by professional experts. PMID:22506175
Brommer, Benedikt; Engel, Odilo; Kopp, Marcel A; Watzlawick, Ralf; Müller, Susanne; Prüss, Harald; Chen, Yuying; DeVivo, Michael J; Finkenstaedt, Felix W; Dirnagl, Ulrich; Liebscher, Thomas; Meisel, Andreas; Schwab, Jan M
Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner.
Brommer, Benedikt; Engel, Odilo; Kopp, Marcel A.; Watzlawick, Ralf; Müller, Susanne; Prüss, Harald; Chen, Yuying; DeVivo, Michael J.; Finkenstaedt, Felix W.; Dirnagl, Ulrich; Liebscher, Thomas; Meisel, Andreas
Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient’s environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS (‘immune paralysis’), sufficient to propagate clinically relevant infection in an injury level dependent manner. PMID:26754788
Bráz, JM; Sharif-Naeini, R; Vogt, D; Kriegstein, A; Alvarez-Buylla, A; Rubenstein, JL; Basbaum, AI
Neuropathic pain is a chronic debilitating disease characterized by mechanical allodynia and spontaneous pain. Because symptoms are often unresponsive to conventional methods of pain treatment, new therapeutic approaches are essential. Here, we describe a strategy that not only ameliorates symptoms of neuropathic pain, but is also potentially disease modifying. We show that transplantation of immature telencephalic GABAergic interneurons from the mouse medial ganglionic eminence (MGE) into the adult mouse spinal cord completely reverses the mechanical hypersensitivity produced by peripheral nerve injury. Underlying this improvement is a remarkable integration of the MGE transplants into the host spinal cord circuitry, in which the transplanted cells make functional connections with both primary afferent and spinal cord neurons. By contrast, MGE transplants were not effective against inflammatory pain. Our findings suggest that MGE-derived GABAergic interneurons overcome the spinal cord hyperexcitability that is a hallmark of nerve-injury induced neuropathic pain. PMID:22632725
Yang, Yong-dong; Yu, Xing; Wang, Xiu-mei; Mu, Xiao-hong; He, Feng
Tanshinone IIA, extracted from Salvia miltiorrhiza Bunge, exerts neuroprotective effects through its anti-inflammatory, anti-oxidative and anti-apoptotic properties. This study intravenously injected tanshinone IIA 20 mg/kg into rat models of spinal cord injury for 7 consecutive days. Results showed that tanshinone IIA could reduce the inflammation, edema as well as compensatory thickening of the bladder tissue, improve urodynamic parameters, attenuate secondary injury, and promote spinal cord regeneration. The number of hypertrophic and apoptotic dorsal root ganglion (L6–S1) cells was less after treatment with tanshinone IIA. The effects of tanshinone IIA were similar to intravenous injection of 30 mg/kg methylprednisolone. These findings suggested that tanshinone IIA improved functional recovery after spinal cord injury-induced lower urinary tract dysfunction by remodeling the spinal pathway involved in lower urinary tract control.
Liu, Zhi-Qiang; Zhang, Hong-Bin; Wang, Jian; Xia, Li-Jian; Zhang, Wei
Ischemia/reperfusion (I/R) induced spinal cord injury is an important pathologic mechanism leading to the paraplegia observed after surgery to repairaortic aneurysms. This study aims to investigate the neuroprotective effects of Lipoxin A4 and its potential mechanism in a rabbit model with I/R spinal cord injury. Forty-five rabbits were randomly divided into three groups: sham group, I/R group and Lipoxin A4 group. Rabbits were subject to 30 min aortic occlusion to induce transient spinal cord ischemia. All animals were sacrificed after neurological evaluation with modified Tarlov criteria at the 48th hour after reperfusion, and the spinal cord segments (L4-6) were harvested for histopathological examination, as well as local malondialdehyde (MDA) and total superoxide dismutase (SOD) activity analysis. All animals in the I/R group became paraplegic. While after 48-hour treatment, compared with I/R group, Lipoxin A4 significantly improved neurological function, reduced cell apoptosis and MDA levels as well as increased SOD activity (P < 0.05). These results suggest that Lipoxin A4 can ameliorate I/R induced spinal cord injury in Rabbit through its antiapoptosis and antioxidant activity. PMID:26550197
Lee, J H; Wilcox, G L; Beitz, A J
Immunocytochemical localization of Fos protein was used to analyze the involvement of nitric oxide (NO) in the expression of Fos in the spinal cord, induced by mechanical noxious stimulation (NS). Mechanical NS was applied to the left hindpaw 30 minutes after intrathecal administration of the NO synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME) and the resulting Fos expression in the spinal cord dorsal horn was compared with that obtained in rats exposed only to the mechanical NS. Pretreatment with L-NAME but not its stereoisomer N omega-nitro-D-arginine methyl ester (D-NAME), produced a dose-dependent suppression of Fos expression induced by mechanical noxious stimulation. These results indicate that NO modulates the expression of Fos in the dorsal horn induced by mechanical noxious stimulation and further support the hypothesis that NO is involved in nociceptive events occurring in the spinal cord in response to a peripheral noxious stimulus.
Kiyatkin, Eugene A; Sharma, Hari S
Acute methamphetamine (METH) intoxication induces metabolic brain activation as well as multiple physiological and behavioral responses that could result in life-threatening health complications. Previously, we showed that METH (9 mg/kg) used in freely moving rats induces robust leakage of blood-brain barrier, acute glial activation, vasogenic edema, and structural abnormalities of brain cells. These changes were tightly correlated with drug-induced brain hyperthermia and were greatly potentiated when METH was used at warm ambient temperatures (29°C), inducing more robust and prolonged hyperthermia. Extending this line of research, here we show that METH also strongly increases the permeability of the blood-spinal cord barrier as evidenced by entry of Evans blue and albumin immunoreactivity in T9-12 segments of the spinal cord. Similar to the blood-brain barrier, leakage of bloodspinal cord barrier was associated with acute glial activation, alterations of ionic homeostasis, water tissue accumulation (edema), and structural abnormalities of spinal cord cells. Similar to that in the brain, all neurochemical alterations correlated tightly with drug-induced elevations in brain temperature and they were enhanced when the drug was used at 29°C and brain hyperthermia reached pathological levels (>40°C). We discuss common features and differences in neural responses between the brain and spinal cord, two inseparable parts of the central nervous system affected by METH exposure.
Kallakuri, Srinivasu; Purkait, Heena S.; Dalavayi, Satya; VandeVord, Pamela; Cavanaugh, John M.
Introduction: Blast induced neurotrauma has been the signature wound in returning soldiers from the ongoing wars in Iraq and Afghanistan. Of importance is understanding the pathomechansim(s) of blast overpressure (OP) induced axonal injury. Although several recent animal models of blast injury indicate the neuronal and axonal injury in various brain regions, animal studies related to axonal injury in the white matter (WM) tracts of cervical spinal cord are limited. Objective: The purpose of this study was to assess the extent of axonal injury in WM tracts of cervical spinal cord in male Sprague Dawley rats subjected to a single insult of blast OP. Materials and Methods: Sagittal brainstem sections and horizontal cervical spinal cord sections from blast and sham animals were stained by neurofilament light (NF-L) chain and beta amyloid precursor protein immunocytochemistry and observed for axonal injury changes. Results: Observations from this preliminary study demonstrate axonal injury changes in the form of prominent swellings, retraction bulbs, and putative signs of membrane disruptions in the brainstem and cervical spinal cord WM tracts of rats subjected to blast OP. Conclusions: Prominent axonal injury changes following the blast OP exposure in brainstem and cervical spinal WM tracts underscores the need for careful evaluation of blast induced injury changes and associated symptoms. NF-L immunocytochemistry can be considered as an additional tool to assess the blast OP induced axonal injury. PMID:26752889
Khazaei, Mohamad; Ahuja, Christopher S.; Fehlings, Michael G.
Spinal cord injury (SCI) is a common cause of mortality and neurological morbidity. Although progress had been made in the last decades in medical, surgical, and rehabilitation treatments for SCI, the outcomes of these approaches are not yet ideal. The use of cell transplantation as a therapeutic strategy for the treatment of SCI is very promising. Cell therapies for the treatment of SCI are limited by several translational road blocks, including ethical concerns in relation to cell sources. The use of iPSCs is particularly attractive, given that they provide an autologous cell source and avoid the ethical and moral considerations of other stem cell sources. In addition, different cell types, that are applicable to SCI, can be created from iPSCs. Common cell sources used for reprogramming are skin fibroblasts, keratinocytes, melanocytes, CD34+ cells, cord blood cells and adipose stem cells. Different cell types have different genetic and epigenetic considerations that affect their reprogramming efficiencies. Furthermore, in SCI the iPSCs can be differentiated to neural precursor cells, neural crest cells, neurons, oligodendrocytes, astrocytes, and even mesenchymal stromal cells. These can produce functional recovery by replacing lost cells and/or modulating the lesion microenvironment. PMID:28154814
Xie, Li-jie; Huang, Jin-xiu; Yang, Jian; Yuan, Fen; Zhang, Shuang-shuang; Yu, Qi-jing; Hu, Ji
Propofol has been shown to exert neuroprotective effects on the injured spinal cord. However, the effect of propofol on the blood-spinal cord barrier (BSCB) after ischemia/reperfusion injury (IRI) is poorly understood. Therefore, we investigated whether propofol could maintain the integrity of the BSCB. Spinal cord IRI (SCIRI) was induced in rabbits by infrarenal aortic occlusion for 30 minutes. Propofol, 30 mg/kg, was intravenously infused 10 minutes before aortic clamping as well as at the onset of reperfusion. Then, 48 hours later, we performed histological and mRNA/protein analyses of the spinal cord. Propofol decreased histological damage to the spinal cord, attenuated the reduction in BSCB permeability, downregulated the mRNA and protein expression levels of matrix metalloprotease-9 (MMP-9) and nuclear factor-κB (NF-κB), and upregulated the protein expression levels of occludin and claudin-5. Our findings suggest that propofol helps maintain BSCB integrity after SCIRI by reducing MMP-9 expression, by inhibiting the NF-κB signaling pathway, and by maintaining expression of tight junction proteins. PMID:28250758
Díaz Galindo, Carmen; Gómez-González, Beatriz; Salinas, Eva; Calderón-Vallejo, Denisse; Hernández-Jasso, Irma; Bautista, Eduardo; Quintanar, J Luis
Gonadotropin-releasing hormone (GnRH) and its synthetic analog leuprolide acetate, a GnRH agonist, have neurotrophic properties. This study was designed to determine whether administration of leuprolide acetate can improve locomotor behavior, gait, micturition reflex, spinal cord morphology and the amount of microglia in the lesion epicenter after spinal cord injury in rats. Rats with spinal cord compression injury were administered leuprolide acetate or saline solution for 5 weeks. At the 5th week, leuprolide acetate-treated rats showed locomotor activity recovery by 38%, had improvement in kinematic gait and exhibited voiding reflex recovery by 60%, as compared with the 1st week. By contrast, saline solution-treated rats showed locomotor activity recovery only by 7%, but voiding reflex did not recover. More importantly, leuprolide acetate treatment reduced microglial immunological reaction and induced a trend towards greater area of white and gray matter in the spinal cord. Therefore, leuprolide acetate has great potential to repair spinal cord injury. PMID:26807118
Díaz Galindo, Carmen; Gómez-González, Beatriz; Salinas, Eva; Calderón-Vallejo, Denisse; Hernández-Jasso, Irma; Bautista, Eduardo; Quintanar, J Luis
Gonadotropin-releasing hormone (GnRH) and its synthetic analog leuprolide acetate, a GnRH agonist, have neurotrophic properties. This study was designed to determine whether administration of leuprolide acetate can improve locomotor behavior, gait, micturition reflex, spinal cord morphology and the amount of microglia in the lesion epicenter after spinal cord injury in rats. Rats with spinal cord compression injury were administered leuprolide acetate or saline solution for 5 weeks. At the 5(th) week, leuprolide acetate-treated rats showed locomotor activity recovery by 38%, had improvement in kinematic gait and exhibited voiding reflex recovery by 60%, as compared with the 1(st) week. By contrast, saline solution-treated rats showed locomotor activity recovery only by 7%, but voiding reflex did not recover. More importantly, leuprolide acetate treatment reduced microglial immunological reaction and induced a trend towards greater area of white and gray matter in the spinal cord. Therefore, leuprolide acetate has great potential to repair spinal cord injury.
Luna, Carlos; Shah, Sameer; Cohen, Avis; Aranda-Espinoza, Helim
Regeneration after spinal cord injury is a serious health issue and there is no treatment for ailing patients. To understand regeneration of the spinal cord we used a system where regeneration occurs naturally, such as the lamprey. In this work, we analyzed the stress response of the spinal cord to tensile loading and obtained the mechanical properties of the cord both in vitro and in vivo. Physiological measurements showed that the spinal cord is pre-stressed to a strain of 10%, and during sinusoidal swimming, there is a local strain of 5% concentrated evenly at the mid-body and caudal sections. We found that the mechanical properties are homogeneous along the body and independent of the meninges. The mechanical behavior of the spinal cord can be characterized by a non-linear viscoelastic model, described by a modulus of 20 KPa for strains up to 15% and a modulus of 0.5 MPa for strains above 15%, in agreement with experimental data. However, this model does not offer a full understanding of the behavior of the spinal cord fibers. Using polymer physics we developed a model that relates the stress response as a function of the number of fibers.
Anderson, Aileen J; Najbauer, Joseph; Huang, Wencheng; Young, Wise; Robert, Stephanie
We have previously described the activation of the classical, alternative, and terminal complement cascade pathways after acute contusion spinal cord injury using the New York University (NYU) weight-drop impactor. In the present study, we examined the induction of protein regulators of the complement cascade, factor H (FH), and clusterin, in the same experimental paradigm. The spinal cord of laminectomized adult rats was subjected to mild or severe injury using impactor weight-drop heights of 12.5 and 50 mm, respectively. The spinal cords of control and injured animals were evaluated at 1, 7, and 42 days after injury. Immunocytochemistry revealed a robust increase in the numbers and intensity of staining of FH, and clusterin-positive cells in the injured cord at all three time points, with the highest increases observed at 1 and 42 days after injury. FH and clusterin-positive cells were observed among neurons as well as oligodendrocytes. The increased expression was detected both rostrally and caudally from the injury site, in the latter case at distances up to 20 mm. The precise biological significance of injury-induced upregulation of these proteins remains to be determined. However, FH and clusterin are potent regulators of complement activity targeting upstream (FH) and downstream (clusterin) molecules of the pro-inflammatory cascade, which could be of vital importance in preventing a "runaway" inflammatory reaction in the injured spinal cord.
... Oh's Intensive Care Manual . 7th ed. Philadelphia, PA: Elsevier; 2014:chap 78. Bryce TN. Spinal cord injury. ... Physical Medicine and Rehabilitation . 5th ed. Philadelphia, PA: Elsevier; 2016:chap 49. Dalzell K, Nouri A, Fehlings ...
... is "Braingate" research? What is the status of stem-cell research? How would stem-cell therapies work in the treatment of spinal cord injuries? What does stem-cell research on animals tell us? When can we ...
Lin, Juntang; Fu, Sulei; Yang, Ciqing; Redies, Christoph
Pax3 is a transcription factor that belongs to the paired box family. In the developing spinal cord it is expressed in the dorsal commissural neurons, which project ascending axons contralaterally to form proper spinal cord-brain circuitry. While it has been shown that Pax3 induces cell aggregation in vitro, little is known about the role of Pax3 in cell aggregation and spinal circuit formation in vivo. We have reported that Pax3 is involved in neuron differentiation and that its overexpression induces ectopic cadherin-7 expression. In this study we report that Pax3 overexpression also induces cell aggregation in vivo. Tissue sections and open book preparations revealed that Pax3 overexpression prevents commissural axons from projecting to the contralateral side of the spinal cord. Cells overexpressing Pax3 aggregated in cell clusters that contained shortened neurites with perturbed axon growth and elongation. Pax3-specific shRNA partially rescued the morphological change induced by Pax3 overexpression in vivo. Our results indicate that the normal expression of Pax3 is necessary for proper axonal pathway finding and commissural axon projection. In conclusion, Pax3 regulates neural circuit formation during embryonic development. J. Comp. Neurol. 525:1618-1632, 2017. © 2016 Wiley Periodicals, Inc.
Xu, Jiajun; Huang, Guoyang; Zhang, Kun; Sun, Jinchuan; Xu, Tao; Li, Runping
Abstract In this study, we investigated whether nuclear factor erythroid 2-related factor 2 (Nrf2) activation in astrocytes contributes to the neuroprotection induced by a single hyperbaric oxygen preconditioning (HBO-PC) against spinal cord ischemia/reperfusion (SCIR) injury. In vivo: At 24 h after a single HBO-PC at 2.5 atmospheres absolute for 90 min, the male ICR mice underwent SCIR injury by aortic cross-clamping surgery and observed for 48 h. HBO-PC significantly improved hindlimb motor function, reduced secondary spinal cord edema, ameliorated the reactivity of spinal motor-evoked potentials, and slowed down the process of apoptosis to exert neuroprotective effects against SCIR injury. At 12 h or 24 h after HBO-PC without aortic cross-clamping surgery, Western blot, enzyme-linked immunosorbent assay, realtime-polymerase chain reaction and double-immunofluorescence staining were used to detect the Nrf2 activity of spinal cord tissue, such as mRNA level, protein content, DNA binding activity, and the expression of downstream gene, such as glutamate-cysteine ligase, γ-glutamyltransferase, multidrug resistance protein 1, which are key proteins for intracellular glutathione synthesis and transit. The Nrf2 activity and downstream genes expression were all enhanced in normal spinal cord with HBO-PC. Glutathione content of spinal cord tissue with HBO-PC significantly increased at all time points after SCIR injury. Moreover, Nrf2 overexpression mainly occurs in astrocytes. In vitro: At 24 h after HBO-PC, the primary spinal astrocyte-neuron co-cultures from ICR mouse pups were subjected to oxygen-glucose deprivation (OGD) for 90 min to simulate the ischemia-reperfusion injury. HBO-PC significantly increased the survival rate of neurons and the glutathione content in culture medium, which was mainly released from asctrocytes. Moreover, the Nrf2 activity and downstream genes expression induced by HBO-PC were mainly enhanced in astrocytes, but not in
Rissi, Daniel R; Barber, Renee; Burnum, Annabelle; Miller, Andrew D
Spinal cord glioma is uncommonly reported in dogs. We describe the clinicopathologic and diagnostic features of 7 cases of canine spinal cord glioma and briefly review the veterinary literature on this topic. The median age at presentation was 7.2 y. Six females and 1 male were affected and 4 dogs were brachycephalic. The clinical course lasted from 3 d to 12 wk, and clinical signs were progressive and associated with multiple suspected neuroanatomic locations in the spinal cord. Magnetic resonance imaging of 6 cases revealed T2-weighted hyperintense lesions with variable contrast enhancement in the spinal cord. All dogs had a presumptive clinical diagnosis of intraparenchymal neoplasia or myelitis based on history, advanced imaging, and cerebrospinal fluid analysis. Euthanasia was elected in all cases because of poor outcome despite anti-inflammatory or immunosuppressive treatment or because of poor prognosis at the time of diagnosis. Tumor location during autopsy ranged from C1 to L6, with no clear predilection for a specific spinal cord segment. The diagnosis was based on histopathology and the immunohistochemistry expression of glial fibrillary acidic protein, oligodendrocyte lineage transcription factor 2, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, neuron-specific enolase, synaptophysin, and Ki-67. Diagnoses consisted of 4 cases of oligodendroglioma, 2 cases of gliomatosis cerebri, and 1 astrocytoma. This case series further defines the clinicopathologic features of canine spinal glioma and highlights the need for comprehensive immunohistochemistry in addition to routine histopathology to confirm the diagnosis of these tumors.
... to send and receive messages to and from the brain. About 200,000 people in the United States have spinal cord injuries. Most injuries occur from a traumatic event, according to the National Spinal Cord Injury ...
Allen, Antiño R.; Smith, G. Troy
The ability to regenerate spinal cord tissue after tail amputation has been well studied in several species of teleost fish. The present study examined proliferation and survival of cells following complete spinal cord transection rather than tail amputation in the weakly electric fish Apteronotus leptorhynchus. To quantify cell proliferation along the length of the spinal cord, fish were given a single bromodeoxyuridine (BrdU) injection immediately after spinal transection or sham surgery. Spinal transection significantly increased the density of BrdU+ cells along the entire length of the spinal cord at 1 day post transection (dpt), and most newly generated cells survived up to 14 dpt. To examine longer term survival of the newly proliferated cells, BrdU was injected for 5 days after the surgery, and fish were sacrificed 14 or 30 dpt. Spinal transection significantly increased proliferation and/or survival, as indicated by an elevated density of BrdU+ cells in the spinal cords of spinally transected compared to sham-operated and intact fish. At 14 dpt, BrdU+ cells were abundant at all levels of the spinal cord. By 30 dpt, the density of BrdU+ cells decreased at all levels of the spinal cord except at the tip of the tail. Thus, newly generated cells in the caudal-most segment of the spinal cord survived longer than those in more rostral segments. Our findings indicate that spinal cord transection stimulates widespread cellular proliferation; however, there were regional differences in the survival of the newly generated cells. PMID:23147638
Zhou, Yulong; Zhang, Hongyu; Zheng, Binbin; Ye, Libing; Zhu, Sipin; Johnson, Noah R; Wang, Zhouguang; Wei, Xiaojie; Chen, Daqing; Cao, Guodong; Fu, Xiaobing; Li, Xiaokun; Xu, Hua-Zi; Xiao, Jian
Spinal cord injury (SCI) induces the disruption of the blood-spinal cord barrier (BSCB) which leads to infiltration of blood cells, an inflammatory response, and neuronal cell death, resulting spinal cord secondary damage. Retinoic acid (RA) has a neuroprotective effect in both ischemic brain injury and SCI, however the relationship between BSCB disruption and RA in SCI is still unclear. In this study, we demonstrated that autophagy and ER stress are involved in the protective effect of RA on the BSCB. RA attenuated BSCB permeability and decreased the loss of tight junction (TJ) molecules such as P120, β-catenin, Occludin and Claudin5 after injury in vivo as well as in Brain Microvascular Endothelial Cells (BMECs). Moreover, RA administration improved functional recovery in the rat model of SCI. RA inhibited the expression of CHOP and caspase-12 by induction of autophagic flux. However, RA had no significant effect on protein expression of GRP78 and PDI. Furthermore, combining RA with the autophagy inhibitor chloroquine (CQ) partially abolished its protective effect on the BSCB via exacerbated ER stress and subsequent loss of tight junctions. Taken together, the neuroprotective role of RA in recovery from SCI is related to prevention of of BSCB disruption via the activation of autophagic flux and the inhibition of ER stress-induced cell apoptosis. These findings lay the groundwork for future translational studies of RA for CNS diseases, especially those related to BSCB disruption. PMID:26722220
Miladinović, Ksenija; Vavra-Hadziahmetović, Narcisa; Muftić, Mirsad; Sakota, Slavica
One of the complications caused by spinal lesion is osteoporosis which development is induced by lesion itself, and its mechanism is not explained enough. Risk factor of this kind of osteoporosis is fracture which management is difficult and is cause of further complications which aggravate already damaged quality of life of patients with spinal cord injury, and demand additional health insurance expenses. Importance of prevention and treatment of spinal cord injury induced osteoporosis is enlightened by case report.
Ramírez-Jarquín, Uri Nimrod; Tapia, Ricardo
Inhibitory GABAergic and glycinergic neurotransmission in the spinal cord play a central role in the regulation of neuronal excitability, by maintaining a balance with the glutamate-mediated excitatory transmission. Glutamatergic agonists infusion in the spinal cord induce motor neuron death by excitotoxicity, leading to motor deficits and paralysis, but little is known on the effect of the blockade of inhibitory transmission. In this work we studied the effects of GABAergic and glycinergic blockade, by means of microdialysis perfusion (acute administration) and osmotic minipumps infusion (chronic administration) of GABA and glycine receptors antagonists directly in the lumbar spinal cord. We show that acute glycinergic blockade with strychnine or GABAergic blockade with bicuculline had no significant effects on motor activity and on motor neuron survival. However, chronic bicuculline infusion, but not strychnine, induced ipsilateral gait alterations, phalange flaccidity and significant motor neuron loss, and these effects were prevented by AMPA receptor blockade with CNQX but not by NMDA receptor blockade with MK801. In addition, we demonstrate that the chronic infusion of bicuculline enhanced the excitotoxic effect of AMPA, causing faster bilateral paralysis and increasing motor neuron loss. These findings indicate a relevant role of GABAergic inhibitory circuits in the regulation of motor neuron excitability and suggest that their alterations may be involved in the neurodegeneration processes characteristic of motor neuron diseases such as amyotrophic lateral sclerosis.
Kaufmann, Nathalie; Zeka, Bleranda; Schanda, Kathrin; Fujihara, Kazuo; Illes, Zsolt; Dahle, Charlotte; Reindl, Markus; Lassmann, Hans; Bradl, Monika
Neuromyelitis optica (NMO) is an acute inflammatory disease of the central nervous system (CNS) which predominantly affects spinal cord and optic nerves. Most patients harbor pathogenic autoantibodies, the so-called NMO-IgGs, which are directed against the water channel aquaporin 4 (AQP4) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from therapies involving type I interferons (I-IFN), NMO patients typically do not profit from such treatments. How is I-IFN involved in NMO pathogenesis? To address this question, we made gene expression profiles of spinal cords from Lewis rat models of experimental neuromyelitis optica (ENMO) and experimental autoimmune encephalomyelitis (EAE). We found an upregulation of I-IFN signature genes in EAE spinal cords, and a further upregulation of these genes in ENMO. To learn whether the local I-IFN signature is harmful or beneficial, we induced ENMO by transfer of CNS antigen-specific T cells and NMO-IgG, and treated the animals with I-IFN at the very onset of clinical symptoms, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation of pathogenic T and B cells in the lymph nodes. We observed that I-IFN treated ENMO rats had spinal cord lesions with fewer T cells, macrophages/activated microglia and activated neutrophils, and less astrocyte damage than their vehicle treated counterparts, suggesting beneficial effects of I-IFN. PMID:26990978
Haidet-Phillips, Amanda M; Roybon, Laurent; Gross, Sarah K; Tuteja, Alisha; Donnelly, Christopher J; Richard, Jean-Philippe; Ko, Myungsung; Sherman, Alex; Eggan, Kevin; Henderson, Christopher E; Maragakis, Nicholas J
The generation of human induced pluripotent stem cells (hiPSCs) represents an exciting advancement with promise for stem cell transplantation therapies as well as for neurological disease modeling. Based on the emerging roles for astrocytes in neurological disorders, we investigated whether hiPSC-derived astrocyte progenitors could be engrafted to the rodent spinal cord and how the characteristics of these cells changed between in vitro culture and after transplantation to the in vivo spinal cord environment. Our results show that human embryonic stem cell- and hiPSC-derived astrocyte progenitors survive long-term after spinal cord engraftment and differentiate to astrocytes in vivo with few cells from other lineages present. Gene profiling of the transplanted cells demonstrates the astrocyte progenitors continue to mature in vivo and upregulate a variety of astrocyte-specific genes. Given this mature astrocyte gene profile, this work highlights hiPSCs as a tool to investigate disease-related astrocyte biology using in vivo disease modeling with significant implications for human neurological diseases currently lacking animal models.
Yarkony, G M; Novick, A K; Roth, E J; Kirschner, K L; Rayner, S; Betts, H B
Galactorrhea, a secretion of milk or milk-like products from the breast in the absence of parturition, has been reported to occur in women with spinal cord injuries in association with amenorrhea and hyperprolactinemia. Four cases of galactorrhea in association with spinal cord injury are reported. Galactorrhea developed in four spinal cord injured women who had thoracic paraplegia. The onset of galactorrhea was from one month to five months after injury. Although the onset of galactorrhea may have been related to prescribed medications in all four cases, insufficient data exist to draw conclusions. The three women whose galactorrhea persisted declined treatment and galactorrhea continuing for more than two years in one instance. We conclude that galactorrhea with or without amenorrhea may develop after a spinal cord injury and that spinal cord injured women may have an enhanced sensitivity to medication-induced galactorrhea.
Sagen, Jacqueline; Pappas, George D.; Pollard, Harvey B.
Chromaffin cells synthesize and secrete several neuroactive substances, including catecholamines and opioid peptides, that, when injected into the spinal cord, induce analgesia. Moreover, the release of these substances from the cells can be stimulated by nicotine. Since chromaffin cells from one species have been shown to survive when transplanted to the central nervous system of another species, these cells are ideal candidates for transplantation to alter pain sensitivity. Bovine chromaffin cells were implanted into the subarachnoid space of the lumbar spinal region in adult rats. Pain sensitivity and response to nicotine stimulation was determined at various intervals following cell implantation. Low doses of nicotine were able to induce potent analgesia in implanted animals as early as one day following their introduction into the host spinal cord. This response could be elicited at least through the 4 months the animals were tested. The induction of analgesia by nicotine in implanted animals was dose related. This analgesia was blocked by the opiate antagonist naloxone and partially attenuated by the adrenergic antagonist phentolamine. These results suggest that the analgesia is due to the stimulated release of opioid peptides and catecholamines from the implanted bovine chromaffin cells and may provide a new therapeutic approach for the relief of pain.
Okada, Starlyn L M; Stivers, Nicole S; Stys, Peter K; Stirling, David P
Injured CNS axons fail to regenerate and often retract away from the injury site. Axons spared from the initial injury may later undergo secondary axonal degeneration. Lack of growth cone formation, regeneration, and loss of additional myelinated axonal projections within the spinal cord greatly limits neurological recovery following injury. To assess how central myelinated axons of the spinal cord respond to injury, we developed an ex vivo living spinal cord model utilizing transgenic mice that express yellow fluorescent protein in axons and a focal and highly reproducible laser-induced spinal cord injury to document the fate of axons and myelin (lipophilic fluorescent dye Nile Red) over time using two-photon excitation time-lapse microscopy. Dynamic processes such as acute axonal injury, axonal retraction, and myelin degeneration are best studied in real-time. However, the non-focal nature of contusion-based injuries and movement artifacts encountered during in vivo spinal cord imaging make differentiating primary and secondary axonal injury responses using high resolution microscopy challenging. The ex vivo spinal cord model described here mimics several aspects of clinically relevant contusion/compression-induced axonal pathologies including axonal swelling, spheroid formation, axonal transection, and peri-axonal swelling providing a useful model to study these dynamic processes in real-time. Major advantages of this model are excellent spatiotemporal resolution that allows differentiation between the primary insult that directly injures axons and secondary injury mechanisms; controlled infusion of reagents directly to the perfusate bathing the cord; precise alterations of the environmental milieu (e.g., calcium, sodium ions, known contributors to axonal injury, but near impossible to manipulate in vivo); and murine models also offer an advantage as they provide an opportunity to visualize and manipulate genetically identified cell populations and subcellular
Franz, Steffen; Ciatipis, Mareva; Pfeifer, Kathrin; Kierdorf, Birthe; Sandner, Beatrice; Bogdahn, Ulrich; Blesch, Armin; Winner, Beate; Weidner, Norbert
After spinal cord injury, transected axons fail to regenerate, yet significant, spontaneous functional improvement can be observed over time. Distinct central nervous system regions retain the capacity to generate new neurons and glia from an endogenous pool of progenitor cells and to compensate neural cell loss following certain lesions. The aim of the present study was to investigate whether endogenous cell replacement (neurogenesis or gliogenesis) in the brain (subventricular zone, SVZ; corpus callosum, CC; hippocampus, HC; and motor cortex, MC) or cervical spinal cord might represent a structural correlate for spontaneous locomotor recovery after a thoracic spinal cord injury. Adult Fischer 344 rats received severe contusion injuries (200 kDyn) of the mid-thoracic spinal cord using an Infinite Horizon Impactor. Uninjured rats served as controls. From 4 to 14 days post-injury, both groups received injections of bromodeoxyuridine (BrdU) to label dividing cells. Over the course of six weeks post-injury, spontaneous recovery of locomotor function occurred. Survival of newly generated cells was unaltered in the SVZ, HC, CC, and the MC. Neurogenesis, as determined by identification and quantification of doublecortin immunoreactive neuroblasts or BrdU/neuronal nuclear antigen double positive newly generated neurons, was not present in non-neurogenic regions (MC, CC, and cervical spinal cord) and unaltered in neurogenic regions (dentate gyrus and SVZ) of the brain. The lack of neuronal replacement in the brain and spinal cord after spinal cord injury precludes any relevance for spontaneous recovery of locomotor function. Gliogenesis was increased in the cervical spinal cord remote from the injury site, however, is unlikely to contribute to functional improvement.
Pfeifer, Kathrin; Kierdorf, Birthe; Sandner, Beatrice; Bogdahn, Ulrich; Blesch, Armin; Winner, Beate; Weidner, Norbert
After spinal cord injury, transected axons fail to regenerate, yet significant, spontaneous functional improvement can be observed over time. Distinct central nervous system regions retain the capacity to generate new neurons and glia from an endogenous pool of progenitor cells and to compensate neural cell loss following certain lesions. The aim of the present study was to investigate whether endogenous cell replacement (neurogenesis or gliogenesis) in the brain (subventricular zone, SVZ; corpus callosum, CC; hippocampus, HC; and motor cortex, MC) or cervical spinal cord might represent a structural correlate for spontaneous locomotor recovery after a thoracic spinal cord injury. Adult Fischer 344 rats received severe contusion injuries (200 kDyn) of the mid-thoracic spinal cord using an Infinite Horizon Impactor. Uninjured rats served as controls. From 4 to 14 days post-injury, both groups received injections of bromodeoxyuridine (BrdU) to label dividing cells. Over the course of six weeks post-injury, spontaneous recovery of locomotor function occurred. Survival of newly generated cells was unaltered in the SVZ, HC, CC, and the MC. Neurogenesis, as determined by identification and quantification of doublecortin immunoreactive neuroblasts or BrdU/neuronal nuclear antigen double positive newly generated neurons, was not present in non-neurogenic regions (MC, CC, and cervical spinal cord) and unaltered in neurogenic regions (dentate gyrus and SVZ) of the brain. The lack of neuronal replacement in the brain and spinal cord after spinal cord injury precludes any relevance for spontaneous recovery of locomotor function. Gliogenesis was increased in the cervical spinal cord remote from the injury site, however, is unlikely to contribute to functional improvement. PMID:25050623
He, Zili; Zou, Shuang; Wang, Qingqing; Li, Jiawei; Zheng, Zengming; Chen, Jian; Wu, Fenzan; Gong, Fanhua; Zhang, Hongyu; Xu, Huazi; Xiao, Jian
Spinal cord injury induces the disruption of blood-spinal cord barrier and triggers a complex array of tissue responses, including endoplasmic reticulum (ER) stress and autophagy. However, the roles of ER stress and autophagy in blood-spinal cord barrier disruption have not been discussed in acute spinal cord trauma. In the present study, we respectively detected the roles of ER stress and autophagy in blood-spinal cord barrier disruption after spinal cord injury. Besides, we also detected the cross-talking between autophagy and ER stress both in vivo and in vitro. ER stress inhibitor, 4-phenylbutyric acid, and autophagy inhibitor, chloroquine, were respectively or combinedly administrated in the model of acute spinal cord injury rats. At day 1 after spinal cord injury, blood-spinal cord barrier was disrupted and activation of ER stress and autophagy were involved in the rat model of trauma. Inhibition of ER stress by treating with 4-phenylbutyric acid decreased blood-spinal cord barrier permeability, prevented the loss of tight junction (TJ) proteins and reduced autophagy activation after spinal cord injury. On the contrary, inhibition of autophagy by treating with chloroquine exacerbated blood-spinal cord barrier permeability, promoted the loss of TJ proteins and enhanced ER stress after spinal cord injury. When 4-phenylbutyric acid and chloroquine were combinedly administrated in spinal cord injury rats, chloroquine abolished the blood-spinal cord barrier protective effect of 4-phenylbutyric acid by exacerbating ER stress after spinal cord injury, indicating that the cross-talking between autophagy and ER stress may play a central role on blood-spinal cord barrier integrity in acute spinal cord injury. The present study illustrates that ER stress induced by spinal cord injury plays a detrimental role on blood-spinal cord barrier integrity, on the contrary, autophagy induced by spinal cord injury plays a furthersome role in blood-spinal cord barrier integrity in
Zhou, Yulong; Wu, Yanqing; Liu, Yanlong; He, Zili; Zou, Shuang; Wang, Qingqing; Li, Jiawei; Zheng, Zengming; Chen, Jian; Wu, Fenzan; Gong, Fanhua; Zhang, Hongyu; Xu, Huazi; Xiao, Jian
Spinal cord injury induces the disruption of blood-spinal cord barrier and triggers a complex array of tissue responses, including endoplasmic reticulum (ER) stress and autophagy. However, the roles of ER stress and autophagy in blood-spinal cord barrier disruption have not been discussed in acute spinal cord trauma. In the present study, we respectively detected the roles of ER stress and autophagy in blood-spinal cord barrier disruption after spinal cord injury. Besides, we also detected the cross-talking between autophagy and ER stress both in vivo and in vitro. ER stress inhibitor, 4-phenylbutyric acid, and autophagy inhibitor, chloroquine, were respectively or combinedly administrated in the model of acute spinal cord injury rats. At day 1 after spinal cord injury, blood-spinal cord barrier was disrupted and activation of ER stress and autophagy were involved in the rat model of trauma. Inhibition of ER stress by treating with 4-phenylbutyric acid decreased blood-spinal cord barrier permeability, prevented the loss of tight junction (TJ) proteins and reduced autophagy activation after spinal cord injury. On the contrary, inhibition of autophagy by treating with chloroquine exacerbated blood-spinal cord barrier permeability, promoted the loss of TJ proteins and enhanced ER stress after spinal cord injury. When 4-phenylbutyric acid and chloroquine were combinedly administrated in spinal cord injury rats, chloroquine abolished the blood-spinal cord barrier protective effect of 4-phenylbutyric acid by exacerbating ER stress after spinal cord injury, indicating that the cross-talking between autophagy and ER stress may play a central role on blood-spinal cord barrier integrity in acute spinal cord injury. The present study illustrates that ER stress induced by spinal cord injury plays a detrimental role on blood-spinal cord barrier integrity, on the contrary, autophagy induced by spinal cord injury plays a furthersome role in blood-spinal cord barrier integrity in
... cord consists of gray matter shaped like a butterfly: The front "wings" (anterior or motor horns) contain ... In the center of the spinal cord, a butterfly-shaped area of gray matter helps relay impulses ...
Borgens, R.B.; Blight, A.R.; McGinnis, M.E.
Applied electric fields were used to promote axonal regeneration in spinal cords of adult guinea pigs. A propriospinal intersegmental reflex (the cutaneous trunci muscle reflex) was used to test lateral tract function after hemisection of the thoracic spinal cord. An electrical field (200 microvolts per millimeter, cathode rostral) applied across the lesion led to functional recovery of the cutaneous trunci muscle reflex in 25 percent of experimental animals, whereas the functional deficit remained in control animals, which were implanted with inactive stimulators.
Saadoun, Samira; Werndle, Melissa C; Lopez de Heredia, Luis; Papadopoulos, Marios C
MR scans from 65 patients with traumatic spinal cord injury were analysed; on admission 95% had evidence of cord compression - in 26% due to the dura, and in the remaining 74% due to extradural factors. Compression due to dural factors resolved with a half-life of 5.5 days. These findings suggest that bony decompression alone may not relieve spinal cord compression in the quarter of patients in whom dural factors are significant.
Orendácová, J; Ondrejcák, T; Kuchárová, K; Cízková, D; Jergová, S; Mitrusková, B; Raceková, E; Vanický, I; Marsala, J
Fluoro-Jade B, a marker of degenerating neurons, was used to label histopathological changes in the rat spinal cord after transient ischemia and ischemic preconditioning (IPC). To characterize postischemic neurodegenerations and consequent neurological changes, a particular attention was paid to the standardization of ischemic conditions in animals of both groups. 1. The control ischemic rats were submitted to a reversible occlusion of descending aorta by insertion and subsequent inflation of a 2F Fogarty catheter for 12 min. 2. In the IPC rats, an episode of short 3 min occlusion and 30 min reperfusion preceded the 12 min ischemia. Postischemic motor function testing (ambulation and stepping) was provided repeatedly for evaluation of neurological status 2 h and 24 h after surgery and at the end of postischemic survival, i.e. after 48 h. Fluoro-Jade B staining was used to demonstrate degenerated neurons. In the control rats, neurological consequences of histopathological changes in lumbosacral spinal cord, manifested as paraplegia, were present after 12 min ischemia. Thus, numbers of degenerated Fluoro-Jade B positive cells were visible in gray matter of the most injured L(4)-S(2) spinal cord segments. Slight motor function impairment, consequential from significant decreasing in Fluoro-Jade B-positivity in the L(4)-S(2) spinal cord segments of the IPC rats, was considered the pathomorpfological evidence that IPC induces spinal cord tolerance to ischemia. Our results are consistent with the previously published silver impregnation method for histopathological demonstration of ischemic degeneration.
Inglis, Hayley R.; Greer, Judith M.; McCombe, Pamela A.
Background Experimental autoimmune encephalomyelitis (EAE), the best available model of multiple sclerosis, can be induced in different animal strains using immunization with central nervous system antigens. EAE is associated with inflammation and demyelination of the nervous system. Micro-array can be used to investigate gene expression and biological pathways that are altered during disease. There are few studies of the changes in gene expression in EAE, and these have mostly been done in a chronic mouse EAE model. EAE induced in the Lewis with myelin basic protein (MBP-EAE) is well characterised, making it an ideal candidate for the analysis of gene expression in this disease model. Methodology/Principal Findings MBP-EAE was induced in female Lewis rats by inoculation with MBP and adjuvants. Total RNA was extracted from the spinal cords and used for micro-array analysis using AffimetrixGeneChip Rat Exon 1.0 ST Arrays. Gene expression in the spinal cords was compared between healthy female rats and female rats with MBP-EAE. Gene expression in the spinal cord of rats with MBP-EAE differed from that in the spinal cord of normal rats, and there was regulation of pathways involved with immune function and nervous system function. For selected genes the change in expression was confirmed with real-time PCR. Conclusions/Significance EAE leads to modulation of gene expression in the spinal cord. We have identified the genes that are most significantly regulated in MBP-EAE in the Lewis rat and produced a profile of gene expression in the spinal cord at the peak of disease. PMID:23139791
Jure, Ignacio; Pietranera, Luciana; De Nicola, Alejandro F; Labombarda, Florencia
The incorporation of newborn neurons with increased synaptic remodeling and activity-dependent plasticity in the dentate gyrus enhances hippocampal-dependent learning performances. Astrocytes and microglial cells are components of the neurogenic niche and regulate neurogenesis under normal and neurophatological conditions leading to functional consequences for learning and memory. Although cognitive impairments were reported in patients after spinal cord injury (SCI), only few studies have considered remote changes in brain structures which are not related with sensory and motor cortex. Thus, we examined neurogenesis and glial reactivity by stereological assessment in dentate gyrus sub-regions after three different intensities of thoracic spinal cord compression in rats. Sixty days after injury we observed a decrease in the Basso-Bresnahan-Beattie locomotor scale scores, rotarod performance and volume of spare tissue that correlated with the severity of the compression. Regarding the hippocampus, we observed that neurogenesis and hilar neurons were reduced after severe SCI, while only neurogenesis decreased in the moderately injured group. In addition, severe SCI induced reactive microglia and astrogliosis in all dentate gyrus sub-regions. Furthermore, the density of reactive microglia increased in the hilus whereas astrogliosis developed in the molecular layer after moderate SCI. No changes were observed in the mildly injured rats. These results suggest glial response and neurogenesis are associated with injury intensity. Interestingly, hippocampal neurogenesis is more sensitive to SCI than astrocytes or microglia reaction, as moderate injury impairs the generation of new neurons without changing glial response in the subgranular zone.
Cameron, T.; Prado, R.; Watson, B.D.; Gonzalez-Carvajal, M.; Holets, V.R. )
The present study describes the production of a spinal cord lesion which is initiated by vascular occlusion resulting from the interaction between the photosensitizing dye erythrosin B and an argon laser beam. The lesion has characteristics similar to those of the central cavity thought to lead to the production of post-traumatic syringomyelia (PTS) in humans. The present study examines the behavioral and morphological characteristics of this injury over a 28-day period. Histological analysis revealed a cavity extending from the dorsal horns to lamina VIII, with some lateral and ventral pathways being spared. The cavity volume reached a maximum 7 days after lesion induction. Behavioral changes were assessed using six different tests of motor and reflex function (motor function, climbing, waterbath, inclined plane, withdrawal to pain, and withdrawal to extension). Lesioned animals exhibited flaccid paralysis for 3-5 days, which resolved afterward. The photochemically induced cavity should provide a reproducible model for examining the effects of cystic spinal cord injury on locomotor and reflex function.
Anderson, Aileen J; Robert, Stephanie; Huang, Wencheng; Young, Wise; Cotman, Carl W
Previous studies have shown that a cellular inflammatory response is initiated, and inflammatory cytokines are synthesized, following experimental spinal cord injury (SCI). In the present study, we tested the hypothesis that the complement cascade, a major component of both the innate and adaptive immune response, is also activated following experimental SCI. We investigated the pathways, cellular localization, timecourse, and degree of complement activation in rat spinal cord following acute contusion-induced SCI using the New York University (NYU) weight drop impactor. Mild and severe injuries (12.5 and 50 mm drop heights) at 1, 7, and 42 days post injury time points were evaluated. Classical (C1q and C4), alternative (Factor B) and terminal (C5b-9) complement pathways were strongly activated within 1 day of SCI. Complement protein immunoreactivity was predominantly found in cell types vulnerable to degeneration, neurons and oligodendrocytes, and was not generally observed in inflammatory or astroglial cells. Surprisingly, immunoreactivity for complement proteins was also evident 6 weeks after injury, and complement activation was observed as far as 20 mm rostral to the site of injury. Axonal staining by C1q and Factor B was also observed, suggesting a potential role for the complement cascade in demyelination or axonal degeneration. These data support the hypothesis that complement activation plays a role in SCI.
Edgerton, V. R.; Leon, R. D.; Harkema, S. J.; Hodgson, J. A.; London, N.; Reinkensmeyer, D. J.; Roy, R. R.; Talmadge, R. J.; Tillakaratne, N. J.; Timoszyk, W.; Tobin, A.
The present review presents a series of concepts that may be useful in developing rehabilitative strategies to enhance recovery of posture and locomotion following spinal cord injury. First, the loss of supraspinal input results in a marked change in the functional efficacy of the remaining synapses and neurons of intraspinal and peripheral afferent (dorsal root ganglion) origin. Second, following a complete transection the lumbrosacral spinal cord can recover greater levels of motor performance if it has been exposed to the afferent and intraspinal activation patterns that are associated with standing and stepping. Third, the spinal cord can more readily reacquire the ability to stand and step following spinal cord transection with repetitive exposure to standing and stepping. Fourth, robotic assistive devices can be used to guide the kinematics of the limbs and thus expose the spinal cord to the new normal activity patterns associated with a particular motor task following spinal cord injury. In addition, such robotic assistive devices can provide immediate quantification of the limb kinematics. Fifth, the behavioural and physiological effects of spinal cord transection are reflected in adaptations in most, if not all, neurotransmitter systems in the lumbosacral spinal cord. Evidence is presented that both the GABAergic and glycinergic inhibitory systems are up-regulated following complete spinal cord transection and that step training results in some aspects of these transmitter systems being down-regulated towards control levels. These concepts and observations demonstrate that (a) the spinal cord can interpret complex afferent information and generate the appropriate motor task; and (b) motor ability can be defined to a large degree by training.
Kao, T; Shumsky, JS; Murray, M; Moxon, KA
Exercise-induced cortical plasticity is associated with improved functional outcome after brain or nerve injury. Exercise also improves functional outcomes after spinal cord injury, but its effects on cortical plasticity are not known. The goal of this investigation was to study the effect of moderate exercise (treadmill locomotion, 3 min/day, 5days/week) on the somatotopic organization of forelimb and hindlimb somatosensory cortex (SI) after neonatal thoracic transection. We used adult rats spinalized as neonates because some of these animals develop weight-supported stepping and, therefore, the relationship between cortical plasticity and stepping could also be examined. Acute, single-neuron mapping was used to determine the percentage of cortical cells responding to cutaneous forelimb stimulation in normal, spinalized, and exercised spinalized rats. Multiple single neuron recording from arrays of chronically implanted microwires examined the magnitude of response of these cells in normal and exercised spinalized rats. Our results show that exercise not only increased the percentage of responding cells in the hindlimb SI, but also increased the magnitude of the response of these cells. This increase in response magnitude was correlated with behavioral outcome measures. In the forelimb SI, neonatal transection reduced the percentage of responding cells to forelimb stimulation but exercise reversed this loss. This restoration in the percentage of responding cells after exercise was accompanied by an increase in their response magnitude. Therefore, the increase in responsiveness of hindlimb SI to forelimb stimulation after neonatal transection and exercise may be due, in part, to the effect of exercise on the forelimb SI. PMID:19515923
Tambeli, Claudia H; Levine, Jon D; Gear, Robert W
The duration of noxious stimulus-induced antinociception (NSIA) has been shown to outlast the pain stimulus that elicited it, however, the mechanism that determines the duration of analgesia is unknown. We evaluated the role of spinal excitatory and inhibitory receptors (NMDA, mGluR(5), mu-opioid, GABA(A), and GABA(B)), previously implicated in NSIA initiation, in its maintenance. As in our previous studies, the supraspinal trigeminal jaw-opening reflex (JOR) in the rat was used for nociceptive testing because of its remoteness from the region of drug application, the lumbar spinal cord. NSIA was reversed by antagonists for two inhibitory receptors (GABA(B) and mu-opioid) but not by antagonists for either of the two excitatory receptors (NMDA and mGluR(5)), indicating that NSIA is maintained by ongoing activity at inhibitory synapses in the spinal cord. Furthermore, spinal administration of the GABA(B) agonist baclofen mimicked NSIA in that it could be blocked by prior injection of the mu-opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) in nucleus accumbens. CTAP also blocked baclofen antinociception when administered in the spinal cord. We conclude that analgesia induced by noxious stimulation is maintained by activity in spinal inhibitory receptors.
Conway, Cassandra Sligh D.; Gooden, Randy; Nowell, Jennifer; Wilson, Navodda
This paper will shed light on the lives of persons with spinal cord injuries by revealing the literature on spinal cord injuries that focuses on research that can shed light on attitudes towards persons with spinal cord injuries. The background literature related to incidences, the definition of spinal cord injury, and vocational opportunities are…
Akimoto, N; Honda, K; Uta, D; Beppu, K; Ushijima, Y; Matsuzaki, Y; Nakashima, S; Kido, M A; Imoto, K; Takano, Y; Noda, M
Cytokines such as interleukins are known to be involved in the development of neuropathic pain through activation of neuroglia. However, the role of chemokine (C-C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, in the nociceptive transmission remains unclear. We found that CCL-1 was upregulated in the spinal dorsal horn after partial sciatic nerve ligation. Therefore, we examined actions of recombinant CCL-1 on behavioural pain score, synaptic transmission, glial cell function and cytokine production in the spinal dorsal horn. Here we show that CCL-1 is one of the key mediators involved in the development of neuropathic pain. Expression of CCL-1 mRNA was mainly detected in the ipsilateral dorsal root ganglion, and the expression of specific CCL-1 receptor CCR-8 was upregulated in the superficial dorsal horn. Increased expression of CCR-8 was observed not only in neurons but also in microglia and astrocytes in the ipsilateral side. Recombinant CCL-1 injected intrathecally (i.t.) to naive mice induced allodynia, which was prevented by the supplemental addition of N-methyl-𝒟-aspartate (NMDA) receptor antagonist, MK-801. Patch-clamp recordings from spinal cord slices revealed that application of CCL-1 transiently enhanced excitatory synaptic transmission in the substantia gelatinosa (lamina II). In the long term, i.t. injection of CCL-1 induced phosphorylation of NMDA receptor subunit, NR1 and NR2B, in the spinal cord. Injection of CCL-1 also upregulated mRNA level of glial cell markers and proinflammatory cytokines (IL-1β, TNF-α and IL-6). The tactile allodynia induced by nerve ligation was attenuated by prophylactic and chronic administration of neutralizing antibody against CCL-1 and by knocking down of CCR-8. Our results indicate that CCL-1 is one of the key molecules in pathogenesis, and CCL-1/CCR-8 signaling system can be a potential target for drug development in the treatment for neuropathic pain. PMID:23788036
WEI, ZHI-JIAN; ZHOU, XIAN-HU; FAN, BAO-YOU; LIN, WEI; REN, YI-MING; FENG, SHI-QING
Spinal cord injury (SCI) may result in skeletal muscle atrophy. Identifying diagnostic biomarkers and effective targets for treatment is an important challenge in clinical work. The aim of the present study is to elucidate potential biomarkers and therapeutic targets for SCI-induced muscle atrophy (SIMA) using proteomic and bioinformatic analyses. The protein samples from rat soleus muscle were collected at different time points following SCI injury and separated by two-dimensional gel electrophoresis and compared with the sham group. The identities of these protein spots were analyzed by mass spectrometry (MS). MS demonstrated that 20 proteins associated with muscle atrophy were differentially expressed. Bioinformatic analyses indicated that SIMA changed the expression of proteins associated with cellular, developmental, immune system and metabolic processes, biological adhesion and localization. The results of the present study may be beneficial in understanding the molecular mechanisms of SIMA and elucidating potential biomarkers and targets for the treatment of muscle atrophy. PMID:27177391
Reynolds, Renee M; Morton, Ryan P; Walker, Marion L; Massagli, Teresa L; Browd, Samuel R
Selective dorsal rhizotomy may have a role in the management of spinal cord injury (SCI)-induced spasticity. Spasticity and spasms are common sequelae of SCI in children. Depending on the clinical scenario, treatments may include physical and occupational therapy, oral medications, chemodenervation, and neurosurgical interventions. Selective dorsal rhizotomy (SDR) is used in the management of spasticity in selected children with cerebral palsy, but, to the authors' knowledge, its use has not been reported in children with SCI. The authors describe the cases of 3 pediatric patients with SCI and associated spasticity treated with SDR. Two of the 3 patients have had significant long-term improvement in their preoperative spasticity. Although the third patient also experienced initial relief, his spasticity quickly returned to its preoperative severity, necessitating additional therapies. Selective dorsal rhizotomy may have a place in the treatment of selected children with spasticity due to SCI.
Nardone, Raffaele; Höller, Yvonne; Brigo, Francesco; Höller, Peter; Christova, Monica; Tezzon, Frediano; Golaszewski, Stefan; Trinka, Eugen
To further investigate the mechanisms of exercise-induced cortical plasticity after spinal cord injury (SCI), the cortical silent period (CoSP) evoked by transcranial magnetic stimulation (TMS) during a fatiguing muscle contraction was evaluated in 5 patients with incomplete cervical SCI and in 5 healthy subjects. The physiological lengthening of CoSP end latency during fatigue was not observed in the SCI patients. This reduced intracortical inhibition, probably secondary to decreased activity of the GABAergic inhibitory interneurons that modulate the corticomotoneuronal output, could represent a 'positive' neuroplastic response in an attempt to compensate for the loss of corticospinal axons. The investigation of motor cortex excitability during fatiguing exercise may shed light on the role of exercise therapy in promoting brain reorganization and functional recovery in humans.
Nakamura, Masaya; Okano, Hideyuki
Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the induced pluripotent stem (iPS) cells and reprograming technologies in medical science. While iPS cells are expected to open a new era providing enormous opportunities in biomedical sciences in terms of cell therapies and regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this review, the pre-clinical investigations of cell therapy for spinal cord injury (SCI) using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo, are outlined. We also wish to discuss the strategy for the first human trails of iPS cell-based cell therapy for SCI patients.
Crowell, Andrew D.; King, Kevin; Deitermann, Annika; Miranpuri, Gurwattan S.; Resnick, Daniel K.
Neuropathic pain (NP) is common among spinal cord injury (SCI) patients, and there remain clinical difficulties in treating NP due to the lack of understanding of underlying mechanisms. Extracellular proteins, such as matrix metalloproteinase and β-catenin, have been shown to be activated in the spinal cord regions following an injury, and may play a key role in contributing to NP states. While these extracellular proteins have been used as therapeutic targets in the spinal cord, there has also been evidence of up-regulation in the hypothalamus following a SCI. We hypothesize that the hypothalamus is involved in regulating NP following a SCI, and hence should be researched further to determine if it is a viable target for future therapeutic treatments. PMID:27721586
pathophysiological basis of neurogenic detrusor overactivity with spinal cord injury (SCI). However, the... bladder distention after SCI. Using adult female rats with chronic spinal cord injury induced by Th4 spinal cord transection, we will investigate: (1...autonomic dysreflexia during bladder distention in rats with spinal cord injury . 111th Annual Meeting AUA, Abstract No. 34, San Diego, May 4-8, 2013.
Fang, Bo; Qin, Meiman; Li, Yun; Li, Xiaoqian; Tan, Wenfei; Zhang, Ying; Ma, Hong
Electroacupuncture (EA) has beneficial effects on spinal cord ischemia reperfusion (I/R) injury, but the underlying mechanisms are not fully understood. This study aimed to investigate the role of autophagy in the protection of EA preconditioning and postconditioning against spinal cord I/R injury. For this, spinal cord I/R injury was induced by 14min occlusion of the aortic arch, and rats were treated with EA for 20min before or after the surgery. The expression of autophagy components, light chain 3 and Beclin 1, was assessed by Western blot. The hind-limb motor function was assessed using the Basso-Beattie-Bresnahan (BBB) criteria, and motor neurons in the ventral gray matter were counted by histological examination. The apoptosis of neurocyte was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. The expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and matrix metalloproteinase-9 (MMP-9) was also measured using Western blot or enzyme-linked immunosorbent assay (ELISA). Either EA preconditioning or postconditioning enhanced autophagy, and minimized the neuromotor dysfunction and histopathological deficits after spinal cord I/R injury. In addition, EA suppressed I/R-induced apoptosis and increased in the expression of TNF-α, IL-1β, and MMP-9. In contrast, the autophagic inhibitor (3-methyladenine, 3-MA) inhibited the neuroprotective effects of EA. Moreover, 3-MA increased the apoptosis and the expression of TNF-α, IL-1β, and MMP-9. In summary, these findings suggested that EA preconditioning and postconditioning could alleviate spinal cord I/R injury, which was partly mediated by autophagy upregulation-induced inhibition of apoptosis and neuroinflammation.
... colleagues, with an educational grant from Pfizer Inc. University of Washington-operated SCI Clinics: Harborview Medical Center ... Spinal Cord Injury Clinic nurses: 206-744-5862 University of Washington Medical Center Rehabilitation Medicine Clinic 1959 ...
Kobayashi, Shigeru; Yoshizawa, Hidezo; Shimada, Seiichiro; Guerrero, Alexander Rodríguez; Miyachi, Masaya
It is generally considered that the genesis of myelopathy associated with the degenerative conditions of the spine may result from both mechanical compression and circulatory disturbance. Many references about spinal cord tissue ischemic damage can be found in the literature, but not detailed studies about spinal cord microvasculature damage related to congestion or blood permeability. This study investigates the effect of ischemia and congestion on the spinal cord using an in vivo model. The aorta was clamped as an ischemia model of the spinal cord and the inferior vena cava was clamped as a congestion model at the 6th costal level for 30 min using forceps transpleurally. Measurements of blood flow, partial oxygen pressure, and conduction velocity in the spinal cord were repeated over a period of 1 h after release of clamping. Finally, we examined the status of blood-spinal cord barrier under fluorescence and transmission electron microscope. Immediately after clamping of the inferior vena cava, the central venous pressure increased by about four times. Blood flow, oxygen tension and action potential were more severely affected by the aorta clamping; but this ischemic model did not show any changes of blood permeability in the spinal cord. The intramedullar edema was more easily produced by venous congestion than by arterial ischemia. In conclusions, venous congestion may be a preceding and essential factor of circulatory disturbance in the compressed spinal cord inducing myelopathy.
Wang, Zhen-Yu; Lin, Jian-Hua; Muharram, Akram; Liu, Wen-Ge
Apoptosis has been widely reported to be involved in the pathogenesis associated with spinal cord injury (SCI). Recently, autophagy has also been implicated in various neuronal damage models. However, the role of autophagy in SCI is still controversial and its interrelationship with apoptosis remains unclear. Here, we used an in vitro SCI model to observe a time-dependent induction of autophagy and apoptosis. Mechanical injury induced autophagy markers such as LC3 lipidation, LC3II/LC3I conversion, and Beclin-1 expression. Injured neurons showed decreased cell viability and increased apoptosis. To elucidate the effect of autophagy on apoptosis, the mechanically-injured neurons were treated with the mTOR inhibitor rapamycin and 3-methyl adenine (3-MA), which are known to regulate autophagy positively and negatively, respectively. Rapamycin-treated neurons showed the highest level of cell viability and lowest level of apoptosis among the injured neurons and those treated with 3-MA showed the reciprocal effect. Notably, rapamycin-treated neurons exhibited slightly reduced Bax expression and significantly increased Bcl-2 expression. Furthermore, by plasmid transfection, we showed that Beclin-1-overexpressing neuronal cells responded to mechanical injury with greater LC3II/LC3I conversion and cell viability, lower levels of apoptosis, higher Bcl-2 expression, and unaltered Bax expression as compared to vector control cells. Beclin-1-knockdown neurons showed almost the opposite effects. Taken together, our results suggest that autophagy may serve as a protection against apoptosis in mechanically-injured spinal cord neurons. Targeting mTOR and/or enhancing Beclin-1 expression might be alternative therapeutic strategies for SCI.
Cho, Yun Kyung; Kim, Gunha; Park, Serah; Sim, Ju Hee; Won, You Jin; Hwang, Chang Ho; Yoo, Jong Yoon; Hong, Hea Nam
Here, we sought to delineate the effect of EPO on the remyelination processes using an in vitro model of demyelination. We report that lysolecithin-induced demyelination elevated EPO receptor (EpoR) expression in oligodendrocyte progenitor cells (OPCs), facilitating the beneficial effect of EPO on the formation of oligodendrocytes (oligodendrogenesis). In the absence of EPO, the resultant remyelination was insufficient, possibly due to a limiting number of oligodendrocytes rather than their progenitors, which proliferate in response to lysolecithin-induced injury. By EPO treatment, lysolecithin-induced proliferation of OPCs was accelerated and the number of myelinating oligodendrocytes and myelin recovery was increased. EPO also enhanced the differentiation of neural progenitor cells expressing EpoR at high level toward the oligodendrocyte-lineage cells through activation of cyclin E and Janus kinase 2 pathways. Induction of myelin-forming oligodendrocytes by high dose of EPO implies that EPO might be the key factor influencing the final differentiation of OPCs. Taken together, our data suggest that EPO treatment could be an effective way to enhance remyelination by promoting oligodendrogenesis in association with elevated EpoR expression in spinal cord slice culture after lysolecithin-induced demyelination.
Peltier, J; Chenin, L; Hannequin, P; Page, C; Havet, É; Foulon, P; Le Gars, D
In this article, we respectively describe the morphology of the spinal cord, spinal meningeal layers, main fiber tracts, and both arterial and venous distribution in order to explain signs of spinal cord compression. We will then describe a surgical technique for spinal cord tumor removal.
in order to minimize scarring and injected dissociated adult DRGs rostral to a dorsal column transection of the spinal cord. From the sensory... columns were dissected and post-fixed overnight in 4% paraformaldehyde, and then spinal cords were dissected from spinal columns and cryoprotected...AD______________ Award Number: W81XWH-10-1-0941 TITLE: Spinal Cord Repair with Engineered Nervous Tissue
Gupta, Sanjeev K; Dua, Anita; Vohra, Bhupinder P S
Withania somnifera is classified in Ayurveda, the ancient Indian system of medicine, as a rasayana, a group of plant-derived drugs which promote physical and mental health, augment resistance of the body against disease and diverse adverse environmental factors, revitalize the body in debilitated conditions and increase longevity. We investigated the effects of Withania somnifera on copper-induced lipid peroxidation and antioxidant enzymes in aging spinal cord of Wistar rats. The activity of glutathione peroxidase (GPx) decreased significantly in the spinal cord from adult to aged mice. Treatment with Withania somnifera successfully attenuated GPx activity and inhibited lipid peroxidation in a dose dependent manner. Withania somnifera inhibited both the lipid peroxidation and protein oxidative modification induced by copper. These effects were similar to those of superoxide dismutase and mannitol. The results indicate the therapeutic potential of Withania somnifera in aging and copper-induced pathophysiological conditions.
Lazo-Gómez, Rafael; Tapia, Ricardo
Motor neuron (MN) degeneration is the pathological hallmark of MN diseases, a group of neurodegenerative disorders clinically manifested as muscle fasciculations and hyperreflexia, followed by paralysis, respiratory failure, and death. Ample evidence supports a role of glutamate-mediated excitotoxicity in motor death. In previous work we showed that stimulation of glutamate release from nerve endings by perfusion of the K+-channel blocker 4-aminopyridine (4-AP) in the rat hippocampus induces seizures and neurodegeneration, and that AMPA infusion in the spinal cord produces paralysis and MN death. On these bases, in this work we have tested the effect of the chronic infusion of 4-AP in the spinal cord, using implanted osmotic minipumps, on motor activity and on MN survival, and the mechanisms underlying this effect. 4-AP produced muscle fasciculations and motor deficits assessed in two motor tests, which start 2–3 h after the implant, which ameliorated spontaneously within 6–7 days, but no neurodegeneration. These effects were prevented by both AMPA and NMDA receptors blockers. The role of GABAA receptors was also explored, and we found that chronic infusion of bicuculline induced moderate MN degeneration and enhanced the hyperexcitation produced by 4-AP. Unexpectedly, the GABAAR agonist muscimol also induced motor deficits and failed to prevent the MN death induced by AMPA. We conclude that motor alterations induced by chronic 4-AP infusion in the spinal cord in vivo is due to ionotropic glutamate receptor overactivation and that blockade of GABAergic neurotransmission induces MN death under chronic conditions. These results shed light on the role of glutamatergic and GABAergic neurotransmission in the regulation of MN excitability in the spinal cord. PMID:27242406
Gwak, Young S; Kim, Hee Young; Lee, Bong Hyo; Yang, Chae Ha
The adequate treatment of spinal cord injury (SCI)-induced neuropathic pain still remains an unresolved problem. The current medications predominantly used in the SCI-induced neuropathic pain therapy are morphine, anticonvulsants, antidepressants, and antiepileptics, which suggests that psychiatric aspects might be important factors in the treatment of neuropathic pain. It is well documented that the modulation of the sensory events is not a unique way for achieving pain relief. In addition, pain patients still express dissatisfaction and complain of unwanted effects of the medications, suggesting that alternative approaches for the treatment of neuropathic pain are essential. In psychiatry, pain relief represents relaxation and a feeling of comfort and satisfaction, which suggests that cognitive and emotional motivations are important factors in the treatment of neuropathic pain. The comorbidity of chronic pain and psychiatric disorders, which is well recognized, suggests that the effective therapeutic relief for neuropathic pain induced by SCI can be achieved in conjunction with the management of the sensory and psychiatric aspects of patient. In this review, we address the feasibility of a combined acupuncture and pharmacotherapy treatment for the relief of neuropathic pain behavior following SCI.
Lewis, Christine M; Rose, James D
Courtship clasping, a reproductive behavior in male roughskin newts (Taricha granulosa), is rapidly blocked by an action of corticosterone (CORT) at a specific neuronal membrane receptor. The CORT-induced impairment of clasping in behaving newts appears to be mediated partly by an elimination of clasping-related activity in medullary reticulospinal neurons. Previous studies of rapid CORT actions in Taricha have focused on the brain, so existence of CORT action in the spinal cord or peripheral nervous system has not been assessed. The present study used newts with a high cervical spinal transection to examine potential spinal or peripheral CORT effects on clasping by the hindlimbs in response to pressure on the cloaca. Spinal transection causes clasps elicited by cloacal stimulation to be very sustained beyond the termination of the eliciting stimulus. In spinally transected newts, CORT caused a dose-dependent depression in the duration as well as quality of the clasp that appeared within 10 min of injection. CORT selectively impaired the usual sustained maintenance of a clasp after termination of cloacal stimulation, but not clasp elicitation during stimulation. These effects were not produced by dexamethasone, a synthetic glucocorticoid that binds poorly to the CORT membrane receptor. The CORT effect on clasp maintenance but not clasp elicitation implies selective action on an intraspinal generator for clasping but not on sensory or efferent neuromuscular aspects of the response. These results indicate the presence in the newt spinal cord of the CORT membrane receptor that exerts functional effects distinctly different from those on the brainstem.
Miranpuri, Gurwattan S.; Schomberg, Dominic T.; Alrfaei, Bahauddeen; King, Kevin C.; Rynearson, Bryan; Wesley, Vishwas S.; Khan, Nayab; Obiakor, Kristen; Wesley, Umadevi V.; Resnick, Daniel K.
Neuropathic pain (NP) affects approximately 4 million people in the United States with spinal cord injury (SCI) being a common cause. Matrix metalloproteinases (MMPs) play an integral role in mediating inflammatory responses, cellular signaling, cell migration, extracellular matrix degradation and tissue remodeling and repair. As such, they are major components in the pathogenesis of secondary injury within the central nervous system. Other gene regulatory pathways, specifically MAPK/extracellular signaling-regulated kinase (ERK) and Wnt/β-catenin, are also believed to participate in secondary injury likely intersect. The study aims to examine the MMP-2 signaling pathway associated with ERK and Wnt/β-catenin activity during contusion SCI (cSCI)-induced NP in a rat model. This is an experimental study investigating the implication of MMP-2 in SCI-induced NP and its association with the cellular and molecular changes in the interactions between extracellular signaling kinase and β-catenin. Adult Sprague-Dawley rats received cSCI injury by NYU impactor by dropping 10 g weight from a height of 12.5 mm. Locomotor functional recovery of injured rats was measured on post cSCI day 1, and weekly thereafter for 6 weeks using Basso, Beattie and Bresnahan scores. Thermal hyperalgesia (TH) testing was performed on days 21, 28, 35 and 42 post cSCI. The expression and/or activity of MMP-2, β-catenin and ERK were studied following harvest of spinal cord tissues between 3 and 6 weeks post cSCI. All experiments were funded by the department of Neurological Surgery at the University of Wisconsin, School of Medicine and Public Health having no conflict of interest. MMP-2 and β-catenin expression were elevated and gradually increased from days 21 to 42 compared to sham-operated rats and injured rats that did not exhibit TH. The expression of phosphorylated ERK (phospho-ERK) increased on day 21 but returned to baseline levels on day 42 whereas total ERK levels remained relatively
Jongen, Joost L. M.; Smits, Helwin; Pederzani, Tiziana; Bechakra, Malik; Hossaini, Mehdi; Koekkoek, Sebastiaan K.; Huygen, Frank J. P. M.; De Zeeuw, Chris I.; Holstege, Jan C.; Joosten, Elbert A. J.
Nerve injury may cause neuropathic pain, which involves hyperexcitability of spinal dorsal horn neurons. The mechanisms of action of spinal cord stimulation (SCS), an established treatment for intractable neuropathic pain, are only partially understood. We used Autofluorescent Flavoprotein Imaging (AFI) to study changes in spinal dorsal horn metabolic activity. In the Seltzer model of nerve-injury induced pain, hypersensitivity was confirmed using the von Frey and hotplate test. 14 Days after nerve-injury, rats were anesthetized, a bipolar electrode was placed around the affected sciatic nerve and the spinal cord was exposed by a laminectomy at T13. AFI recordings were obtained in neuropathic rats and a control group of naïve rats following 10 seconds of electrical stimulation of the sciatic nerve at C-fiber strength, or following non-noxious palpation. Neuropathic rats were then treated with 30 minutes of SCS or sham stimulation and AFI recordings were obtained for up to 60 minutes after cessation of SCS/sham. Although AFI responses to noxious electrical stimulation were similar in neuropathic and naïve rats, only neuropathic rats demonstrated an AFI-response to palpation. Secondly, an immediate, short-lasting, but strong reduction in AFI intensity and area of excitation occurred following SCS, but not following sham stimulation. Our data confirm that AFI can be used to directly visualize changes in spinal metabolic activity following nerve injury and they imply that SCS acts through rapid modulation of nociceptive processing at the spinal level. PMID:25279562
AWARD NUMBER: W81XWH-12-1-0587 TITLE: Directing Spinal Cord Plasticity: The Impact of Stretch ...Directing Spinal Cord Plasticity: The Impact of Stretch Therapy on Functional Recovery after Spinal Cord Injury. 5b. GRANT NUMBER W81XWH-12-1...ABSTRACT Essentially all spinal cord injured patients receive stretching therapies beginning within the first few weeks post-injury. Despite
... spinal cord injury? Where is the nearest SCI Model System of Care? Emergency Medical Services Hospital (Acute) Care Rehabilitation More ... spinal cord injury? Where is the nearest SCI Model System of Care? Follow Us! Get Email Updates Questions & Comments Suggest ...
Leonard, Anna V; Vink, Robert
The blood spinal cord barrier (BSCB) is disrupted following spinal cord injury (SCI) resulting in vasogenic edema and increased intrathecal pressure (ITP). The neuropeptide substance P (SP) has been implicated in the development of blood-brain barrier (BBB) disruption, edema, and increased intracranial pressure following brain injury, although it has not been investigated in SCI. The balloon compression model of experimental SCI has many advantages in that it replicates the "closed" environment observed clinically. Accordingly, this study characterized whether this model produces an increase in BSCB permeability and edema, and whether a SP, NK1 tachykinin receptor antagonist, N-acetyl-L-tryptophan (NAT) reduces such BSCB disruption and edema formation. At 30 min post-injury, animals were administered 2.5 mg/kg NAT or saline. Subgroups of animals were assessed for BSCB permeability (Evan's Blue) and spinal cord edema (wet weight/dry weight). BSCB permeability and edema were significantly increased in injured groups compared with sham (p < 0.001). There was no significant difference between vehicle and NAT treatment. We conclude that the balloon compression model of SCI produces significant BSCB disruption although NAT treatment did not attenuate BSCB permeability or edema. Further studies are required to fully elucidate the role of SP following SCI.
... diseases Autoimmune diseases Degenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy Symptoms vary but might include pain, numbness, loss of sensation and muscle weakness. These symptoms can occur around the spinal ...
Xu, Mei; Petraschka, Michael; McLaughlin, Jay P.; Westenbroek, Ruth E.; Caron, Marc G.; Lefkowitz, Robert J.; Czyzyk, Traci A.; Pintar, John E.; Terman, Gregory W.; Chavkin, Charles
Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [κ opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4 –L5 spinal dorsal horn of wild-type C57BL/6 mice (7–21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the κ agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance. PMID:15140929
Piazza, Matthew; Schuster, James
Although timing for surgical intervention after spinal cord injury remains controversial, there is accumulating evidence suggesting that early surgery may improve neurologic outcomes, particularly with incomplete spinal cord injury, and may reduce non-neurologic complications and health care resource utilization. Moreover, even in patients with complete spinal cord injury, minor improvement in neurologic function can lead to significant changes in quality of life. This article reviews the experimental and clinical data examining surgical timing after spinal cord injury.
Vaziri, N. D.; Purdy, R. E. (Principal Investigator)
Prolonged exposure to microgravity results in cardiovascular deconditioning which is marked by orthostatic intolerance in the returning astronauts and recovering bed-ridden patients. Recent studies conducted in our laboratories at University of California, Irvine have revealed marked elevation of nitric oxide (NO) production in the kidney, heart, brain, and systemic arteries coupled with significant reduction of NO production in the cerebral arteries of microgravity-adapted animals. We have further demonstrated that the observed alteration of NO metabolism is primarily responsible for the associated cardiovascular deconditioning. Recovery from acute spinal cord injury (SCI) is frequently complicated by orthostatic intolerance that is due to the combined effects of the disruption of efferent sympathetic pathway and cardiovascular deconditioning occasioned by prolonged confinement to bed. In this presentation, I will review the nature of altered NO metabolism and its role in the pathogenesis of microgravity-induced cardiovascular deconditioning. The possible relevance of the new findings to orthostatic intolerance in patients with acute SCI and its potential therapeutic implications will be discussed.
Oklinski, Michal K.; Skowronski, Mariusz T.; Skowronska, Agnieszka; Rützler, Michael; Nørgaard, Kirsten; Nieland, John D.; Kwon, Tae-Hwan; Nielsen, Søren
Aquaporins (AQPs) are water channel proteins robustly expressed in the central nervous system (CNS). A number of previous studies described the cellular expression sites and investigated their major roles and function in the brain and spinal cord. Among thirteen different mammalian AQPs, AQP1 and AQP4 have been mainly studied in the CNS and evidence has been presented that they play important roles in the pathogenesis of CNS injury, edema and multiple diseases such as multiple sclerosis, neuromyelitis optica spectrum disorders, amyotrophic lateral sclerosis, glioblastoma multiforme, Alzheimer’s disease and Parkinson’s disease. The objective of this review is to highlight the current knowledge about AQPs in the spinal cord and their proposed roles in pathophysiology and pathogenesis related to spinal cord lesions and injury. PMID:27941618
Background/Objective: In the course of examining spinal motor function in many hundreds of people with traumatic spinal cord injury, we encountered 6 individuals who developed involuntary and rhythmic contractions in muscles of their legs. Although there are many reports of unusual muscle activation patterns associated with different forms of myoclonus, we believe that certain aspects of the patterns seen with these 6 subjects have not been previously reported. These patterns share many features with those associated with a spinal central pattern generator for walking. Methods: Subjects in this case series had a history of chronic injury to the cervical spinal cord, resulting in either complete (ASIA A; n = 4) or incomplete (ASIA D; n = 2) quadriplegia. We used multi-channel electromyography recordings of trunk and leg muscles of each subject to document muscle activation patterns associated with different postures and as influenced by a variety of sensory stimuli. Results: Involuntary contractions spanned multiple leg muscles bilaterally, sometimes including weak abdominal contractions. Contractions were smooth and graded and were highly reproducible in rate for a given subject (contraction rates were 0.3–0.5 Hz). These movements did not resemble the brief rapid contractions (ie, "jerks") ascribed to some forms of spinal myoclonus. For all subjects, the onset of involuntary muscle contraction was dependent upon hip angle; contractions did not occur unless the hips (and knees) were extended (ie, subjects were supine). In the 4 ASIA A subjects, contractions occurred simultaneously in all muscles (agonists and antagonists) bilaterally. In sharp contrast, contractions in the 2 ASIA D subjects were reciprocal between agonists and antagonists within a limb and alternated between limbs, such that movements in these 2 subjects looked just like repetitive stepping. Finally, each of the 6 subjects had a distinct pathology of their spinal cord, nerve roots, distal trunk
... Search Search En Español Category Cancer A-Z Brain and Spinal Cord Tumors in Adults If you have a brain or spinal cord tumor or are close to ... cope. Here you can find out all about brain and spinal cord tumors in adults, including risk ...
Zhang, Ning; Fang, Marong; Chen, Haohao; Gou, Fangming; Ding, Mingxing
Because there is no curative treatment for spinal cord injury, establishing an ideal animal model is important to identify injury mechanisms and develop therapies for individuals suffering from spinal cord injuries. In this article, we systematically review and analyze various kinds of animal models of spinal cord injury and assess their advantages and disadvantages for further studies. PMID:25598784
Mrozkova, Petra; Spicarova, Diana; Palecek, Jiri
Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) receptors in the peripheral nerve endings are implicated in the development of increased sensitivity to mechanical and thermal stimuli, especially during inflammatory states. Both PAR2 and TRPV1 receptors are co-expressed in nociceptive dorsal root ganglion (DRG) neurons on their peripheral endings and also on presynaptic endings in the spinal cord dorsal horn. However, the modulation of nociceptive synaptic transmission in the superficial dorsal horn after activation of PAR2 and their functional coupling with TRPV1 is not clear. To investigate the role of spinal PAR2 activation on nociceptive modulation, intrathecal drug application was used in behavioural experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) were performed on superficial dorsal horn neurons in acute rat spinal cord slices. Intrathecal application of PAR2 activating peptide SLIGKV-NH2 induced thermal hyperalgesia, which was prevented by pretreatment with TRPV1 antagonist SB 366791 and was reduced by protein kinases inhibitor staurosporine. Patch-clamp experiments revealed robust decrease of mEPSC frequency (62.8 ± 4.9%), increase of sEPSC frequency (127.0 ± 5.9%) and eEPSC amplitude (126.9 ± 12.0%) in dorsal horn neurons after acute SLIGKV-NH2 application. All these EPSC changes, induced by PAR2 activation, were prevented by SB 366791 and staurosporine pretreatment. Our results demonstrate an important role of spinal PAR2 receptors in modulation of nociceptive transmission in the spinal cord dorsal horn at least partially mediated by activation of presynaptic TRPV1 receptors. The functional coupling between the PAR2 and TRPV1 receptors on the central branches of DRG neurons may be important especially during different pathological states when it may enhance pain perception. PMID:27755539
Menon, Preeti Kumaran; Muresanu, Dafin Fior; Sharma, Aruna; Mössler, Herbert; Sharma, Hari Shanker
Spinal cord injury (SCI) is the world's most disastrous disease for which there is no effective treatment till today. Several studies suggest that nanoparticles could adversely influence the pathology of SCI and thereby alter the efficacy of many neuroprotective agents. Thus, there is an urgent need to find suitable therapeutic agents that could minimize cord pathology following trauma upon nanoparticle intoxication. Our laboratory has been engaged for the last 7 years in finding suitable therapeutic strategies that could equally reduce cord pathology in normal and in nanoparticle-treated animal models of SCI. We observed that engineered nanoparticles from metals e.g., aluminum (Al), silver (Ag) and copper (Cu) (50-60 nm) when administered in rats daily for 7 days (50 mg/kg, i.p.) resulted in exacerbation of cord pathology after trauma that correlated well with breakdown of the blood-spinal cord barrier (BSCB) to serum proteins. The entry of plasma proteins into the cord leads to edema formation and neuronal damage. Thus, future drugs should be designed in such a way to be effective even when the SCI is influenced by nanoparticles. Previous research suggests that a suitable combination of neurotrophic factors could induce marked neuroprotection in SCI in normal animals. Thus, we examined the effects of a new drug; cerebrolysin that is a mixture of different neurotrophic factors e.g., brain-derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and other peptide fragments to treat normal or nanoparticle-treated rats after SCI. Our observations showed that cerebrolysin (2.5 ml/kg, i.v.) before SCI resulted in good neuroprotection in normal animals, whereas nanoparticle-treated rats required a higher dose of the drug (5.0 ml/kg, i.v.) to induce comparable neuroprotection in the cord after SCI. Cerebrolysin also reduced spinal cord water content, leakage of plasma proteins
Abrams, Gary M.; Ganguly, Karunesh
Purpose of Review: Both acute and chronic spinal cord disorders present multisystem management problems to the clinician. This article highlights key issues associated with chronic spinal cord dysfunction. Recent Findings: Advances in symptomatic management for chronic spinal cord dysfunction include use of botulinum toxin to manage detrusor hyperreflexia, pregabalin for management of neuropathic pain, and intensive locomotor training for improved walking ability in incomplete spinal cord injuries. Summary: The care of spinal cord dysfunction has advanced significantly over the past 2 decades. Management and treatment of neurologic and non-neurologic complications of chronic myelopathies ensure that each patient will be able to maximize their functional independence and quality of life. PMID:25651225
Lagraize, S. C.; Guo, W.; Yang, K.; Wei, F.; Ren, K.; Dubner, R.
Hyperalgesia in animal injury models is linked to activation of descending raphespinal modulatory circuits originating in the rostral ventromedial medulla (RVM). A neurokinin-1 (NK-1) receptor antagonist microinjected into the RVM before or after inflammation produced by complete Freund’s adjuvant (CFA) resulted in an attenuation of thermal hyperalgesia. A transient (acute) or a continuous infusion of Substance P (SP) microinjected into the RVM of non-inflamed animals led to similar pain hypersensitivity. Intrathecal pretreatment or post-treatment of a 5-HT3 receptor antagonist (Y-25130 or ondansetron) blocked the SP-induced hyperalgesia. The SP-induced hyperalgesia was both GABAA and NMDA receptor-dependent after pre- and post-treatment with selective antagonists at the spinal level. A microinjection of SP into the RVM also led to increased NMDA NR1 receptor subunit phosphorylation in spinal cord tissue. The GABAA receptor-mediated hyperalgesia involved a shift in the anionic gradient in dorsal horn nociceptive neurons and an increase in phosphorylated NKCC1 protein (isoform of the Na-K-Cl cotransporter). Following a low dose of SP infused into the RVM, intrathecal muscimol (GABAA agonist) increased SP-induced thermal hyperalgesia, phosphorylated NKCC1 protein expression, and NMDA NR1 subunit phosphorylation in the spinal cord. The thermal hyperalgesia was blocked by intrathecal gabazine, the GABAA receptor antagonist, and MK-801, the NMDA receptor channel blocker. These findings indicate that NK-1 receptors in the RVM are involved in SP-induced thermal hyperalgesia, this hyperalgesia is 5-HT3-receptor dependent at the spinal level, and involves the functional interaction of spinal GABAA and NMDA receptors. PMID:20888891
Ullrich, Philip M
Pain is one of the most common, severe, and treatment-resistant complications that follows SCI. Recent years have seen a surge of research on methods for assessing and treating spinal cord injury pain. In this article, pain after SCI is reviewed in terms of nature, scope, assessment techniques, and treatment strategies.
Shulman, Stanford T.; Madden, John D.; Esterly, John R.; Shanklin, Douglas R.
A newborn infant, delivered following mid-forceps rotation, presented with apnoea, anaesthesia below the level of the mid-neck, and flaccid quadriplegia. At necropsy there was transection of the cord, and atlanto-occipital and atlantoaxial dislocations. Cord injury usually follows breech presentation, the lesion is in the lower cervical or upper thoracic segments, and results from excessive traction. By contrast, in the rare cases following cephalic delivery, the lesion is most often in the upper cervical cord and probably results from rotational forces. PMID:5104538
Chen, Gang; Park, Chul-Kyu; Xie, Rou-Gang; Berta, Temugin; Nedergaard, Maiken
Accumulating evidence suggests that spinal cord astrocytes play an important role in neuropathic pain sensitization by releasing astrocytic mediators (e.g. cytokines, chemokines and growth factors). However, it remains unclear how astrocytes control the release of astrocytic mediators and sustain late-phase neuropathic pain. Astrocytic connexin-43 (now known as GJ1) has been implicated in gap junction and hemichannel communication of cytosolic contents through the glial syncytia and to the extracellular space, respectively. Connexin-43 also plays an essential role in facilitating the development of neuropathic pain, yet the mechanism for this contribution remains unknown. In this study, we investigated whether nerve injury could upregulate connexin-43 to sustain late-phase neuropathic pain by releasing chemokine from spinal astrocytes. Chronic constriction injury elicited a persistent upregulation of connexin-43 in spinal astrocytes for >3 weeks. Spinal (intrathecal) injection of carbenoxolone (a non-selective hemichannel blocker) and selective connexin-43 blockers (connexin-43 mimetic peptides 43Gap26 and 37,43Gap27), as well as astroglial toxin but not microglial inhibitors, given 3 weeks after nerve injury, effectively reduced mechanical allodynia, a cardinal feature of late-phase neuropathic pain. In cultured astrocytes, TNF-α elicited marked release of the chemokine CXCL1, and the release was blocked by carbenoxolone, Gap26/Gap27, and connexin-43 small interfering RNA. TNF-α also increased connexin-43 expression and hemichannel activity, but not gap junction communication in astrocyte cultures prepared from cortices and spinal cords. Spinal injection of TNF-α-activated astrocytes was sufficient to induce persistent mechanical allodynia, and this allodynia was suppressed by CXCL1 neutralization, CXCL1 receptor (CXCR2) antagonist, and pretreatment of astrocytes with connexin-43 small interfering RNA. Furthermore, nerve injury persistently increased excitatory
Neutel, Dulce; Teodoro, Tiago; Coelho, Miguel; Pimentel, José; Albuquerque, Luísa
Introduction Differential diagnosis of acute/subacute intrinsic spinal cord lesions can be challenging. In addition, intramedullary neoplasms typically show gadolinium enhancement, mass effect, and cord expansion. Case report We report a patient with spinal cord and brain stem lesions resembling multifocal myelitis. Magnetic resonance imaging showed no spinal cord enlargement or gadolinium enhancing. Treatment of myelitis was undertaken without stopping the progression of the disease. Biopsy was made and led to a histological diagnosis of astrocytoma. Discussion Astrocytoma must remain as a possible diagnosis of spinal cord lesions, even without typical characteristics of neoplasms. Furthermore, biopsy should always be considered when diagnosis is uncertain. PMID:24621037
Ibarra, Antonio; Martiñón, Susana
Spinal cord (SC) injury causes serious neurological alterations that importantly disturb the physical, emotional and economical stability of affected individuals. Damage to the neural tissue is primarily caused by the lesion itself and secondarily by a multitude of destructive mechanisms that develop afterwards. Unfortunately, the restoring capacity of the central nervous system is very limited because of reduced intrinsic growth capacity and non-permissive environment for axonal elongation. The regenerative processes are blocked by diverse factors such as growth inhibitory proteins and the glial scar formed in the site of lesion. In spite of these problems, central neurons regenerate if a permissive environment is provided. In line with this thought, some pharmacological compounds have been tested to achieve neuroregeneration. The main objective of this manuscript is to provide the state-of-art of chemotherapeutic treatments for spinal cord regeneration after injury in the field. The efficacy and usefulness of different therapeutic strategies will be reviewed, including Rho-ROCK inhibitors, cyclic AMP-enhancers, glial scar inhibitors and immunophilin ligands. Aside from this, the use of hydrogels alone or in combination with drugs, growth factors or stem cells will also be revised.
Cook, Daniel W.
Reviewing literature on the psychological impact of spinal cord injury suggests: (a) depression may not be a precondition for injury adjustment; (b) many persons sustaining cord injury may have experienced psychological disruption prior to injury; and (c) indexes of rehabilitation success need to be developed for the spinal cord injured. (Author)
Sun, Peng; Murphy, Rory K. J.; Gamble, Paul; George, Ajit; Song, Sheng-Kwei; Ray, Wilson Z.
Promising treatments are being developed to promote functional recovery after spinal cord injury (SCI). Magnetic resonance imaging, specifically Diffusion Tensor Imaging (DTI) has been shown to non-invasively measure both axonal and myelin integrity following traumatic brain and SCI. A novel data-driven model-selection algorithm known as Diffusion Basis Spectrum Imaging (DBSI) has been proposed to more accurately delineate white matter injury. The objective of this study was to investigate whether DTI/DBSI changes that extend to level of the cerebral peduncle and internal capsule following a SCI could be correlated with clinical function. A prospective non-randomized cohort of 23 patients with chronic spinal cord injuries and 17 control subjects underwent cranial diffusion weighted imaging, followed by whole brain DTI and DBSI computations. Region-based analyses were performed on cerebral peduncle and internal capsule. Three subgroups of patients were included in the region-based analysis. Tract-Based Spatial Statistics (TBSS) was also applied to allow whole-brain white matter analysis between controls and all patients. Functional assessments were made using International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) as modified by the American Spinal Injury Association (ASIA) Scale. Whole brain white matter analysis using TBSS finds no statistical difference between controls and all patients. Only cervical ASIA A/B patients in cerebral peduncle showed differences from controls in DTI and DBSI results with region-based analysis. Cervical ASIA A/B SCI patients had higher levels of axonal injury and edema/tissue loss as measured by DBSI at the level of the cerebral peduncle. DTI Fractional Anisotropy (FA), Axial Diffusivity (AD) and Radial Diffusivity (RD) was able to detect differences in cervical ASIA A/B patients, but were non-specific to pathologies. Increased water fraction indicated by DBSI non-restricted isotropic diffusion fraction
Borghi, Sergio M; Fattori, Victor; Ruiz-Miyazawa, Kenji W; Miranda-Sapla, Milena M; Casagrande, Rúbia; Pinge-Filho, Phileno; Pavanelli, Wander R; Verri, Waldiceu A
Cutaneous leishmaniasis (CL) is the most common form of the leishmaniasis in humans. Ulcerative painless skin lesions are predominant clinical features of CL. Wider data indicate pain accompanies human leishmaniasis, out with areas of painless ulcerative lesions per se. In rodents, Leishmania (L.) major infection induces nociceptive behaviors that correlate with peripheral cytokine levels. However, the role of the spinal cord in pain processing after Leishmania infection has not been investigated. Balb/c mice received intraplantar (i.pl.) injection of Leishmania (L). amazonensis and hyperalgesia, edema, parasitism, and spinal cord TNFα, TNFR1 and TNFR2 mRNA expression, and NFκB activation were evaluated. The effects of intrathecal (i.t.) injection of morphine, TNFα, TNFα inhibitors (etanercept and adalimumab) and NFκB inhibitor (PDTC) were investigated. The present study demonstrates that Leishmania (L.) amazonensis infection in balb/c mice induces chronic mechanical and thermal hyperalgesia in an opioid-sensitive manner. Spinal cord TNFα mRNA expression increased in a time-dependent manner, peaking between 30 and 40 days after infection. At the peak of TNFα mRNA expression (day 30), there was a concomitant increase in TNFR1 and TNFR2 mRNA expression. TNFα i.t. injection enhanced L. (L.) amazonensis-induced hyperalgesia. Corroborating a role for TNFα in L. (L.) amazonensis-induced hyperalgesia, i.t. treatment with the TNFα inhibitors, etanercept and adalimumab inhibited the hyperalgesia. L. (L.) amazonensis also induced spinal cord activation of NFκB, and PDTC (given i.t.), also inhibited L. (L.) amazonensis-induced hyperalgesia, and spinal cord TNFα, TNFR1 and TNFR2 mRNA expression. Moreover, L. (L.) amazonensis-induced spinal cord activation of NFκB was also inhibited by etanercept and adalimumab as well as PDTC i.t.
Uehara, Masato; Hosaka, Yoshinao Z; Doi, Hiroyuki; Sakai, Harumi
In teleosts, the spinal cord generally extends along the entire vertebral canal. The Tetraodontiformes, in which the spinal cord is greatly reduced in length with a distinct long filum terminale and cauda equina, have been regarded as an aberration. The aims of this study are: 1) to elucidate whether the spinal cord in all tetraodontiform fishes shorten with the filum terminale, and 2) to describe the gross anatomical and histological differences in the spinal cord among all families of the Tetraodontiformes. Representative species from all families of the Tetraodontiformes, and for comparison the carp as a common teleost, were investigated. In the Triacanthodidae, Triacanthidae, and Triodontidae, which are the more ancestral taxa of the Tetraodontiformes, the spinal cord extends through the entire vertebral canal. In the Triacanthidae and Triodontidae, the caudal half or more spinal segments of the spinal cord, however, lack gray matter and consist largely of nerve fibers. In the other tetraodontiform families, the spinal cord is shortened forming a filum terminale with the cauda equina, which is prolonged as far as the last vertebra. The shortened spinal cord is divided into three groups. In the Ostraciidae and Molidae, the spinal cord tapers abruptly at the cranium or first vertebra forming a cord-like filum terminale. In the Monacanthidae, Tetraodontidae, and Diodontidae, it abruptly flattens at the rostral vertebrae forming a flat filum terminale. The spinal cord is relatively longer in the Monacanthidae than that in the other two families. It is suggested by histological features of the flat filum terminale that shortening of the spinal cord in this group progresses in order of the Monacanthidae, Tetraodontidae, and Diodontidae. In the Balistidae and Aracanidae, the cord is relatively long and then gradually decreased in dorso-ventral thickness.
Cristante, Alexandre Fogaça; de Barros Filho, Tarcísio Eloy Pessoa; Marcon, Raphael Martus; Letaif, Olavo Biraghi; da Rocha, Ivan Dias
This study reviews the literature concerning possible therapeutic approaches for spinal cord injury. Spinal cord injury is a disabling and irreversible condition that has high economic and social costs. There are both primary and secondary mechanisms of damage to the spinal cord. The primary lesion is the mechanical injury itself. The secondary lesion results from one or more biochemical and cellular processes that are triggered by the primary lesion. The frustration of health professionals in treating a severe spinal cord injury was described in 1700 BC in an Egyptian surgical papyrus that was translated by Edwin Smith; the papyrus reported spinal fractures as a “disease that should not be treated.” Over the last two decades, several studies have been performed to obtain more effective treatments for spinal cord injury. Most of these studies approach a patient with acute spinal cord injury in one of four manners: corrective surgery or a physical, biological or pharmacological treatment method. Science is unraveling the mechanisms of cell protection and neuroregeneration, but clinically, we only provide supportive care for patients with spinal cord injuries. By combining these treatments, researchers attempt to enhance the functional recovery of patients with spinal cord injuries. Advances in the last decade have allowed us to encourage the development of experimental studies in the field of spinal cord regeneration. The combination of several therapeutic strategies should, at minimum, allow for partial functional recoveries for these patients, which could improve their quality of life. PMID:23070351
funded grant, we demonstrated proof-of-concept success of bridging a lateral hemisection of the rat spinal cord with engineered (“stretch-grown...AD_________________ Award Number: W81XWH-10-1-0941 TITLE: Spinal Cord Repair with Engineered...5a. CONTRACT NUMBER Spinal Cord Repair with Engineered Nervous Tissue 5b. GRANT NUMBER W81XWH-10-1-0941 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR
success of bridging a lateral hemisection in the rat spinal cord with engineered (“stretch-grown”) living nervous tissue constructs 2 . For the current...AD_________________ Award Number: W81XWH-10-1-0941 TITLE: Spinal Cord Repair with Engineered...SUBTITLE Spinal Cord Repair with Engineered Nervous Tissue 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-10-1-0941 5c. PROGRAM ELEMENT NUMBER 6
... Diagnosis, and Staging Survival Rates for Selected Childhood Brain and Spinal Cord Tumors Survival rates are often ... Childhood Brain and Spinal Cord Tumors More In Brain and Spinal Cord Tumors in Children About Brain ...
Spinal Cord Injury; Spinal Cord Injuries; Trauma, Nervous System; Wounds and Injuries; Central Nervous System Diseases; Nervous System Diseases; Spinal Cord Diseases; Gonadal Disorders; Endocrine System Diseases; Hypogonadism; Genital Diseases, Male
Decimo, Ilaria; Bifari, Francesco; Rodriguez, Francisco Javier; Malpeli, Giorgio; Dolci, Sissi; Lavarini, Valentina; Pretto, Silvia; Vasquez, Sandra; Sciancalepore, Marina; Montalbano, Alberto; Berton, Valeria; Krampera, Mauro; Fumagalli, Guido
Adult spinal cord has little regenerative potential, thus limiting patient recovery following injury. In this study, we describe a new population of cells resident in the adult rat spinal cord meninges that express the neural stem/precursor markers nestin and doublecortin. Furthermore, from dissociated meningeal tissue a neural stem cell population was cultured in vitro and subsequently shown to differentiate into functional neurons or mature oligodendrocytes. Proliferation rate and number of nestin- and doublecortin-positive cells increased in vivo in meninges following spinal cord injury. By using a lentivirus-labeling approach, we show that meningeal cells, including nestin- and doublecortin-positive cells, migrate in the spinal cord parenchyma and contribute to the glial scar formation. Our data emphasize the multiple roles of meninges in the reaction of the parenchyma to trauma and indicate for the first time that spinal cord meninges are potential niches harboring stem/precursor cells that can be activated by injury. Meninges may be considered as a new source of adult stem/precursor cells to be further tested for use in regenerative medicine applied to neurological disorders, including repair from spinal cord injury.
Gwak, Young S.; Hulsebosch, Claire E.
Spinal cord injury induces maladaptive synaptic transmission in the somatosensory system that results in chronic central neuropathic pain. Recent literature suggests that glial-neuronal interactions are important modulators in synaptic transmission following spinal cord injury. Neuronal hyperexcitability is one of the predominant phenomenon caused by maladaptive synaptic transmission via altered glial-neuronal interactions after spinal cord injury. In the somatosensory system, spinal inhibitory neurons counter balance the enhanced synaptic transmission from peripheral input. For a decade, the literature suggests that hypofunction of GABAergic inhibitory tone is an important factor in the enhanced synaptic transmission that often results in neuronal hyperexcitability in dorsal horn neurons following spinal cord injury. Neurons and glial cells synergistically control intracellular chloride ion gradients via modulation of chloride transporters, extracellular glutamate and GABA concentrations via uptake mechanisms. Thus, the intracellular “GABA-glutamate-glutamine cycle” is maintained for normal physiological homeostasis. However, hyperexcitable neurons and glial activation after spinal cord injury disrupts the balance of chloride ions, glutamate and GABA distribution in the spinal dorsal horn and results in chronic neuropathic pain. In this review, we address spinal cord injury induced mechanisms in hypofunction of GABAergic tone that results in chronic central neuropathic pain. PMID:21216257
Butler, Jane E; Godfrey, Sharlene; Thomas, Christine K
Whether interlimb reflexes emerge only after a severe insult to the human spinal cord is controversial. Here the aim was to examine interlimb reflexes at rest in participants with chronic (>1 year) spinal cord injury (SCI, n = 17) and able-bodied control participants (n = 5). Cutaneous reflexes were evoked by delivering up to 30 trains of stimuli to either the superficial peroneal nerve on the dorsum of the foot or the radial nerve at the wrist (5 pulses, 300 Hz, approximately every 30 s). Participants were instructed to relax the test muscles prior to the delivery of the stimuli. Electromyographic activity was recorded bilaterally in proximal and distal arm and leg muscles. Superficial peroneal nerve stimulation evoked interlimb reflexes in ipsilateral and contralateral arm and contralateral leg muscles of SCI and control participants. Radial nerve stimulation evoked interlimb reflexes in the ipsilateral leg and contralateral arm muscles of control and SCI participants but only contralateral leg muscles of control participants. Interlimb reflexes evoked by superficial peroneal nerve stimulation were longer in latency and duration, and larger in magnitude in SCI participants. Interlimb reflex properties were similar for both SCI and control groups for radial nerve stimulation. Ascending interlimb reflexes tended to occur with a higher incidence in participants with SCI, while descending interlimb reflexes occurred with a higher incidence in able-bodied participants. However, the overall incidence of interlimb reflexes in SCI and neurologically intact participants was similar which suggests that the neural circuitry underlying these reflexes does not necessarily develop after central nervous system injury.
Benzel, E C; Khare, V; Fowler, M R
The neural injury prevention capabilities of narcotic antagonists have previously been reported. Of the available narcotic antagonists, naloxone has been the most widely studied. Other agents with higher potency, longer half-lives, and greater specificity, however, may be more desirable for the prevention of the "secondary injury" following a primary neural insult. The relative neural injury prevention efficacies of the various narcotic antagonists is not known. The establishment of the relative effectiveness of these drugs is warranted and is of potential clinical importance. Therefore, a study was undertaken to compare the effects of the two narcotic antagonists, naloxone and nalmefene, with respect to their neuro-protective efficacy following experimental spinal cord injury (SCI) in rats. Ninety adult Sprague-Dawley rats were divided into three groups--control; naloxone (2 mg/kg i.p., 45 min following injury); and nalmefene (0.1 mg/kg i.p., 45 min following injury)--following lesioning with the ventral SCI technique. Results were evaluated by the inclined-plane technique and neurologic examination at 1 day and 1 week following injury. Histomorphological evaluation of the injured segment of spinal cord was performed following euthanasia at 1 week following injury. A significant improvement (compared with the control group) was noted in both treatment groups. This was observed with respect to neurological examination and inclined-plane scores in both treatment groups at 24 h and 1 week following lesioning (with a significance level of at least p less than 0.001; analysis of variance). The nalmefene group demonstrated a greater level of function than the naloxone group at both 24 h and 1 week following injury (not significant; p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Butler, Jane E.; Godfrey, Sharlene; Thomas, Christine K.
Whether interlimb reflexes emerge only after a severe insult to the human spinal cord is controversial. Here the aim was to examine interlimb reflexes at rest in participants with chronic (>1 year) spinal cord injury (SCI, n = 17) and able-bodied control participants (n = 5). Cutaneous reflexes were evoked by delivering up to 30 trains of stimuli to either the superficial peroneal nerve on the dorsum of the foot or the radial nerve at the wrist (5 pulses, 300 Hz, approximately every 30 s). Participants were instructed to relax the test muscles prior to the delivery of the stimuli. Electromyographic activity was recorded bilaterally in proximal and distal arm and leg muscles. Superficial peroneal nerve stimulation evoked interlimb reflexes in ipsilateral and contralateral arm and contralateral leg muscles of SCI and control participants. Radial nerve stimulation evoked interlimb reflexes in the ipsilateral leg and contralateral arm muscles of control and SCI participants but only contralateral leg muscles of control participants. Interlimb reflexes evoked by superficial peroneal nerve stimulation were longer in latency and duration, and larger in magnitude in SCI participants. Interlimb reflex properties were similar for both SCI and control groups for radial nerve stimulation. Ascending interlimb reflexes tended to occur with a higher incidence in participants with SCI, while descending interlimb reflexes occurred with a higher incidence in able-bodied participants. However, the overall incidence of interlimb reflexes in SCI and neurologically intact participants was similar which suggests that the neural circuitry underlying these reflexes does not necessarily develop after central nervous system injury. PMID:27049521
Mizoguchi, H; Wu, H E; Narita, M
The partial agonistic properties of endogenous mu-opioid peptides endomorphin-1 and endomorphin-2 for G-protein activation were determined in the mouse spinal cord, monitoring the increases in guanosine-5'-o-(3-[35S]thio)triphosphate binding. The G-protein activation induced by endogenous opioid peptide beta-endorphin in the spinal cord was significantly, but partially, attenuated by co-incubation with endomorphin-1 or endomorphin-2. The data indicates that endomorphin-1 and endomorphin-2 are endogenous partial agonists for mu-opioid receptor in the mouse spinal cord.
Brand, M Colleen
Neonatal spinal cord injury can occur in utero, as well as after either a difficult delivery or a nontraumatic delivery. Spinal cord injury can also be related to invasive nursery procedures or underlying neonatal pathology. Early clinical signs of spinal cord injury that has occurred in utero or at delivery includes severe respiratory compromise and profound hypotonia. Knowledge of risk factors and awareness of symptoms is required for early recognition and appropriate treatment. This article reviews the embryological development of the spinal column highlighting mechanisms of injury and identifying underlying factors that increase the risk of spinal cord injury in newborns. Signs and symptoms of injury, cervical spine immobilization, and the differential diagnosis are discussed. Nursing implications, general prognosis, and research in spinal cord injury are provided.
Gabr, Hala; El-Kheir, Wael Abo; Farghali, Haithem A M A; Ismail, Zeinab M K; Zickri, Maha B; El Maadawi, Zeinab M; Kishk, Nirmeen A; Sabaawy, Hatem E
Spinal cord injury (SCI) results in demyelination of surviving axons, loss of oligodendrocytes, and impairment of motor and sensory functions. We have developed a clinical strategy of cell therapy for SCI through the use of autologous bone marrow cells for transplantation to augment remyelination and enhance neurological repair. In a preclinical large mammalian model of SCI, experimental dogs were subjected to a clipping contusion of the spinal cord. Two weeks after the injury, GFP-labeled autologous minimally manipulated adherent bone marrow cells (ABMCs) were transplanted intrathecally to investigate the safety and efficacy of autologous ABMC therapy. The effects of ABMC transplantation in dogs with SCI were determined using functional neurological scoring, and the integration of ABMCs into the injured cords was determined using histopathological and immunohistochemical investigations and electron microscopic analyses of sections from control and transplanted spinal cords. Our data demonstrate the presence of GFP-labeled cells in the injured spinal cord for up to 16 weeks after transplantation in the subacute SCI stage. GFP-labeled cells homed to the site of injury and were detected around white matter tracts and surviving axons. ABMC therapy in the canine SCI model enhanced remyelination and augmented neural regeneration, resulting in improved neurological functions. Therefore, autologous ABMC therapy appears to be a safe and promising therapy for spinal cord injuries.
Gongal'skiĭ, V V; Kuftyreva, T P
Microcirculation disorders may cause functional deviation in gray matter cells of the spinal cord. One of the setting moments of the disorders is the subluxation of a vertebra as a result of the disturbance in carrying ability of the spinal disc in case of spinal osteochondrosis. In this position the soft tissues of the spinal motional well innervated segment are stretched, which induces irritation in the segmental part of the spinal cord including vegetative nervous structures. Subluxation of a vertebra causes changes in the structures and in the microcirculation vessels which grow simultaneously and this permits supposing their interrelation.
This conference proceeding summarizes current knowledge about the nutritional status and needs of the spinal cord injured patient. Topics covered include the aspects of spinal cord injury that influence nutrient intakes and status, and the nutrients most likely to be problematic in this diverse gro...
Jones, Zachary B; Ren, Yi
Spinal cord injury (SCI) is a debilitating condition that affects millions of individuals worldwide. Despite progress over the last few decades, the molecular mechanisms of secondary SCI that continue to occur days and weeks after the original trauma remain poorly understood. As a result, current therapies for SCI are only marginally effective. Sphingolipids, a diverse class of bioactive lipids, have been shown to regulate SCI repair and key secondary injury processes such as apoptosis, ischemia and inflammation. This review will discuss the numerous roles of sphingolipids and highlight the potential of sphingolipid-targeted therapies for SCI. PMID:27570580
Su, Jie; Gao, Tianle; Shi, Tiejun; Xiang, Qiong; Xu, Xiaojun; Wiesenfeld-Hallin, Zsuzsanna; Hökfelt, Tomas; Svensson, Camilla I
The mechanisms underlying rheumatoid arthritis (RA)-induced pain are still not fully elucidated, and accumulating data indicate that peripheral inflammation is not the only factor driving pain in these patients. The focus of our work is to investigate the molecular basis for long-term alterations in nociceptive pathways induced by polyarthritis using the collagen antibody-induced arthritis (CAIA) mouse model. In this model, mechanical hypersensitivity outlasts the joint inflammation by weeks. Here we examined expression levels of neuropeptides, ion channels, and nerve injury markers associated with neuropathic and/or inflammatory pain in dorsal root ganglia (DRGs) and spinal cord both during the peak of inflammation (day 15) and when the inflammation has resolved but the hypersensitivity persists (days 45-47). No apparent differences were observed in substance P, calcitonin gene-related peptide, or neuropeptide Y protein expression in DRGs and spinal cord of CAIA mice. However, the neuropeptide galanin, the ATP-gated ion channel P2X3, and calcium channel subunit α2δ1 were significantly increased in the CAIA DRGs as compared to controls, both 15 and 47 days after induction of arthritis. On day 15 there was an increase in expression of two factors associated with nerve injury and cell stress, activating transcription factor 3 and growth-associated protein 43 in DRGs, whereby the latter was still dramatically upregulated after 47 days. In conclusion, this study suggests that long-term joint inflammation has an impact on DRG neurons that resembles both inflammation and nerve injury-induced pain states. Thus, antibody-driven inflammation generates a pain state with a unique neurochemical profile.
Xie, Lei; Wang, Zhenfei; Li, Changwei; Yang, Kai; Liang, Yu
As previous studies demonstrate that oxidative stress and apoptosis play crucial roles in ischemic pathogenesis and nicotinamide adenine dinucleotide (NAD(+)) treatment attenuates oxidative stress-induced cell death among primary neurons and astrocytes as well as significantly reduce cerebral ischemic injury in rats. We used a spinal cord ischemia injury (SCII) model in rats to verify our hypothesis that NAD(+) could ameliorate oxidative stress-induced neuronal apoptosis. Adult male rats were subjected to transient spinal cord ischemia for 60min, and different doses of NAD(+) were administered intraperitoneally immediately after the start of reperfusion. Neurological function was determined by Basso, Beattie, Bresnahan (BBB) scores. The oxidative stress level was assessed by superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. The degree of apoptosis was analyzed by deoxyuridinetriphosphate nick-end labeling (TUNEL) staining and protein levels of cleaved caspase-3 and AIF (apoptosis inducing factor). The results showed that NAD(+) at 50 or 100mg/kg significantly decreased the oxidative stress level and neuronal apoptosis in the spinal cord of ischemia-reperfusion rats compared with saline, as accompanied with the decreased oxidative stress, NAD(+) administration significantly restrained the neuronal apoptosis after ischemia injury while improved the neurological and motor function. These findings suggested that NAD(+) might protect against spinal cord ischemia-reperfusion via reducing oxidative stress-induced neuronal apoptosis.
Freund, Patrick; Weiskopf, Nikolaus; Ward, Nick S; Hutton, Chloe; Gall, Angela; Ciccarelli, Olga; Craggs, Michael; Friston, Karl; Thompson, Alan J
The impact of traumatic spinal cord injury on structural integrity, cortical reorganization and ensuing disability is variable and may depend on a dynamic interaction between the severity of local damage and the capacity of the brain for plastic reorganization. We investigated trauma-induced anatomical changes in the spinal cord and brain, and explored their relationship to functional changes in sensorimotor cortex. Structural changes were assessed using cross-sectional cord area, voxel-based morphometry and voxel-based cortical thickness of T1-weighted images in 10 subjects with cervical spinal cord injury and 16 controls. Cortical activation in response to right-sided (i) handgrip; and (ii) median and tibial nerve stimulation were assessed using functional magnetic resonance imaging. Regression analyses explored associations between cord area, grey and white matter volume, cortical activations and thickness, and disability. Subjects with spinal cord injury had impaired upper and lower limb function bilaterally, a 30% reduced cord area, smaller white matter volume in the pyramids and left cerebellar peduncle, and smaller grey matter volume and cortical thinning in the leg area of the primary motor and sensory cortex compared with controls. Functional magnetic resonance imaging revealed increased activation in the left primary motor cortex leg area during handgrip and the left primary sensory cortex face area during median nerve stimulation in subjects with spinal cord injury compared with controls, but no increased activation following tibial nerve stimulation. A smaller cervical cord area was associated with impaired upper limb function and increased activations with handgrip and median nerve stimulation, but reduced activations with tibial nerve stimulation. Increased sensory deficits were associated with increased activations in the left primary sensory cortex face area due to median nerve stimulation. In conclusion, spinal cord injury leads to cord atrophy
Liu, Yao-sheng; He, Qi-zhen; Liu, Shu-bin; Jiang, Wei-gang; Lei, Ming-xing
Metastatic epidural compression of the spinal cord is a significant source of morbidity in patients with systemic cancer. With improvment of oncotheray, survival period in the patients is improving and metastatic cord compression is en- countered increasingly often. Surgical management performed for early circumferential decompression for the spinal cord com- pression with spine instability, and spine reconstruction performed. Patients with radiosensitive tumours without spine instabili- ty, radiotherapy is an effective therapy. Spinal stereotactic radiosurgery and minimally invasive techniques, such as vertebro- plasty and kyphoplasty, percutaneous pedicle screw fixation, radiofrequency ablation are promising options for treatment of cer- tain selected patients with spinal metastases.
Oh, Jacob Yl; Kapoor, Siddhant; Koh, Roy Km; Yang, Eugene Wr; Hee, Hwan-Tak
A 44-year-old male presented with symptoms of spinal cord compression secondary to metastatic prostate cancer. An urgent decompression at the cervical-thoracic region was performed, and there were no complications intraoperatively. Three hours postoperatively, the patient developed acute bilateral lower-limb paralysis (motor grade 0). Clinically, he was in class 3 hypovolemic shock. An urgent magnetic resonance imaging (MRI) was performed, showing no epidural hematoma. He was managed aggressively with medical therapy to improve his spinal cord perfusion. The patient improved significantly, and after one week, he was able to regain most of his motor functions. Although not commonly reported, spinal cord ischemia post-surgery should be recognized early, especially in the presence of hypovolemic shock. MRI should be performed to exclude other potential causes of compression. Spinal cord ischemia needs to be managed aggressively with medical treatment to improve spinal cord perfusion. The prognosis depends on the severity of deficits, and is usually favorable.
Qiu, Feng; Yang, Jin-Cheng; Ma, Xiang-Yang; Xu, Jun-Jie; Yang, Qing-Lei; Zhou, Xin; Xiao, Yao-Sheng; Hu, Hai-Sheng; Xia, Li-Hui
Vertebral column resection is associated with a risk of spinal cord injury. In the present study, using a goat model, we aimed to investigate the relationship between changes in spinal cord volume and spinal cord injury due to spinal shortening, and to quantify the spinal cord volume per 1-mm height in order to clarify a safe limit for shortening. Vertebral column resection was performed at T10 in 10 goats. The spinal cord was shortened until the somatosensory-evoked potential was decreased by 50% from the baseline amplitude or delayed by 10% relative to the baseline peak latency. A wake-up test was performed, and the goats were observed for two days postoperatively. Magnetic resonance imaging was used to measure the spinal cord volume, T10 height, disc height, osteotomy segment height, and spinal segment height pre- and postoperatively. Two of the 10 goats were excluded, and hence, only data from eight goats were analyzed. The somatosensory-evoked potential of these eight goats demonstrated meaningful changes. With regard to neurologic function, five and three goats were classified as Tarlov grades 5 and 4 at two days postoperatively. The mean shortening distance was 23.6 ± 1.51 mm, which correlated with the d-value (post-pre) of the spinal cord volume per 1-mm height of the osteotomy segment (r = 0.95, p < 0.001) and with the height of the T10 body (r = 0.79, p = 0.02). The mean d-value (post-pre) of the spinal cord volume per 1-mm height of the osteotomy segment was 142.87 ± 0.59 mm3 (range, 142.19–143.67 mm3). The limit for shortening was approximately 106% of the vertebral height. The mean volumes of the osteotomy and spinal segments did not significantly change after surgery (t = 0.310, p = 0.765 and t = 1.241, p = 0.255, respectively). Thus, our results indicate that the safe limit for shortening can be calculated using the change in spinal cord volume per 1-mm height. PMID:26001196
A novel thermoelectric cooling device using Peltier modules for inducing local hypothermia of the spinal cord: the effect of local electrically controlled cooling for the treatment of spinal cord injuries in conscious rats.
Morizane, Kei; Ogata, Tadanori; Morino, Tadao; Horiuchi, Hideki; Yamaoka, Gotaro; Hino, Masayuki; Miura, Hiromasa
We developed a novel thermoelectric cooling device using Peltier modules for the treatment of spinal cord injury in rats. The extracorporeal electrically cooling component was attached to the aluminum arched plate which was placed on the surface of the spinal cord after the contusion injury in the 11th thoracic spinal cord. During the hypothermic treatment, rats were awake and could move in the cage. Hind limb motor function, evaluated using a BBB scale, in the hypothermic animals (33°C for 48 h) was significantly higher than that in the normothermic animals from 2 weeks to 8 weeks after the injury.
Petrie, Michael A; Suneja, Manish; Faidley, Elizabeth; Shields, Richard K
Paralysis after a spinal cord injury (SCI) induces physiological adaptations that compromise the musculoskeletal and metabolic systems. Unlike non-SCI individuals, people with spinal cord injury experience minimal muscle activity which compromises optimal glucose utilization and metabolic control. Acute or chronic muscle activity, induced through electrical stimulation, may regulate key genes that enhance oxidative metabolism in paralyzed muscle. We investigated the short and long term effects of electrically induced exercise on mRNA expression of human paralyzed muscle. We developed an exercise dose that activated the muscle for only 0.6% of the day. The short term effects were assessed 3 hours after a single dose of exercise, while the long term effects were assessed after training 5 days per week for at least one year (adherence 81%). We found a single dose of exercise regulated 117 biological pathways as compared to 35 pathways after one year of training. A single dose of electrical stimulation increased the mRNA expression of transcriptional, translational, and enzyme regulators of metabolism important to shift muscle toward an oxidative phenotype (PGC-1α, NR4A3, IFRD1, ABRA, PDK4). However, chronic training increased the mRNA expression of specific metabolic pathway genes (BRP44, BRP44L, SDHB, ACADVL), mitochondrial fission and fusion genes (MFF, MFN1, MFN2), and slow muscle fiber genes (MYH6, MYH7, MYL3, MYL2). These findings support that a dose of electrical stimulation (∼10 minutes/day) regulates metabolic gene signaling pathways in human paralyzed muscle. Regulating these pathways early after SCI may contribute to reducing diabetes in people with longstanding paralysis from SCI.
Petrie, Michael A.; Suneja, Manish; Faidley, Elizabeth; Shields, Richard K.
Paralysis after a spinal cord injury (SCI) induces physiological adaptations that compromise the musculoskeletal and metabolic systems. Unlike non-SCI individuals, people with spinal cord injury experience minimal muscle activity which compromises optimal glucose utilization and metabolic control. Acute or chronic muscle activity, induced through electrical stimulation, may regulate key genes that enhance oxidative metabolism in paralyzed muscle. We investigated the short and long term effects of electrically induced exercise on mRNA expression of human paralyzed muscle. We developed an exercise dose that activated the muscle for only 0.6% of the day. The short term effects were assessed 3 hours after a single dose of exercise, while the long term effects were assessed after training 5 days per week for at least one year (adherence 81%). We found a single dose of exercise regulated 117 biological pathways as compared to 35 pathways after one year of training. A single dose of electrical stimulation increased the mRNA expression of transcriptional, translational, and enzyme regulators of metabolism important to shift muscle toward an oxidative phenotype (PGC-1α, NR4A3, IFRD1, ABRA, PDK4). However, chronic training increased the mRNA expression of specific metabolic pathway genes (BRP44, BRP44L, SDHB, ACADVL), mitochondrial fission and fusion genes (MFF, MFN1, MFN2), and slow muscle fiber genes (MYH6, MYH7, MYL3, MYL2). These findings support that a dose of electrical stimulation (∼10 minutes/day) regulates metabolic gene signaling pathways in human paralyzed muscle. Regulating these pathways early after SCI may contribute to reducing diabetes in people with longstanding paralysis from SCI. PMID:25531450
Lorente-Muñoz, Asís; Cortés-Franco, Severiano; Moles-Herbera, Jesús; Casado-Pellejero, Juan; Rivero-Celada, David; Alberdi-Viñas, Juan
Idiopathic spinal cord herniation is a rare cause of thoracic myelopathy and its recurrence is even more infrequent. Cord herniation is through an anterior dural defect in thoracic spine with unknown causes. Symptomatic cases must be surgically treated to reduce the hernia and seal the defect to prevent recurrences. We report a patient presenting a Brown-Séquard syndrome secondary to a D5 spinal cord herniation treated successfully and its posterior traumatic recurrence.
Fernandes, Natália C C A; Nogueira, Juliana S; Réssio, Rodrigo A; Cirqueira, Cinthya S; Kimura, Lidia M; Fernandes, Karolina R; Cunha, Mariana S; Souza, Renato P; Guerra, Juliana M
A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America, with neurological symptons including meningoencephalitis and Guillain-Barré syndrome in adults, besides an apparent increased incidence of microcephaly in infants born to infected mothers. It is becoming a necessity to have a trustworthy animal model to better understand ZIKV infection. In this study we used newborn white Swiss mice as a model to investigate the ZIKV strain recently isolated in Brazil. ZIKV was inoculated via intracerebral and subcutaneous routes and analysed through gross histopathology and immunohistochemistry. Here we demonstrated first that the intracerebral group (ICG) displayed severe cerebral lesions, with neuronal death, presence of apoptotic bodies, white matter degeneration and neutrophil perivascular cuffing. In the subcutaneous group (SCG), we observed moderate cerebral lesions, morphologically similar to that found in ICG and additional myelopathy, with architectural loss, marked by neuronal death and apoptotic bodies. Interestingly, we found an intense astrogliosis in brain of both groups, with increased immunoexpression of GFAP (glial fibrillary acidic protein) and presence of hypertrophic astrocytes. The spinal cord of subcutaneous group (SCG) exhibited reduction of astrocytes, but those positive for GFAP were hypertrophic and presented prolonged cellular processes. Finally significant lesions in the central nervous system (CNS) were present in newborn mice inoculated by both routes, but SCG method led to an important neurological manifestations (including myelopathy), during a longer period of time and appears for us to be a better model for ZIKV infection.
Serradj, Najet; Agger, Sydney F; Hollis, Edmund R
Restoring corticospinal function after spinal cord injury is a significant challenge as the corticospinal tract elicits no substantive, spontaneous regeneration, and its interruption leaves a permanent deficit. The corticospinal circuit serves multiple motor and sensory functions within the mammalian nervous system as the direct link between isocortex and spinal cord. Maturation of the corticospinal circuit involves the refinement of projections within the spinal cord and a subsequent refinement of motor maps within the cortex. The plasticity of these cortical motor maps mirrors the acquisition of skilled motor learning, and both the maps and motor skills are disrupted following injury to the corticospinal tract. The motor cortex exhibits the capacity to incorporate changes in corticospinal projections induced by both spontaneous and therapeutic-mediated plasticity of corticospinal axons through appropriate rehabilitation. An understanding of the mechanisms of corticospinal plasticity in motor learning will undoubtedly help inform strategies to improve motor rehabilitation after spinal cord injury.
Nas, Kemal; Yazmalar, Levent; Şah, Volkan; Aydın, Abdulkadir; Öneş, Kadriye
Spinal cord injury (SCI) is the injury of the spinal cord from the foramen magnum to the cauda equina which occurs as a result of compulsion, incision or contusion. The most common causes of SCI in the world are traffic accidents, gunshot injuries, knife injuries, falls and sports injuries. There is a strong relationship between functional status and whether the injury is complete or not complete, as well as the level of the injury. The results of SCI bring not only damage to independence and physical function, but also include many complications from the injury. Neurogenic bladder and bowel, urinary tract infections, pressure ulcers, orthostatic hypotension, fractures, deep vein thrombosis, spasticity, autonomic dysreflexia, pulmonary and cardiovascular problems, and depressive disorders are frequent complications after SCI. SCI leads to serious disability in the patient resulting in the loss of work, which brings psychosocial and economic problems. The treatment and rehabilitation period is long, expensive and exhausting in SCI. Whether complete or incomplete, SCI rehabilitation is a long process that requires patience and motivation of the patient and relatives. Early rehabilitation is important to prevent joint contractures and the loss of muscle strength, conservation of bone density, and to ensure normal functioning of the respiratory and digestive system. An interdisciplinary approach is essential in rehabilitation in SCI, as in the other types of rehabilitation. The team is led by a physiatrist and consists of the patients’ family, physiotherapist, occupational therapist, dietician, psychologist, speech therapist, social worker and other consultant specialists as necessary. PMID:25621206
Nas, Kemal; Yazmalar, Levent; Şah, Volkan; Aydın, Abdulkadir; Öneş, Kadriye
Spinal cord injury (SCI) is the injury of the spinal cord from the foramen magnum to the cauda equina which occurs as a result of compulsion, incision or contusion. The most common causes of SCI in the world are traffic accidents, gunshot injuries, knife injuries, falls and sports injuries. There is a strong relationship between functional status and whether the injury is complete or not complete, as well as the level of the injury. The results of SCI bring not only damage to independence and physical function, but also include many complications from the injury. Neurogenic bladder and bowel, urinary tract infections, pressure ulcers, orthostatic hypotension, fractures, deep vein thrombosis, spasticity, autonomic dysreflexia, pulmonary and cardiovascular problems, and depressive disorders are frequent complications after SCI. SCI leads to serious disability in the patient resulting in the loss of work, which brings psychosocial and economic problems. The treatment and rehabilitation period is long, expensive and exhausting in SCI. Whether complete or incomplete, SCI rehabilitation is a long process that requires patience and motivation of the patient and relatives. Early rehabilitation is important to prevent joint contractures and the loss of muscle strength, conservation of bone density, and to ensure normal functioning of the respiratory and digestive system. An interdisciplinary approach is essential in rehabilitation in SCI, as in the other types of rehabilitation. The team is led by a physiatrist and consists of the patients' family, physiotherapist, occupational therapist, dietician, psychologist, speech therapist, social worker and other consultant specialists as necessary.
Kamei, Junzo; Hayashi, Shunsuke; Sakai, Akane; Nakanishi, Yuki; Kai, Misa; Ikegami, Megumi; Ikeda, Hiroko
Peripheral neuropathy is the major side effect caused by paclitaxel, a microtubule-binding antineoplastic drug. Paclitaxel-induced peripheral neuropathy causes a long-term negative impact on the patient's quality of life. However, the mechanism underlying paclitaxel-induced peripheral neuropathy is still unknown, and there is no established treatment. Ghrelin is known to attenuate thermal hyperalgesia and mechanical allodynia in chronic constriction injury of the sciatic nerve, and inhibit the activation of nuclear factor kappa B (NFκB) in the spinal dorsal horn. Rikkunshito (RKT), a kampo medicine, increases the secretion of ghrelin in rodents and humans. Thus, RKT may attenuate paclitaxel-induced peripheral neuropathy by inhibiting phosphorylated NFκB (pNFκB) in the spinal cord. We found that paclitaxel dose-dependently induced mechanical hyperalgesia in mice. Paclitaxel increased the protein levels of spinal pNFκB, but not those of spinal NFκB. NFκB inhibitor attenuated paclitaxel-induced mechanical hyperalgesia suggesting that the activation of NFκB mediates paclitaxel-induced hyperalgesia. RKT dose-dependently attenuated paclitaxel-induced mechanical hyperalgesia. Ghrelin receptor antagonist reversed the RKT-induced attenuation of paclitaxel-induced mechanical hyperalgesia. RKT inhibited the paclitaxel-induced increase in the protein levels of spinal pNFκB. Taken together, the present study indicates that RKT exerts an antihyperalgesic effect in paclitaxel-induced neuropathic pain by suppressing the activation of spinal NFκB.
Kamei, Junzo; Hayashi, Shunsuke; Sakai, Akane; Nakanishi, Yuki; Kai, Misa; Ikegami, Megumi; Ikeda, Hiroko
Peripheral neuropathy is the major side effect caused by paclitaxel, a microtubule-binding antineoplastic drug. Paclitaxel-induced peripheral neuropathy causes a long-term negative impact on the patient's quality of life. However, the mechanism underlying paclitaxel-induced peripheral neuropathy is still unknown, and there is no established treatment. Ghrelin is known to attenuate thermal hyperalgesia and mechanical allodynia in chronic constriction injury of the sciatic nerve, and inhibit the activation of nuclear factor kappa B (NFκB) in the spinal dorsal horn. Rikkunshito (RKT), a kampo medicine, increases the secretion of ghrelin in rodents and humans. Thus, RKT may attenuate paclitaxel-induced peripheral neuropathy by inhibiting phosphorylated NFκB (pNFκB) in the spinal cord. We found that paclitaxel dose-dependently induced mechanical hyperalgesia in mice. Paclitaxel increased the protein levels of spinal pNFκB, but not those of spinal NFκB. NFκB inhibitor attenuated paclitaxel-induced mechanical hyperalgesia suggesting that the activation of NFκB mediates paclitaxel-induced hyperalgesia. RKT dose-dependently attenuated paclitaxel-induced mechanical hyperalgesia. Ghrelin receptor antagonist reversed the RKT-induced attenuation of paclitaxel-induced mechanical hyperalgesia. RKT inhibited the paclitaxel-induced increase in the protein levels of spinal pNFκB. Taken together, the present study indicates that RKT exerts an antihyperalgesic effect in paclitaxel-induced neuropathic pain by suppressing the activation of spinal NFκB. PMID:28182729
De Leener, Benjamin; Taso, Manuel; Cohen-Adad, Julien; Callot, Virginie
Segmenting the spinal cord contour is a necessary step for quantifying spinal cord atrophy in various diseases. Delineating gray matter (GM) and white matter (WM) is also useful for quantifying GM atrophy or for extracting multiparametric MRI metrics into specific WM tracts. Spinal cord segmentation in clinical research is not as developed as brain segmentation, however with the substantial improvement of MR sequences adapted to spinal cord MR investigations, the field of spinal cord MR segmentation has advanced greatly within the last decade. Segmentation techniques with variable accuracy and degree of complexity have been developed and reported in the literature. In this paper, we review some of the existing methods for cord and WM/GM segmentation, including intensity-based, surface-based, and image-based methods. We also provide recommendations for validating spinal cord segmentation techniques, as it is important to understand the intrinsic characteristics of the methods and to evaluate their performance and limitations. Lastly, we illustrate some applications in the healthy and pathological spinal cord. One conclusion of this review is that robust and automatic segmentation is clinically relevant, as it would allow for longitudinal and group studies free from user bias as well as reproducible multicentric studies in large populations, thereby helping to further our understanding of the spinal cord pathophysiology and to develop new criteria for early detection of subclinical evolution for prognosis prediction and for patient management. Another conclusion is that at the present time, no single method adequately segments the cord and its substructure in all the cases encountered (abnormal intensities, loss of contrast, deformation of the cord, etc.). A combination of different approaches is thus advised for future developments, along with the introduction of probabilistic shape models. Maturation of standardized frameworks, multiplatform availability, inclusion
Smeester, B A; O'Brien, E E; Michlitsch, K S; Lee, J-H; Beitz, A J
Recently, our group established a relationship between tumor-induced spinal cord astrocyte activation and aromatase expression and the development of bone tumor nociception in male mice. As an extension of this work, we now report on the association of tumor-induced mechanical hyperalgesia and cold hypersensitivity to changes in spinal cord dorsal horn GFAP and aromatase expression in intact (INT) female mice and the effect of ovariectomy on these parameters. Implantation of fibrosarcoma cells produced robust mechanical hyperalgesia in INT animals, while ovariectomized (OVX) females had significantly less mechanical hyperalgesia. Cold hypersensitivity was apparent by post-implantation day 7 in INT and OVX females compared to their saline-injected controls and increased throughout the experiment. The decrease in mechanical hyperalgesia in OVX females was mirrored by significant decreases in spinal astrocyte activity in laminae I-II, III-IV, V-VI and X and aromatase expression in laminae V-VI and X in the dorsal horn of tumor-bearing animals. Administration of the aromatase inhibitor letrozole reduced tumor-induced hyperalgesia in INT females only suggesting that the tumor-induced increase in aromatase expression and its associated increase in spinal estrogen play a role in the development of bone tumor-induced hyperalgesia. Finally, intrathecal (i.t.) administration of 17β-estradiol caused a significant increase in tumor-induced hyperalgesia in INT tumor-bearing females. Since i.t. 17β-estradiol increases tumor pain and ovariectomy significantly decreases tumor pain, as well as spinal aromatase, estrogen may play a critical role in the spinal cord response to the changing tumor environment and the development of tumor-induced nociception.
Yu, Sifei; Wang, Zhenfei; Yang, Kai; Liu, Zhuochao
The role of autophagy, neuroprotective mechanisms of nicotinamide adenine dinucleotide (NAD+), and their relationship in spinal cord ischemic reperfusion injury (SCIR) was assessed. Forty-eight Sprague-Dawley rats were divided into four groups: sham, ischemia reperfusion (I/R), 10 mg/kg NAD+, and 75 mg/kg NAD+. Western blotting, immunofluorescence, and immunohistochemistry were used to assess autophagy and apoptosis. Basso, Beattie, and Bresnahan (BBB) scores were used to assess neurological function. Expression levels of Beclin-1, Atg12-Atg5, LC3B-II, cleaved caspase 3, and Bax were upregulated in the I/R group and downregulated in the 75 mg/kg NAD+ group; p-mTOR, p-AKT, p62, and Bcl-2 were downregulated in the I/R group and upregulated in the 75 mg/kg NAD+ group. Numbers of LC3B-positive, caspase 3-positive, Bax-positive, and TUNEL-positive cells were significantly increased in the I/R group and decreased in the 75 mg/kg NAD+ group. The mean integrated option density of Bax increased and that of Nissl decreased in the I/R group, and it decreased and increased, respectively, in the 75 mg/kg NAD+ group. BBB scores significantly increased in the 75 mg/kg NAD+ group relative to the I/R group. No difference was observed between I/R and 10 mg/kg NAD+ groups for these indicators. Therefore, excessive and sustained autophagy aggravates SCIR; administration of NAD+ alleviates injury. PMID:28367271
Objective To investigate the incidence of adrenal insufficiency (AI) in patients with spinal cord injury (SCI) with symptoms similar to those of AI and to assess the relevance of AI and large-dose glucocorticoids in SCI. Methods The medical records of 228 patients who were admitted to the rehabilitation center after SCI from January 2014 to January 2016 were reviewed retrospectively. Twenty-nine of 228 patients had persistent symptoms suspicious for AI despite continuous care for more than 4 weeks. Therefore, adrenocorticotropic hormone (ACTH) stimulation tests were conducted in these 29 patients. Results Twelve of these 29 patients (41.4%) with SCI who manifested AI-like symptoms were diagnosed as having AI. Among these 29 patients, 15 patients had a history of large-dose glucocorticoid treatment use and the other 14 patients did not have such a history. Ten of the 15 patients (66.7%) with SCI treated with large-dose glucocorticoids after injury were diagnosed as having AI. In 12 patients with AI, the most frequent symptom was fatigue (66%), followed by orthostatic dizziness (50%), and anorexia (25%). In the chi-square test, the presence of AI was positively correlated with large-dose glucocorticoid use (p=0.008, Fisher exact test). Conclusion Among the patients with SCI who manifested similar symptoms as those of AI, high incidence of AI was found especially in those who were treated with large-dose glucocorticoids. During management of SCI, if a patient has similar symptoms as those of AI, clinicians should consider the possibility of AI, especially when the patient has a history of large-dose glucocorticoid use. Early recognition and treatment of the underlying AI should be performed. PMID:28119833
Wu, Sheng-Hua; Cheng, Kuang-I; Chai, Chee-Yin; Yeh, Jwu-Lai; Wu, Tai-Cheng; Kwan, Aij-Lie
Background. Severe burns result in hypercatabolic state and concomitant muscle atrophy that persists for several months, thereby limiting patient recovery. However, the effects of burns on the corresponding spinal dermatome remain unknown. This study aimed to investigate whether burns induce apoptosis of spinal cord ventral horn motor neurons (VHMNs) and consequently cause skeletal muscle wasting. Methods. Third-degree hindpaw burn injury with 1% total body surface area (TBSA) rats were euthanized 4 and 8 weeks after burn injury. The apoptosis profiles in the ventral horns of the lumbar spinal cords, sciatic nerves, and gastrocnemius muscles were examined. The Schwann cells in the sciatic nerve were marked with S100. The gastrocnemius muscles were harvested to measure the denervation atrophy. Result. The VHMNs apoptosis in the spinal cord was observed after inducing third-degree burns in the hindpaw. The S100 and TUNEL double-positive cells in the sciatic nerve increased significantly after the burn injury. Gastrocnemius muscle apoptosis and denervation atrophy area increased significantly after the burn injury. Conclusion. Local hindpaw burn induces apoptosis in VHMNs and Schwann cells in sciatic nerve, which causes corresponding gastrocnemius muscle denervation atrophy. Our results provided an animal model to evaluate burn-induced muscle wasting, and elucidate the underlying mechanisms. PMID:25695065
Gungor, Bilgi; Kahraman, Tamer; Gursel, Mayda; Yilmaz, Bilge
Reduced immune activation or immunosuppression is seen in patients withneurological diseases. Urinary and respiratory infections mainly manifested as septicemia and pneumonia are the most frequent complications following spinal cord injuries and they account for the majority of deaths. The underlying reason of these losses is believed to arise due to impaired immune responses to pathogens. Here, we hypothesized that susceptibility to infections of chronic spinal cord injured (SCI) patients might be due to impairment in recognition of pathogen associated molecular patterns and subsequently declining innate and adaptive immune responses that lead to immune dysfunction. We tested our hypothesis on healthy and chronic SCI patients with a level of injury above T-6. Donor PBMCs were isolated and stimulated with different toll like receptor ligands and T-cell inducers aiming to investigate whether chronic SCI patients display differential immune activation to multiple innate and adaptive immune cell stimulants. We demonstrate that SCI patients' B-cell and plasmacytoid dendritic cells retain their functionality in response to TLR7 and TLR9 ligand stimulation as they secreted similar levels of IL6 and IFNα. The immune dysfunction is not probably due to impaired T-cell function, since neither CD4+ T-cell dependent IFNγ producing cell number nor IL10 producing regulatory T-cells resulted different outcomes in response to PMA-Ionomycin and PHA-LPS stimulation, respectively. We showed that TLR7 dependent IFNγ and IP10 levels and TLR9 mediated APC function reduced substantially in SCI patients compared to healthy subjects. More importantly, IP10 producing monocytes were significantly fewer compared to healthy subjects in response to TLR7 and TLR9 stimulation of SCI PBMCs. When taken together this work implicated that these defects could contribute to persistent complications due to increased susceptibility to infections of chronic SCI patients. PMID:28170444
Makino, Michio; Saiki, Chikako; Ide, Ryoji; Matsumoto, Shigeji
Abnormalities of the serotonin (5-hydroxytryptamine, 5-HT) system may induce respiratory disorders. We examined which regions in the rostral medulla are important for the effect of 5-HT on the frequency of respiratory-like nerve (fR-like) activity by transecting the preparations at different levels near the facial nucleus (nVII) in newborn rat brainstem-spinal cord preparations. The fR-like activity at the fourth cervical ventral root (C4) of the Pons-medulla-spinal cord preparations in 2-3-day-old rats (n=25) was monitored at 26°C, and the change in fR-like activity in response to application of 10μM 5-HT before and after transection was compared among three groups, in which nVII was retained (group A, n=10), partially retained (group B, n=7), or eliminated (group C, n=8) by the transection. Before transection, the resting fR-like activity (set to 100%) and stimulant effect of 5-HT (+101-143%) were similar among the groups. After transection, resting fR-like activity increased in all groups, but the facilitatory effects of 5-HT on the fR-like activity were abolished in groups A and C (fR-like activity of -4% and +7%, respectively). In group B, 5-HT became inhibitory (fR-like activity of -28%). In conclusion, a distinct part of the rostral medulla in the absence of pontine influences may mediate the inhibitory effects of 5-HT on the respiratory rhythm.
Wang, Kun; Kong, Xiangang
This study aimed to explore the neuroprotection and mechanism of isoflurane on rats with spinal cord ischemic injury. Total 40 adult male Sprague-Dawley rats were divided into the four groups (n=10). Group A was sham-operation group; group B was ischemia group; group C was isoflurane preconditioning group; group D was isoflurane preconditioning followed by ischemia treatment group. Then the expressions of TWIK-related K+ channel 1 (TREK1) in the four groups were detected by immunofluorescent assay, real time-polymerase chain reactions (RT-PCR) and western blot. The primary neurons of rats were isolated and cultured under normal and hypoxic conditions. Besides, the neurons under two conditions were transfected with green fluorescent protein (GFP)-TREK1 and lentivirual to overexpress and silence TREK1. Additionally, the neurons were treated with isoflurane or not. Then caspase-3 activity and cell cycle of neurons under normal and hypoxic conditions were detected. Furthermore, nicotinamide adenine dinucleotide hydrate (NADH) was detected using NAD+/NADH quantification colorimetric kit. Results showed that the mRNA and protein expressions of TREK1 increased significantly in group C and D. In neurons, when TREK1 silenced, isoflurane treatment improved the caspase-3 activity. In hypoxic condition, the caspase-3 activity and sub-G1 cell percentage significantly increased, however, when TREK1 overexpressed the caspase-3 activity and sub-G1 cell percentage decreased significantly. Furthermore, both isoflurane treatment and overexpression of TREK1 significantly decreased NADH. In conclusion, isoflurane-induced neuroprotection in spinal cord ischemic injury may be associated with the up-regulation of TREK1. PMID:27469140
Mackie, J. William; McCormack, Rebecca; Campbell, Duncan
Activity for many disabled persons often begins as therapy, but the additional rewards derived from exercise must be appreciated. Public attitudes toward disabled persons have changed during the last few decades, recently focusing on abilities rather than on disabilities. The family physician of patients with spinal cord injuries will assist in managing acute medical problems and the association with loss of some degree of physical capacity. Physicians also can guide these individuals to choose a life that remains active and interesting over a “house-bound,” but safe, existence. Sensitivity and timing play key roles in establishing exercise as an intergral part of a disabled individuals' altered lifestyle. The physician can advocate increased access to wheelchairs and other facilities that make life easier for disabled individuals. ImagesFigure 1Figure 2Figure 3Figure 4 PMID:21248871
Apple, D F; Anson, C A; Hunter, J D; Bell, R B
To identify special characteristics of the pediatric spinal cord-injured (SCI) population, we analyzed a database of 1,770 traumatic SCI patients; 88 (5%) fell into the two pediatric subgroups: 0-12 years (n = 26) and 13-15 years (n = 62) at time of injury. Differences between age groups were identified with regard to demographics, neurologic characteristics, associated injuries and complications, and management. Mode level of bony injury was C2 in preteens, C4 in teens, and C4-C5 in adults. Scoliosis developed far more frequently in children, particularly preteens (23%), than in adults (5%). Violent etiologies, predominantly gunshots, accounted for a disproportionate share of injuries to preteens (19%) and African-Americans (28%), as compared with adults (12%) and Caucasians (7%). This last finding underscores the urgent need to mount a response to the nationwide proliferation of gunshot-related SCI in children and minorities.
Briona, Lisa K; Dorsky, Richard I
Mammals fail in sensory and motor recovery following spinal cord injury due to lack of axonal regrowth below the level of injury as well as an inability to reinitiate spinal neurogenesis. However, some anamniotes including the zebrafish Danio rerio exhibit both sensory and functional recovery even after complete transection of the spinal cord. The adult zebrafish is an established model organism for studying regeneration following spinal cord injury, with sensory and motor recovery by 6 weeks post-injury. To take advantage of in vivo analysis of the regenerative process available in the transparent larval zebrafish as well as genetic tools not accessible in the adult, we use the larval zebrafish to study regeneration after spinal cord transection. Here we demonstrate a method for reproducibly and verifiably transecting the larval spinal cord. After transection, our data shows sensory recovery beginning at 2 days post-injury (dpi), with the C-bend movement detectable by 3 dpi and resumption of free swimming by 5 dpi. Thus we propose the larval zebrafish as a companion tool to the adult zebrafish for the study of recovery after spinal cord injury.
The present study provides an overview of the spinal cord injury focusing mainly on aspects related to rehabilitation. Spinal cord injury affects young people in an active phase of life, determining severe handicaps. Most of the lesions are traumatic, caused by car accidents. Until fifty years ago, the survival of individuals with spinal cord injury was very reduced and the leading cause of death was renal failure. Due to developments in medical knowledge and technical advances, the survival rates have significantly improved. The causes of death have also changed being respiratory complications, particularly pneumonia, the leading causes. Immediately after a spinal cord lesion there is a phase of spinal shock which is characterized by flaccid paralysis and bladder and bowel retention. Progressively there is a return of the spinal cord automatism with the beginning of some reflex activities. Based on neurological evaluation it is pos-sible to predict motor and functional recovery and establish the rehabilitation program. We can consider three phases on the rehabilitation program: the first while the patient is still in bed, directed to prevent or treat complications due to immobility and begin sphincters reeducation; the second phase is intended to achieve wheelchair autonomy; the last phase is training in ortostatism. The rehabilitation program also comprises sports and recreational activities, psychological and social support in order to achieve an integral of the individual with a spinal cord injury.
Park, Soo-Jin; Jung, Nam-Jin; Na, Sang-Su
[Purpose] The purpose of the study was to investigate the effects of exercise on the recovery of spinal cord nerve cells damaged due to pain signals which are a major symptom of osteoarthritis. [Subjects and Methods] Adult male Sprague-Dawley rats (n=40) were used and induction of osteoarthritis by monosodium iodoacetate. Injected rats were randomly divided into 4 groups: Sham control group without MIA injection (SG), control group with injected MIA (CG), OA without exercise (NEG), OA with exercise (EG). Sham control group was injected normal cell line instead of MIA. The exercise group was submitted to 4-week training program on a treadmill for 5 days/week, 30 min/day, 16 m/min velocity, then spinal cord were removed and measured the GAP-43 expression by immunohistochemistry analysis. [Results] In this study, a results of measuring the expression of GAP-43. GAP-43 was observed in all groups, showed that the significant difference in each group. [Conclusion] It could be seen that exercise increased the GAP-43 expression in the spinal cord to promote the recovery of spinal cord nerve cells damaged due to chronic osteoarthritis. PMID:27821962
Krityakiarana, W.; Espinosa-Jeffrey, A.; Ghiani, C.A.; Zhao, P. M.; Gomez-Pinilla, F.; Yamaguchi, M.; Kotchabhakdi, N.; de Vellis, J.
Exercise has been shown to increase hippocampal neurogenesis, but the effects of exercise on oligodendrocyte generation have not yet been reported. In this study, we evaluated the hypothesis that voluntary exercise may affect neurogenesis, and more in particular, oligodendrogenesis, in the thoracic segment of the intact spinal cord of adult nestin-GFP transgenic mice. Voluntary exercise for 7 and 14 days increased nestin-GFP expression around the ependymal area. In addition, voluntary exercise for 7 days significantly increased nestin-GFP expression in both the white and gray matter of the thoracic segment of the intact spinal cord, whereas, 14 days-exercise decreased nestin-GFP expression. Markers for immature oligodendrocytes (Transferrin and CNPase) were significantly increased after 7 days of voluntary exercise. These results suggest that voluntary exercise positively influences oligodendrogenesis in the intact spinal cord, emphasizing the beneficial effect of voluntary exercise as a possible co-treatment for spinal cord injury. PMID:20374076
Larson, Alice A; Nunez, Myra G; Kissel, Casey L; Kovács, Katalin J
Stress is antinociceptive in some models of pain, but enhances musculoskeletal nociceptive responses in mice and muscle pain in patients with fibromyalgia syndrome. To test the hypothesis that urocortins are stress hormones that are sufficient to enhance tactile and musculoskeletal hyperalgesia, von Frey fibre sensitivity and grip force after injection of corticotropin-releasing factor (CRF), urocortin I and urocortin II were measured in mice. Urocortin I (a CRF1 and CRF2 receptor ligand) produced hyperalgesia in both assays when injected intrathecally (i.t.) but not intracerebroventricularly, and only at a large dose when injected peripherally, suggesting a spinal action. Morphine inhibited urocortin I-induced changes in nociceptive responses in a dose-related fashion, confirming that changes in behaviour reflect hyperalgesia rather than weakness. No tolerance developed to the effect of urocortin I (i.t.) when injected repeatedly, consistent with a potential to enhance pain chronically. Tactile hyperalgesia was inhibited by NBI-35965, a CRF1 receptor antagonist, but not astressin 2B, a CRF2 receptor antagonist. However, while urocortin I-induced decreases in grip force were not observed when co-administered i.t. with either NBI-35965 or astressin 2B, they were even more sensitive to inhibition by astressin, a non-selective CRF receptor antagonist. Together these data indicate that urocortin I acts at CRF receptors in the mouse spinal cord to elicit a reproducible and persistent tactile (von Frey) and musculoskeletal (grip force) hyperalgesia. Urocortin I-induced hyperalgesia may serve as a screen for drugs that alleviate painful conditions that are exacerbated by stress.
Larson, Alice A.; Nunez, Myra G.; Kissel, Casey L.; Kovács, Katalin J.
Stress is antinociceptive in some models of pain but enhances musculoskeletal nociceptive responses in mice and muscle pain in patients with fibromyalgia syndrome. To test the hypothesis that urocortins are stress hormones that are sufficient to enhance tactile and musculoskeletal hyperalgesia, we measured von Frey fiber sensitivity and grip force after injection of corticotrophin releasing factor (CRF), urocortin I and urocortin II in mice. Urocortin I (a CRF1 and CRF2 receptor ligand) produced hyperalgesia in both assays when injected intrathecally (i.t.) but not intracerebroventricularly (i.c.v.), and only at a large dose when injected peripherally, suggesting a spinal action. Morphine inhibited urocortin I-induced changes in nociceptive responses in a dose-related fashion, confirming that changes in behavior reflect hyperalgesia rather than weakness. No tolerance developed to the effect of urocortin I (i.t.) when injected repeatedly, consistent with a potential to enhance pain chronically. Tactile hyperalgesia was inhibited by NBI-35965, a CRF1 receptor antagonist, but not astressin 2B, a CRF2 receptor antagonist. However, while urocortin I-induced decreases in grip force were not observed when coadministered i.t. with either NBI-35965 or astressin 2B, they were even more sensitive to inhibition by astressin, a nonselective CRF receptor antagonist. Together these data indicate that urocortin I acts at CRF receptors in the mouse spinal cord to elicit a reproducible and persistent tactile (von Frey) and musculoskeletal (grip force) hyperalgesia. Urocortin I-induced hyperalgesia may serve as a screen for drugs that alleviate painful conditions that are exacerbated by stress. PMID:26332847
He, Zili; Zhou, Yulong; Huang, Yan; Wang, Qingqing; Zheng, Binbin; Zhang, Hongyu; Li, Jiawei; Liu, Yanlong; Wu, Fenzan; Zhang, Xie; Tong, Songlin; Wang, Maofeng; Wang, Zhouguang; He, Huacheng; Xu, Huazi; Xiao, Jian
Endoplasmic reticulum (ER) stress-induced apoptosis occurs in the spinal cord following traumatic spinal cord injury (SCI). Dl-3-n-butylphthalide (NBP) exerts an neuroprotective effects against both ischemic brain injury and neurodegenerative diseases; however, the relationship between ER stress-induced apoptosis and the therapeutic effect of NBP in SCI remains unclear. In this study, moderate spinal cord injuries were induced in Sprague-Dawley (SD) rats with a vascular clip. NBP was administered by oral (80 mg/kg/d) gavage 2 h before injury and then once daily for 28 d thereafter. Neurological recovery was assessed using the Basso, Beattie, and Bresnahan (BBB) locomotion rating scale, the inclined plane test, and the footprint analysis. Neuronal cell death was examined by TUNEL staining at 7 days post-injury. ER stress and apoptosis-related proteins were quantified by immunofluorescence staining and western blotting both in vivo and in vitro. Our results showed that NBP significantly decreased spinal cord lesion cavity area and improved locomotor recovery in SD rats after SCI. NBP also decreased neuronal apoptosis and inhibited activation of the caspase 3 cascade. Upregulation of ER stress-related proteins, such as GRP78, ATF-6, ATF-4, PDI, XBP-1, and CHOP, was reversed by NBP treatment in SD rats with SCI. Similarly, NBP effectively ameliorated ER stress and apoptosis-related protein expression induced by incubation with thapsigargin (TG) in PC12 cells. Our findings demonstrate that NBP treatment alleviates secondary SCI by inhibiting ER stress-induced apoptosis, thereby promoting neurological and locomoter functional recovery. PMID:28386335
Martinez, Marina; Delivet-Mongrain, Hugo; Rossignol, Serge
After a spinal hemisection at thoracic level in cats, the paretic hindlimb progressively recovers locomotion without treadmill training but asymmetries between hindlimbs persist for several weeks and can be seen even after a further complete spinal transection at T13. To promote optimal locomotor recovery after hemisection, such asymmetrical changes need to be corrected. In the present study we determined if the locomotor deficits induced by a spinal hemisection can be corrected by locomotor training and, if so, whether the spinal stepping after the complete spinal cord transection is also more symmetrical. This would indicate that locomotor training in the hemisected period induces efficient changes in the spinal cord itself. Sixteen adult cats were first submitted to a spinal hemisection at T10. One group received 3 wk of treadmill training, whereas the second group did not. Detailed kinematic and electromyographic analyses showed that a 3-wk period of locomotor training was sufficient to improve the quality and symmetry of walking of the hindlimbs. Moreover, after the complete spinal lesion was performed, all the trained cats reexpressed bilateral and symmetrical hindlimb locomotion within 24 h. By contrast, the locomotor pattern of the untrained cats remained asymmetrical, and the hindlimb on the side of the hemisection was still deficient. This study highlights the beneficial role of locomotor training in facilitating bilateral and symmetrical functional plastic changes within the spinal circuitry and in promoting locomotor recovery after an incomplete spinal cord injury.
Berta, T; Liu, Y-C; Xu, Z-Z; Ji, R-R
Accumulating evidence indicates that activation of spinal cord astrocytes contributes importantly to nerve injury and inflammation-induced persistent pain and chronic opioid-induced antinociceptive tolerance. Phosphorylation of extracellular signal-regulated kinase (pERK) and induction of interleukin-1 beta (IL-1β) in spinal astrocytes have been implicated in astrocytes-mediated pain. Tissue plasminogen activator (tPA) is a serine protease that has been extensively used to treat stroke. We examined the potential involvement of tPA in chronic opioid-induced antinociceptive tolerance and activation of spinal astrocytes using tPA knockout (tPA(-/-)) mice and astrocyte cultures. tPA(-/-) mice exhibited unaltered nociceptive pain and morphine-induced acute analgesia. However, the antinociceptive tolerance, induced by chronic morphine (10mg/kg/day, s.c.), is abrogated in tPA(-/-) mice. Chronic morphine induces tPA expression in glial fibrillary acidic protein (GFAP)-expressing spinal cord astrocytes. Chronic morphine also increases IL-1β expression in GFAP-expressing astrocytes, which is abolished in tPA-deficient mice. In cultured astrocytes, morphine treatment increases tPA, IL-1β, and pERK expression, and the increased IL-1β and pERK expression is abolished in tPA-deficient astrocytes. tPA is also sufficient to induce IL-1β and pERK expression in astrocyte cultures. Intrathecal injection of tPA results in up-regulation of GFAP and pERK in spinal astrocytes but not up-regulation of ionized calcium binding adapter molecule 1 in spinal microglia. Finally, intrathecal tPA elicits persistent mechanical allodynia, which is inhibited by the astroglial toxin alpha-amino adipate and the MEK (ERK kinase) inhibitor U0126. Collectively, these data suggest an important role of tPA in regulating astrocytic signaling, pain hypersensitivity, and morphine tolerance.
Berta, Temugin; Liu, Yen-Chin; Xu, Zhen-Zhong; Ji, Ru-Rong
Accumulating evidence indicates that activation of spinal cord astrocytes contributes importantly to nerve injury and inflammation-induced persistent pain and chronic opioid-induced antinociceptive tolerance. Phosphorylation of extracellular signal-regulated kinase (pERK) and induction of interleukin-1 beta (IL-1β) in spinal astrocytes have been implicated in astrocytes-mediated pain. Tissue plasminogen activator (tPA) is a serine protease that has been extensively used to treat stroke. We examined the potential involvement of tPA in chronic opioid-induced antinociceptive tolerance and activation of spinal astrocytes using tPA knockout (tPA−/−) mice and astrocyte cultures. tPA−/− mice exhibited unaltered nociceptive pain and morphine-induced acute analgesia. However, the antinociceptive tolerance, induced by chronic morphine (10 mg/kg/day, s.c.), is abrogated in tPA−/− mice. Chronic morphine induces tPA expression in GFAP-expressing spinal cord astrocytes. Chronic morphine also increases IL-1β expression in GFAP-expressing astrocytes, which is abolished in tPA-deficient mice. In cultured astrocytes, morphine treatment increases tPA, IL-1β, and pERK expression, and the increased IL-1β and pERK expression is abolished in tPA-deficient astrocytes. tPA is also sufficient to induce IL-1β and pERK expression in astrocyte cultures. Intrathecal injection of tPA results in up-regulation of GFAP and pERK in spinal astrocytes but not up-regulation of IBA-1 in spinal microglia. Finally, intrathecal tPA elicits persistent mechanical allodynia, which is inhibited by the astroglial toxin alpha-amino adipate and the MEK (ERK kinase) inhibitor U0126. Collectively, these data suggest an important role of tPA in regulating astrocytic signaling, pain hypersensitivity, and morphine tolerance. PMID:23707980
develop from 1) aberrant plasticity and 2) the loss of tonic input onto sympathetic preganglionic neurons (SPN) in the spinal cord that drive...life. Another cause of autonomic dysreflexia is aberrant plasticity of spinal circuits that increase activity of the sympathetic preganglionic neurons...modulatory circuitry and pharmacological mitigation of hyperexcitability resulting from aberrant plasticity will result in greater mitigation of
Borghi, Sergio M.; Pinho-Ribeiro, Felipe A.; Fattori, Victor; Bussmann, Allan J. C.; Vignoli, Josiane A.; Camilios-Neto, Doumit; Casagrande, Rubia; Verri, Waldiceu A.
The present study aimed to evaluate the effects of the flavonoid quercetin (3,3´,4´,5,7-pentahydroxyflavone) in a mice model of intense acute swimming-induced muscle pain, which resembles delayed onset muscle soreness. Quercetin intraperitoneal (i.p.) treatment dose-dependently reduced muscle mechanical hyperalgesia. Quercetin inhibited myeloperoxidase (MPO) and N-acetyl-β-D- glucosaminidase (NAG) activities, cytokine production, oxidative stress, cyclooxygenase-2 (COX-2) and gp91phox mRNA expression and muscle injury (creatinine kinase [CK] blood levels and myoblast determination protein [MyoD] mRNA expression) as well as inhibited NFκB activation and induced Nrf2 and HO-1 mRNA expression in the soleus muscle. Beyond inhibiting those peripheral effects, quercetin also inhibited spinal cord cytokine production, oxidative stress and glial cells activation (glial fibrillary acidic protein [GFAP] and ionized calcium-binding adapter molecule 1 [Iba-1] mRNA expression). Concluding, the present data demonstrate that quercetin is a potential molecule for the treatment of muscle pain conditions related to unaccustomed exercise. PMID:27583449
Wang, J; Zhang, Q; Zhao, L; Li, D; Fu, Z; Liang, L
Obesity is associated with augmented peripheral inflammation and pain sensitivity in response to inflammatory stimulation, but the underlying mechanisms remain unclear. Emerging evidence has shown that activation of peroxisome proliferator-activated receptor-α (PPARα) in the central nervous system controls peripheral inflammation and pain. We hypothesized that obesity might down-regulate PPARα in the spinal cord, leading to enhanced peripheral inflammation and inflammatory hyperalgesia. Sprague-Dawley rats fed a high-fat diet (HF) for 12weeks developed metabolic disorder and displayed significantly decreased spinal PPARα expression and activity. Interestingly, intracerebroventricular (ICV) infusion of the PPARα activator palmitoylethanolamide (PEA) in HF-fed rats for 2weeks normalized spinal PPARα expression and activity without altering metabolic parameters. HF-fed rats were more sensitive to stimulation of the inflamed paw, and exhibited more severe paw edema following carrageenan injection, whereas HF-fed rats receiving ICV PEA had similar pain sensitivity and paw edema to LF-fed rats. No difference in the expression of inflammatory mediators or nuclear factor (NF)-κB activity was observed at baseline among groups. Carrageenan induced decreased PPARα expression and activity, increased spinal cord inflammatory mediator expression and NF-κB activity in both LF-and HF-fed rats. However, the increase was more pronounced in HF-fed rats and corrected by PEA. Intrathecal injection of small interfering RNA (siRNA) against PPARα in HF-fed rats completely abolished PEA effects on peripheral pain sensitivity and paw edema. These findings suggest that diet-induced obesity causes down-regulation of spinal PPARα, which facilitates the susceptibility to peripheral inflammatory challenge by increasing inflammatory response in the spinal cord, contributing to augmented peripheral inflammation and inflammatory hyperalgesia in obesity.
Spinal cord stimulation has been used successfully for more than 40 years. The application of an electrical impulse field on to the spinal cord is used with a battery generator source and a variety of either cylindrical or paddle/plate leads. Energy is delivered from either a conventional internal programmable generator or a rechargeable style battery. Many clinical conditions such as complex regional pain syndrome, failed back spinal syndrome, and extremity neuropathic pain involving the trunk and limbs are approved for its use. This device allows patients to live a successful life without pain.
Flanagan, E P; Pittock, S J
Most spinal cord injury is seen with trauma. Nontraumatic spinal cord emergencies are discussed in this chapter. These myelopathies are rare but potentially devastating neurologic disorders. In some situations prior comorbidity (e.g., advanced cancer) provides a clue, but in others (e.g., autoimmune myelopathies) it may come with little warning. Neurologic examination helps distinguish spinal cord emergencies from peripheral nervous system emergencies (e.g., Guillain-Barré), although some features overlap. Neurologic deficits are often severe and may quickly become irreversible, highlighting the importance of early diagnosis and treatment. Emergent magnetic resonance imaging (MRI) of the entire spine is the imaging modality of choice for nontraumatic spinal cord emergencies and helps differentiate extramedullary compressive causes (e.g., epidural abscess, metastatic compression, epidural hematoma) from intramedullary etiologies (e.g., transverse myelitis, infectious myelitis, or spinal cord infarct). The MRI characteristics may give a clue to the diagnosis (e.g., flow voids dorsal to the cord in dural arteriovenous fistula). However, additional investigations (e.g., aquaporin-4-IgG) are often necessary to diagnose intramedullary etiologies and guide treatment. Emergency decompressive surgery is necessary for many extramedullary compressive causes, either alone or in combination with other treatments (e.g., radiation) and preoperative neurologic deficit is the best predictor of outcome.
apply for 6- moths no-cost extension to conduct immunochemistry analyses of spinal cord tissue from this completed experiment. 15. SUBJECT TERMS...Neuroscience Forum, Prague 9/10/2013). We apply for 6- moths no-cost extension to complete post-mortem immunochemistry analyses in order to...Thus all 4 specific aims of the project have been successfully accomplished. We apply for 6- moths no-cost extension to complete post-mortem
Ohkubo, T.; Shibata, M.; Takahashi, H.; Inoki, R. )
Nociceptive response induced by 0.5% Formalin in the hindpaw of mice had two peaks, 0-5 min (first phase) and 15-20 min (second phase). By using the distinct biphasic response, the nature of the transmitter systems activated by Formalin in the spinal cord was studied for the purpose of determining the difference of the role of substance P (SP) and somatostatin (SST). The injection of (D-Pro2, D-Trp7,9)SP, (D-Arg1, D-Pro2, D-Trp7,9, Leu11)SP and SP antiserum inhibited only the first phase response. The i.t. injection of -Aminoheptanoyl-Phe-D-Trp-Lys-(OBz)-Thr- (an SST antagonist), SST antiserum and cysteamine (an SST depletor) inhibited only the second phase. This result indicates that SP is involved in the transmission of the first phase, and SST is involved in the transmission of the second phase of the Formalin-induced nociceptive response. With regard to other nociceptive stimuli, two i.t. SP antagonists produced a significant analgesia in the hot plate and tail pinch tests but had no effect in the acetic acid writhing test. However, i.t. SST antagonist and cysteamine produced a significant analgesia in the writhing test but had no effect in the hot plate and tail pinch test. These results suggest that SP participates in the transient pain induced by such acute stimuli as hot plate, tail pinch and the first phase of Formalin response and that SST participates in the prolonged and inflammatory pain induced by stimuli such as acetic acid and the second phase response.
Dai, Bin; Yan, Ting; Shen, Yi-xing; Xu, You-jia; Shen, Hai-bin; Chen, Dong; Wang, Jin-rong; He, Shuang-hua; Dong, Qi-rong; Zhang, Ai-liang
We previously found that oxygen-glucose-serum deprivation/restoration (OGSD/R) induces apoptosis of spinal cord astrocytes, possibly via caspase-12 and the integrated stress response, which involves protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2-alpha (eIF2α) and activating transcription factor 4 (ATF4). We hypothesized that edaravone, a low molecular weight, lipophilic free radical scavenger, would reduce OGSD/R-induced apoptosis of spinal cord astrocytes. To test this, we established primary cultures of rat astrocytes, and exposed them to 8 hours/6 hours of OGSD/R with or without edaravone (0.1, 1, 10, 100 μM) treatment. We found that 100 μM of edaravone significantly suppressed astrocyte apoptosis and inhibited the release of reactive oxygen species. It also inhibited the activation of caspase-12 and caspase-3, and reduced the expression of homologous CCAAT/enhancer binding protein, phosphorylated (p)-PERK, p-eIF2α, and ATF4. These results point to a new use of an established drug in the prevention of OGSD/R-mediated spinal cord astrocyte apoptosis via the integrated stress response.
Solis, Leandro R.; Twist, Elizabeth; Seres, Peter; Thompson, Richard B.
Deep tissue injury (DTI) is a severe medical complication that commonly affects those with spinal cord injury. It is caused by prolonged external loading of the muscles, entrapping them between a bony prominence and the support surface. The entrapment causes excessive mechanical deformation and increases in interstitial pressure, leading to muscle breakdown deep around the bony prominences. We proposed the use of intermittent electrical stimulation (IES) as a novel prophylactic method for the prevention of DTI. In this study, we assessed the long-term effectiveness of this technique in pigs that had received a partial spinal cord injury that paralyzed one hindlimb. The pigs recovered for 2 wk postsurgery, and subsequently, their paralyzed limbs were loaded to 25% of their body weights 4 h/day for 4 consecutive days each week for 1 mo. One group of pigs (n = 3) received IES during the loading, whereas another group (n = 3) did not. DTI was quantified using magnetic resonance imaging (MRI) and postmortem histology. In the group that did not receive IES, MRI assessments revealed signs of tissue damage in 48% of the volume of the loaded muscle. In the group that did receive IES, only 8% of the loaded muscle volume showed signs of tissue damage. Similar findings were found through postmortem histology. This study demonstrates, for the first time, that IES may be an effective technique for preventing the formation of DTI in loaded muscles after spinal cord injury. PMID:23172030
Epstein, Lawrence J; Palmieri, Marco
Since its introduction as a procedure of last resort in a terminally ill patient with intractable cancer-related pain, spinal cord stimulation has been used to effectively treat chronic pain of varied origins. Spinal cord stimulation is commonly used for control of pain secondary to failed back surgery syndrome and complex regional pain syndrome, as well as pain from angina pectoris, peripheral vascular disease, and other causes. By stimulating one or more electrodes implanted in the posterior epidural space, the patient feels paresthesias in their areas of pain, which reduces the level of pain. Pain is reduced without the side effects associated with analgesic medications. Patients have improved quality of life and improved function, with many returning to work. Spinal cord stimulation has been shown to be cost effective as compared with conservative management alone. There is strong evidence for efficacy and cost effectiveness of spinal cord stimulation in the treatment of pain associated with intractable angina, failed back surgery syndrome, and complex regional pain syndrome. In this article, we review the history and pathophysiology of spinal cord stimulation, and the evidence (or lack thereof) for efficacy in common clinical practice.
... Children Early Detection, Diagnosis, and Staging How Are Brain and Spinal Cord Tumors Diagnosed in Children? Brain ... resonance angiography (MRA) or computerized tomographic angiography (CTA). Brain or spinal cord tumor biopsy Imaging tests such ...
Poor, Charles R.
Reviews historical development of organized vocational rehabilitation programming for the spinal cord injured in the United States. Significant factors that affect vocational rehabilitation outcomes with spinal cord injured persons are listed and discussed. (Author)
Wang, Fangyong; Zhang, Junwei; Tang, Hehu; Li, Xiang; Jiang, Shudong; Lv, Zhen; Liu, Shujia; Chen, Shizheng; Liu, Jiesheng; Hong, Yi
[Purpose] The objective of the study was to compare the incidence, diagnosis, treatment, and prognosis of patients with spinal cord stab injury to those with the more common spinal cord contusion injury. [Subjects] Of patients hospitalized in China Rehabilitation Research Center from 1994 to 2014, 40 of those having a spinal cord stab injury and 50 with spinal cord contusion were selected. [Methods] The data of all patients were analyzed retrospectively. The cases were evaluated by collecting admission and discharge ASIA (American Spinal Injury Association) and ADL (activity of daily living) scores. [Results] After a comprehensive rehabilitation program, ASIA and ADL scores of patients having both spinal cord stab injury and spinal cord contusion significantly increase. However, the increases were noted to be higher in patients having a spinal cord stab injury than those having spinal cord contusion. [Conclusion] Comprehensive rehabilitation is effective both for patients having spinal cord stab injury and those with spinal cord contusion injury. However, the prognosis of patients having spinal cord stab injury is better than that of patients with spinal cord contusion.
Zhou, Jun; Lin, Wenjing; Chen, Hongtao; Fan, Youling; Yang, Chengxiang
The mechanism underlying neuropathic pain (NP) is complex and has not been fully elucidated. The TWIK-related spinal cord K(+) (TRESK) is the major background potassium current in dorsal root ganglia (DRG), we found that mitogen-activated protein kinase (MAPK) signal pathway were activated in spinal cord accompanied by TRESK down regulation in response to NP. Therefore, we investigated whether TRESK mediates inflammation and apoptosis by MAPK pathway in the spinal cord of NP rats. SNI rats exhibited reduced TRESK expression in DRG and spinal cord and higher sensitivity to mechanical stimuli but no effect on thermal stimuli. Intrathecal injections of TRESK overexpressing adenovirus alleviated mechanical allodynia, inhibited phosphorylation of extracellular signal-regulated kinase (ERK) and p38, and decreased inflammatory reactions and apoptosis in the spinal cords of SNI rats. Down regulation of TRESK in DRG and spinal cord was detected in normal rats after intrathecal TRESK shRNA lentivirus injection, which induced mechanical allodynia but had no effect on pain thresholds for heat stimulation. Phosphorylated ERK and p38 were increased in the spinal cord. Intrathecal injection of an ERK antagonist (PD98059) and p38 antagonist (SB203580) prevented ERK and p38 activation in the spinal cord and mechanical allodynia induced by TRESK shRNA lentivirus. In conclusion, our study clearly demonstrated an important role for TRESK in NP and that TRESK regulation contributes to pain sensitivity mediates inflammation and apoptosis by ERK and p38 MAPK signaling in the spinal cord.
Zhang, Ying; Dun, Siok L; Chen, Yi-Hung; Luo, Jin J; Cowan, Alan; Dun, Nae J
This study tested the hypothesis that repetitive scratching provoked by two known pruritogens, compound 48/80 and 5'-guanidinonaltrindole (GNTI), is accompanied by activation of microglial cells in the mouse spinal cord. Immunohistochemical studies revealed that the complement receptor 3, also known as cluster determinant 11b (CD11b), a cell surface marker of microglial cells, was upregulated in the spinal cord 10-30 min after a subcutaneous (s.c.) injection of compound 48/80 (50 μg/100 μl) or GNTI (0.3 mg/kg) to the back of the mouse neck. Numerous intensely labeled CD11b-immunoreactive (CD11b-ir) cells, with the appearance of hypertrophic reactive microglia, were distributed throughout the gray and white matter. In contrast, weakly labeled CD11b-ir cells were distributed in the spinal cord from mice injected with saline. Western blots showed that CD11b expression levels were significantly increased in spinal cords of mice injected s.c. with either pruritogen, reached a peak response in about 30 min, and declined to about the basal level in the ensuing 60 min. In addition, phospho-p38 (p-p38) but not p38 levels were upregulated in spinal cords from mice injected with compound 48/80 or GNTI, with a time course parallel to that of CD11b expression. Pretreatment of the mice with nalfurafine (20 µg/kg; s.c.), a κ-opioid receptor agonist that has been shown to suppress scratching, reduced CD11b and p-p38 expression induced by either pruritogen. The results demonstrate, for the first time, that scratch behavior induced by the pruritogens GNTI and compound 48/80 is accompanied by a parallel activation of microglial cells in the spinal cord.
Zhang, Ying; Dun, Siok L.; Chen, Yi-Hung; Luo, Jin J.; Cowan, Alan; Dun, Nae J.
The present study tested the hypothesis that repetitive scratching provoked by either of two known pruritogens, compound 48/80 and 5′-guanidinonaltrindole (GNTI), is accompanied by activation of microglia cells in the mouse spinal cord. Immunohistochemical studies revealed that CD11b, a cell surface marker of microglia cells, was up-regulated in the spinal cord 10–30 min post subcutaneous (s.c.) injection of compound 48/80 (50 μg/100 μl) or GNTI (0.3 mg/kg) to the back of the mouse neck. Numerous intensely labeled CD11b immunoreactive (irCD11b) cells, with the appearance of hypertrophic reactive microglia, were distributed throughout the gray and white matter. In contrast, weakly labeled irCD11b cells were distributed in the spinal cord from mice injected with saline. Western blots showed that CD11b expression levels were significantly increased in spinal cords of mice injected s.c. with either pruritogen, reached a peak response in about 30 min, and declined toward the basal level in the ensuing 60 min. In addition, phospho-p38 (p-p38), but not p38, levels were up-regulated in spinal cords from mice injected with compound 48/80 or GNTI, with a time course parallel to that of CD11b expression. Pretreatment of the mice with nalfurafine (20 μg/kg; s.c.), a κ opioid receptor agonist that has been shown to suppress scratching, reduced CD11b and p-p38 expression induced by either pruritogen. The result demonstrates, for the first time, that scratch behavior induced by pruritogens GNTI and compound 48/80 is accompanied by a parallel activation of microglia cells in the spinal cord. PMID:25354468
Background: Knowledge of the causes of spinal cord injury (SCI) and associated factors is critical in the development of successful prevention programs. Objective: This study analyzed data from the National SCI Database (NSCID) and National Shriners SCI Database (NSSCID) in the United States to examine specific etiologies of SCI by age, sex, race, ethnicity, day and month of injury, and neurologic outcomes. Methods: NSCID and NSSCID participants who had a traumatic SCI from 2005 to 2011 with known etiology were included in the analyses (N=7,834). Thirty-seven causes of injury documented in the databases were stratified by personal characteristics using descriptive analysis. Results: The most common causes of SCI were automobile crashes (31.5%) and falls (25.3%), followed by gunshot wounds (10.4%), motorcycle crashes (6.8%), diving incidents (4.7%), and medical/surgical complications (4.3%), which collectively accounted for 83.1% of total SCIs since 2005. Automobile crashes were the leading cause of SCI until age 45 years, whereas falls were the leading cause after age 45 years. Gunshot wounds, motorcycle crashes, and diving caused more SCIs in males than females. The major difference among race/ethnicity was in the proportion of gunshot wounds. More SCIs occurred during the weekends and warmer months, which seemed to parallel the increase of motorcycle- and diving-related SCIs. Level and completeness of injury are also associated with etiology of injury. Conclusions: The present findings suggest that prevention strategies should be tailored to the targeted population and major causes to have a meaningful impact on reducing the incidence of SCI. PMID:23678280
Patel, Sonali; Naidoo, Khimara; Thomas, Peter
Spinal cord infarction is rare and represents a diagnostic challenge for many physicians. There are few reported cases worldwide with a prevalence of 1.2% of all strokes. Circulation to the spinal cord is supplied by a rich anastomosis. The anterior spinal artery supplies the anterior two thirds of the spinal cord and infarction to this area is marked by paralysis, spinothalamic sensory deficit and loss of sphincter control depending on where the lesion is. Treatment of spinal cord infarction focuses on rehabilitation with diverse outcomes. This report presents a case of acute spinal cord infarction with acquisition of MRI to aid diagnosis.
Kohanawa, M; Asano, M; Min, Y; Minagawa, T; Nakane, A
Intravenous infection by Theiler's murine encephalomyelitis virus strain GD VII causes acute encephalomyelitis and paralysis in infected mice. However, nude mice and cyclophosphamide-treated ddY mice did not show paralysis when they were able to survive until day 20 post-infection (p.i.). Of ddY mice infected with 5 x 10(7) p.f.u./mouse, 70-80% showed symptoms of paralysis on day 20 p.i. The viral titres in the brain and spinal cord in infected mice were not significantly different between paralytic and non-paralytic mice. In all of the mice infected with the virus, CD4+ lymphocytes and CD8+ lymphocytes had infiltrated the brain on days 10, 12, 14 and 20 p.i. as demonstrated by flow cytometric analysis. In contrast, few T lymphocytes infiltrated the spinal cord in the non-paralytic mice. Administration of an anti-CD4 monoclonal antibody (MAb) or anti-T cell receptor-alpha beta MAb on day 6 p.i. inhibited paralysis until day 20 p.i., though 20% of the MAb-treated mice and 80% of the control mice showed paralysis. Administration of anti-CD8 MAb was not effective in the suppression of paralysis. The MAb treatment did not significantly augment viral replication in the spinal cord, although the viral titres in the brain of the MAb-treated mice increased significantly. After the transfer of spleen cells from infected C3H mice, the recipient mice infected with a small amount of the virus showed paralysis, though uninfected mice did not. This transfer could be blocked by CD4+ lymphocyte depletion of the donor mice. These results indicate that paralysis caused by acute myelitis in Theiler's virus strain GD VII infection is induced by CD4+ lymphocytes infiltrating the spinal cord.
Chari, Aswin; Hentall, Ian D.; Papadopoulos, Marios C.; Pereira, Erlick A. C.
Traumatic spinal cord injury (SCI) is a devastating neurological condition characterized by a constellation of symptoms including paralysis, paraesthesia, pain, cardiovascular, bladder, bowel and sexual dysfunction. Current treatment for SCI involves acute resuscitation, aggressive rehabilitation and symptomatic treatment for complications. Despite the progress in scientific understanding, regenerative therapies are lacking. In this review, we outline the current state and future potential of invasive and non-invasive neuromodulation strategies including deep brain stimulation (DBS), spinal cord stimulation (SCS), motor cortex stimulation (MCS), transcutaneous direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) in the context of SCI. We consider the ability of these therapies to address pain, sensorimotor symptoms and autonomic dysregulation associated with SCI. In addition to the potential to make important contributions to SCI treatment, neuromodulation has the added ability to contribute to our understanding of spinal cord neurobiology and the pathophysiology of SCI. PMID:28208601
Crane, Deborah A; Jaffee, Kenneth M; Kundu, Anjana
Background: This report describes a young woman with incomplete traumatic cervical spinal cord injury and intractable pruritus involving her dorsal forearm. Method: Case report. Findings: Anatomic distribution of the pruritus corresponded to the dermatomal distribution of her level of spinal cord injury and vertebral fusion. Symptoms were attributed to the spinal cord injury and possible cervical root injury. Pruritus was refractory to all treatments, including topical lidocaine, gabapentin, transcutaneous electrical nerve stimulation, intravenous Bier block, stellate ganglion block, and acupuncture. Conclusions: Further understanding of neuropathic pruritus is needed. Diagnostic workup of intractable pruritus should include advanced imaging to detect ongoing nerve root compression. If diagnostic studies suggest radiculopathy, epidural steroid injection should be considered. Because the autonomic nervous system may be involved in complex chronic pain or pruritic syndromes, sympatholysis via such techniques as stellate ganglion block might be effective. PMID:19777867
Yin, Hong Z.; Yu, Stephen; Hsu, Cheng-I; Liu, Joe; Acab, Allan; Wu, Richard; Tao, Anna; Chiang, Benjamin J.; Weiss, John H.
The neurotoxin beta-N-methylamino-L-alanine (BMAA) was first identified as a “toxin of interest” in regard to the amyotrophic lateral sclerosis–Parkinsonism Dementia Complex of Guam (ALS/PDC); studies in recent years highlighting widespread environmental sources of BMAA exposure and providing new clues to toxic mechanisms have suggested possible relevance to sporadic ALS as well. However, despite clear evidence of uptake into tissues and a range of toxic effects in cells and animals, an animal model in which BMAA induces a neurodegenerative picture resembling ALS is lacking, possibly in part reflecting limited understanding of critical factors pertaining to its absorption, biodistribution and metabolism. To bypass some of these issues and ensure delivery to a key site of disease pathology, we examined effects of prolonged (30 day) intrathecal infusion in wild type (WT) rats, and rats harboring the familial ALS associated G93A SOD1 mutation, over an age range (80±2 to 110±2 days) during which the G93A rats are developing disease pathology yet remain asymptomatic. The BMAA exposures induced changes that in many ways resembles those seen in the G93A rats, with degenerative changes in ventral horn motor neurons (MNs) with relatively little dorsal horn pathology, marked ventral horn astrogliosis and increased 3-nitrotyrosine labeling in and surrounding MNs, a loss of labeling for the astrocytic glutamate transporter, GLT-1, surrounding MNs, and mild accumulation and aggregation of TDP-43 in the cytosol of some injured and degenerating MNs. Thus, prolonged intrathecal infusion of BMAA can reproduce a picture in spinal cord incorporating many of the pathological hallmarks of diverse forms of human ALS, including substantial restriction of overt pathological changes to the ventral horn, consistent with the possibility that environmental BMAA exposure could be a risk factor and/or contributor to some human disease. PMID:24918341
Yin, Hong Z; Yu, Stephen; Hsu, Cheng-I; Liu, Joe; Acab, Allan; Wu, Richard; Tao, Anna; Chiang, Benjamin J; Weiss, John H
The neurotoxin beta-N-methylamino-l-alanine (BMAA) was first identified as a "toxin of interest" in regard to the amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC); studies in recent years highlighting widespread environmental sources of BMAA exposure and providing new clues to toxic mechanisms have suggested possible relevance to sporadic ALS as well. However, despite clear evidence of uptake into tissues and a range of toxic effects in cells and animals, an animal model in which BMAA induces a neurodegenerative picture resembling ALS is lacking, possibly in part reflecting limited understanding of critical factors pertaining to its absorption, biodistribution and metabolism. To bypass some of these issues and ensure delivery to a key site of disease pathology, we examined effects of prolonged (30day) intrathecal infusion in wild type (WT) rats, and rats harboring the familial ALS associated G93A SOD1 mutation, over an age range (80±2 to 110±2days) during which the G93A rats are developing disease pathology yet remain asymptomatic. The BMAA exposures induced changes that in many ways resemble those seen in the G93A rats, with degenerative changes in ventral horn motor neurons (MNs) with relatively little dorsal horn pathology, marked ventral horn astrogliosis and increased 3-nitrotyrosine labeling in and surrounding MNs, a loss of labeling for the astrocytic glutamate transporter, GLT-1, surrounding MNs, and mild accumulation and aggregation of TDP-43 in the cytosol of some injured and degenerating MNs. Thus, prolonged intrathecal infusion of BMAA can reproduce a picture in spinal cord incorporating many of the pathological hallmarks of diverse forms of human ALS, including substantial restriction of overt pathological changes to the ventral horn, consistent with the possibility that environmental BMAA exposure could be a risk factor and/or contributor to some human disease.
Examines effects of spinal cord injury on sexuality. Discusses areas of sexual concern. Provides suggestions for treating clients with spinal cord injuries experiencing sexual difficulties. Concludes that major goal in working with clients with spinal cord injuries who have sexual difficulties should be the facilitation of a creative and…
Kesiktas, Nur; Paker, Nurdan; Bugdayci, Derya; Sencan, Sureyya; Karan, Ayse; Muslumanoglu, Lutfiye
Various rating scales have been used to assess ability in individuals with spinal cord injury. There is no specific functional assessment scale for Turkish patients with spinal cord injury. The Spinal Cord Independence Measure (SCIM) is a specific test, which has become popular in the last decade. A study was conducted to validate and evaluate the…
Misiaszek, J E; Barclay, J K; Brooke, J D
1. H reflexes were elicited in the second interosseous muscle of the hindpaw of the anesthetized dog during passive rotation of the shank about the ipsilateral or contralateral knee. Reflexes sampled at four points in the cycle of movement were compared with stationary controls. For both the ipsilateral and contralateral limb manipulations, reflexes were significantly reduced (P < 0.05) across the cycle of movement. Position-related modulation of the reflex amplitude was not detected (P > 0.05) in either instance. 2. The experiments were then repeated after the spinal transection of each animal at the level of T13. Passive rotation about either the ipsilateral or contralateral knee significantly attenuated (P < 0.05) the H reflex across a cycle of movement in the spinal dog. There was little difference in the amount of inhibition produced by the movement between the intact and spinal animals. On average, the reflex was attenuated 29 +/- 2.4% (mean +/- SE) in the intact animals and 32 +/- 2.1% in the spinal animals. 3. It is concluded that passive rotation about the knee of either leg leads to suppression of the H reflex of the second interosseous muscle both in the ipsilateral, moving leg and the contralateral, stationary one. This reflex suppression occurs across the cycle of movement. The mediating circuitry lies within the spinal cord, caudal to T13.
Liu, Jinbo; Du, Lijian
Mitochondrial dysfunction is a direct target of hypoxic/ischemic stress in astrocytes, which results in the increased production of reactive oxygen species (ROS). Previous reports showed that ROS can activate NF-kB in spinal cord astrocytes, which occurs as a secondary injury during the pathological process of spinal cord injury (SCI). Protein kinase RNA (PKR)-like ER kinase (PERK) plays an important role in mitochondrial dysfunction. To elucidate the specific role of PERK in hypoxic/ischemic-induced NF-kB activation in spinal astrocytes, we utilized an in vitro oxygen-glucose deprivation (OGD) model, which showed an enhanced formation of ROS and NF-kB activation. Knockdown of PERK resulted in reduced activation of PERK and ROS generation in astrocytes under OGD conditions. Notably, the knockdown of PERK also induced NF-kB activation in astrocytes. These data suggest that PERK is required for the hypoxic/ischemic-induced-dependent regulation of ROS and that it is involved in NF-kB activation in the astrocytes.
Nardone, Raffaele; Höller, Yvonne; Thomschewski, Aljoscha; Höller, Peter; Lochner, Piergiorgio; Golaszewski, Stefan; Brigo, Francesco; Trinka, Eugen
Changes in descending serotonergic innervation of spinal neural activity have been implicated in symptoms of paralysis, spasticity, sensory disturbances and pain following spinal cord injury (SCI). Serotonergic neurons possess an enhanced ability to regenerate or sprout after many types of injury, including SCI. Current research suggests that serotonine (5-HT) release within the ventral horn of the spinal cord plays a critical role in motor function, and activation of 5-HT receptors mediates locomotor control. 5-HT originating from the brain stem inhibits sensory afferent transmission and associated spinal reflexes; by abolishing 5-HT innervation SCI leads to a disinhibition of sensory transmission. 5-HT denervation supersensitivity is one of the key mechanisms underlying the increased motoneuron excitability that occurs after SCI, and this hyperexcitability has been demonstrated to underlie the pathogenesis of spasticity after SCI. Moreover, emerging evidence implicates serotonergic descending facilitatory pathways from the brainstem to the spinal cord in the maintenance of pathologic pain. There are functional relevant connections between the descending serotonergic system from the rostral ventromedial medulla in the brainstem, the 5-HT receptors in the spinal dorsal horn, and the descending pain facilitation after tissue and nerve injury. This narrative review focussed on the most important studies that have investigated the above-mentioned effects of impaired 5-HT-transmission in humans after SCI. We also briefly discussed the promising therapeutical approaches with serotonergic drugs, monoclonal antibodies and intraspinal cell transplantation.
Petrie, Michael A.; Suneja, Manish; Faidley, Elizabeth; Shields, Richard K.
Abstract Spinal cord injury (SCI) is associated with muscle atrophy, transformation of muscle fibers to a fast fatigable phenotype, metabolic inflexibility (diabetes), and neurogenic osteoporosis. Electrical stimulation of paralyzed muscle may mitigate muscle metabolic abnormalities after SCI, but there is a risk for a fracture to the osteoporotic skeletal system. The goal of this study was to determine if low force stimulation (3 Hz) causes fatigue of chronically paralyzed muscle consistent with selected muscle gene expression profiles. We tested 29 subjects, nine with a SCI and 20 without and SCI, during low force fatigue protocol. Three SCI and three non‐SCI subjects were muscle biopsied for gene and protein expression analysis. The fatigue index (FI) was 0.21 ± 0.27 and 0.91 ± 0.01 for the SCI and non‐SCI groups, respectively, supporting that the low force protocol physiologically fatigued the chronically paralyzed muscle. The post fatigue potentiation index (PI) for the SCI group was increased to 1.60 ± 0.06 (P <0.001), while the non‐SCI group was 1.26 ± 0.02 supporting that calcium handling was compromised with the low force stimulation. The mRNA expression from genes that regulate atrophy and fast properties (MSTN, ANKRD1, MYH8, and MYCBP2) was up regulated, while genes that regulate oxidative and slow muscle properties (MYL3, SDHB, PDK2, and RyR1) were repressed in the chronic SCI muscle. MSTN, ANKRD1, MYH8, MYCBP2 gene expression was also repressed 3 h after the low force stimulation protocol. Taken together, these findings support that a low force single twitch activation protocol induces paralyzed muscle fatigue and subsequent gene regulation. These findings suggest that training with a low force protocol may elicit skeletal muscle adaptations in people with SCI. PMID:24744911
Sheliakin, A M; Preobrazhenskaia, I G; Komantsev, V N; Makarovskiĭ, A N; Bogdanov, O V
Transdermal micropolarization of the spinal cord was made in patients with consequences of the spinal cord injury or tuberculous spondylitis. Changes in clinical and electrophysiologic status were evaluated. It was found that local direct current through dermal electrodes promotes an improvement of both motor and autonomic functions in such patients. This corresponded to a positive dynamics both of the spinal cord state and cardiac activity. Possible mechanisms of influence of the direct current on the spinal cord as well as perspectives of application of micropolarization in spinal cord's damage are outlined.
Hofstoetter, Ursula S; Krenn, Matthias; Danner, Simon M; Hofer, Christian; Kern, Helmut; McKay, William B; Mayr, Winfried; Minassian, Karen
The level of sustainable excitability within lumbar spinal cord circuitries is one of the factors determining the functional outcome of locomotor therapy after motor-incomplete spinal cord injury. Here, we present initial data using noninvasive transcutaneous lumbar spinal cord stimulation (tSCS) to modulate this central state of excitability during voluntary treadmill stepping in three motor-incomplete spinal cord-injured individuals. Stimulation was applied at 30 Hz with an intensity that generated tingling sensations in the lower limb dermatomes, yet without producing muscle reflex activity. This stimulation changed muscle activation, gait kinematics, and the amount of manual assistance required from the therapists to maintain stepping with some interindividual differences. The effect on motor outputs during treadmill-stepping was essentially augmentative and step-phase dependent despite the invariant tonic stimulation. The most consistent modification was found in the gait kinematics, with the hip flexion during swing increased by 11.3° ± 5.6° across all subjects. This preliminary work suggests that tSCS provides for a background increase in activation of the lumbar spinal locomotor circuitry that has partially lost its descending drive. Voluntary inputs and step-related feedback build upon the stimulation-induced increased state of excitability in the generation of locomotor activity. Thus, tSCS essentially works as an electrical neuroprosthesis augmenting remaining motor control.
Ruiz-Miyazawa, Kenji W.; Zarpelon, Ana C.; Pinho-Ribeiro, Felipe A.; Pavão-de-Souza, Gabriela F.; Casagrande, Rubia; Verri, Waldiceu A.
Vinpocetine is a safe nootropic agent used for neurological and cerebrovascular diseases. The anti-inflammatory activity of vinpocetine has been shown in cell based assays and animal models, leading to suggestions as to its utility in analgesia. However, the mechanisms regarding its efficacy in inflammatory pain treatment are still not completely understood. Herein, the analgesic effect of vinpocetine and its anti-inflammatory and antioxidant mechanisms were addressed in murine inflammatory pain models. Firstly, we investigated the protective effects of vinpocetine in overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone (PBQ) and formalin. The intraplantar injection of carrageenan was then used to induce inflammatory hyperalgesia. Mechanical and thermal hyperalgesia were evaluated using the electronic von Frey and the hot plate tests, respectively, with neutrophil recruitment to the paw assessed by a myeloperoxidase activity assay. A number of factors were assessed, both peripherally and in the spinal cord, including: antioxidant capacity, reduced glutathione (GSH) levels, superoxide anion, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) levels, as well as nuclear factor kappa B (NF-κB) activation. Vinpocetine inhibited the overt pain-like behavior induced by acetic acid, PBQ and formalin (at both phases), as well as the carrageenan-induced mechanical and thermal hyperalgesia and associated neutrophil recruitment. Both peripherally and in the spinal cord, vinpocetine also inhibited: antioxidant capacity and GSH depletion; increased superoxide anion; IL-1β and TNF-α levels; and NF-κB activation. As such, vinpocetine significantly reduces inflammatory pain by targeting oxidative stress, cytokine production and NF-κB activation at both peripheral and spinal cord levels. PMID:25822523
Dowler, Denetta; Batiste, Linda; Whidden, Eddie
Examination of over 1,000 calls to the Job Accommodation Network involving workers with spinal cord injury identified the nature of the industry, job, career progression, and accessibility solutions. The number of calls increased dramatically after passage of the Americans with Disabilities Act. (SK)
Berić, A; Light, J K
Three male and two female patients with anorgasmia and dissociated sensory loss due to an anterior spinal cord syndrome are described. Clinical, neurophysiological and quantitative sensory evaluation revealed preservation of the large fibre dorsal column functions from the lumbosacral segments with concomitant severe dysfunction or absence of the small fibre neospinothalamic mediated functions. These findings indicate a role for the spinothalamic system in orgasm.
Aksu, Gorkem; Fayda, Merdan; Saynak, Mert; Karadeniz, Ahmet
This article presents a case of multiple vertebral hemangiomas in a 58-year-old man with pain in the dorsal region and bilateral progressive foot numbness. Magnetic resonance imaging revealed multiple vertebral hemangiomas. One hemangioma at the T7 level demonstrated epidural extension, causing spinal cord compression. After treatment with radiotherapy, the patient's symptoms improved significantly.
Engel, S.; Murphy, G. S.; Athanasou, J. A.; Hickey, L.
A study of 83 Australian adults with spinal cord injuries found that at least 56% had worked at some time post-injury and those who were working when surveyed had done so for an average of close to 10 years. Clerical, office, and administrative occupations proved to be the most suitable. (Author/CR)
Adachi, Y.; Oyama, D.; Somchai, N.; Kawabata, S.; Uehara, G.
Spinal cord functional imaging by magnetospinography (MSG) is a noninvasive diagnostic method for spinal cord diseases. However, the accuracy and spatial resolution of lesion localization by MSG have barely been evaluated in detail so far. We developed a simplified spinal cord phantom for MSG evaluation. The spinal cord phantom is composed of a cylindrical vessel filled with saline water, which acts as a model of a neck. A set of modeled vertebrae is arranged in the cylindrical vessel, which has a neural current model made from catheter electrodes. The neural current model emulates the current distribution around the activated site along the axon of the spinal cord nerve. Our MSG system was used to observe the magnetic field from the phantom; a quadrupole-like pattern of the magnetic field distribution, which is a typical distribution pattern for spinal cord magnetic fields, was successfully reproduced by the phantom. Hence, the developed spinal cord phantom can be used to evaluate MSG source analysis methods.
Züchner, Mark; Glover, Joel C.; Boulland, Jean-Luc
Spinal cord injury (SCI) typically causes devastating neurological deficits, particularly through damage to fibers descending from the brain to the spinal cord. A major current area of research is focused on the mechanisms of adaptive plasticity that underlie spontaneous or induced functional recovery following SCI. Spontaneous functional recovery is reported to be greater early in life, raising interesting questions about how adaptive plasticity changes as the spinal cord develops. To facilitate investigation of this dynamic, we have developed a SCI model in the neonatal mouse. The model has relevance for pediatric SCI, which is too little studied. Because neural plasticity in the adult involves some of the same mechanisms as neural plasticity in early life1, this model may potentially have some relevance also for adult SCI. Here we describe the entire procedure for generating a reproducible spinal cord compression (SCC) injury in the neonatal mouse as early as postnatal (P) day 1. SCC is achieved by performing a laminectomy at a given spinal level (here described at thoracic levels 9-11) and then using a modified Yasargil aneurysm mini-clip to rapidly compress and decompress the spinal cord. As previously described, the injured neonatal mice can be tested for behavioral deficits or sacrificed for ex vivo physiological analysis of synaptic connectivity using electrophysiological and high-throughput optical recording techniques1. Earlier and ongoing studies using behavioral and physiological assessment have demonstrated a dramatic, acute impairment of hindlimb motility followed by a complete functional recovery within 2 weeks, and the first evidence of changes in functional circuitry at the level of identified descending synaptic connections1. PMID:27078037
Scott, Si; Antwi-Yeboah, Y; Bucur, Sd
Carcinoid tumours are rare with an incidence of 5.25/100,000. They predominantly originate in the gastrointestinal tract (50-60%) or bronchopulmonary system (25-30%). Common sites of metastasis are lymph nodes, liver, lungs and bone. Spinal metastasis are rare, but has been reported in patients with symptoms of spinal cord compression including neurological deficits. We report a rare case of carcinoid metastasis with spinal cord compression, in a 63-year-old man, presenting with a one-year history of back pain without any neurological symptoms. The patient underwent a two-level decompressive laminectomy of T10 and T11 as well as piecemeal tumour resection. Post-operatively the patient made a good recovery without complications.
Scott, SI; Antwi-Yeboah, Y; Bucur, SD
Carcinoid tumours are rare with an incidence of 5.25/100,000. They predominantly originate in the gastrointestinal tract (50-60%) or bronchopulmonary system (25-30%). Common sites of metastasis are lymph nodes, liver, lungs and bone. Spinal metastasis are rare, but has been reported in patients with symptoms of spinal cord compression including neurological deficits. We report a rare case of carcinoid metastasis with spinal cord compression, in a 63-year-old man, presenting with a one-year history of back pain without any neurological symptoms. The patient underwent a two-level decompressive laminectomy of T10 and T11 as well as piecemeal tumour resection. Post-operatively the patient made a good recovery without complications. PMID:24960730
Zhou, Yulong; Ye, Libing; Zheng, Binbin; Zhu, Sipin; Shi, Hongxue; Zhang, Hongyu; Wang, Zhouguang; Wei, Xiaojie; Chen, Daqing; Li, Xiaokun; Xu, Huazi; Xiao, Jian
This study aims to investigate the role of endocytoplasmic reticulum (ER) stress induced by spinal cord injury (SCI) in blood-spinal cord barrier (BSCB) disruption and the effect of phenylbutyrate (PBA) on BSCB disruption after SCI. After a moderate contusion injury at the T9 level of spinal cord with a vascular clip, PBA was immediately administered into injured rat via intraperitoneal injection (100 mg/kg) and then further treated once a day for 2 weeks for behavior test. Spinal cord was collected at 1 day post-injury for evaluation of the effects of ER stress and PBA on BSCB disruption after SCI. PBA significantly attenuated BSCB permeability and degradation of tight junction molecules such as P120, β-catenin, Occludin and Claudin5 at 1 day after injury and improved functional recovery in the rat model of trauma. The BSCB protective effect of PBA is related to the inhibition of ER stress induced by SCI. In addition, PBA significantly inhibited the increase of ER stress markers and prevents loss of tight junction and adherens junction proteins in TG-treated human brain microvascular endothelial cells (HBMEC). Taken together, our data demonstrate that therapeutic strategies targeting ER stress may be suitable for the therapy of preserving BSCB integrity after SCI. PBA may be a new candidate as a therapeutic agent for protecting SCI by a compromised BSCB. PMID:27186310
Mukaino, Masahiko; Nakamura, Masaya; Yamada, Osamu; Okada, Seiji; Morikawa, Satoru; Renault-Mihara, Francois; Iwanami, Akio; Ikegami, Takeshi; Ohsugi, Yoshiyuki; Tsuji, Osahiko; Katoh, Hiroyuki; Matsuzaki, Yumi; Toyama, Yoshiaki; Liu, Meigen; Okano, Hideyuki
We previously reported the beneficial effect of administering an anti-mouse IL-6 receptor antibody (MR16-1) immediately after spinal cord injury (SCI). The purpose of our present study was to clarify the mechanism underlying how MR16-1 improves motor function after SCI. Quantitative analyses of inflammatory cells using flow cytometry, and immunohistochemistry with bone marrow-chimeric mice generated by transplanting genetically marked purified hematopoietic stem cells, revealed that MR16-1 dramatically switched the central player in the post-traumatic inflammation, from hematogenous macrophages to resident microglia. This change was accompanied by alterations in the expression of relevant cytokines within the injured spinal cord; the expression of recruiting chemokines including CCL2, CCL5, and CXCL10 was decreased, while that of Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF), a known mitogen for microglia, was increased. We also showed that the resident microglia expressed higher levels of phagocytic markers than the hematogenous macrophages. Consistent with these findings, we observed significantly decreased tissue damage and reduced levels of myelin debris and Nogo-A, the axonal growth inhibitor, by MR16-1 treatment. Moreover, we observed increased axonal regeneration and/or sprouting in the MR16-1-treated mice. Our findings indicate that the functional improvement elicited by MR16-1 involves microglial functions, and provide new insights into the role of IL-6 signaling in the pathology of SCI.
Sellers, Drew L.; Maris, Don O.; Horner, Philip J.
Progenitors that express NG2-proteoglycan are the predominant self-renewing cell within the CNS. NG2-progenitors replenish oligodendrocyte populations within the intact stem-cell niche, and cycling NG2-cells are among the first cells to react to CNS insults. We investigated the role of NG2-progenitors after spinal cord injury (SCI) and how bone morphogen protein (BMP) signals remodel the progressive post-injury niche. Progeny labeled by an NG2-specific reporter virus undergo a coordinated shift in differentiation profile. NG2-progeny born 24-hours post-injury (PI) produce scar-forming astrocytes and transient populations of novel phagocytic astrocytes shown to contain denatured myelin within cathepsin-D labeled endosomes, but NG2-progenitors born 7-days PI differentiate into oligodendrocytes and express myelin on processes that wrap axons. Analysis of spinal cord mRNA shows a temporal-shift in the niche-transcriptome of ligands that affect post-injury remodeling and direct progenitor differentiation. We conclude that NG2-progeny are diverse lineages that obey progressive-cues after trauma to replenish the injured niche. PMID:19458241
Kirkpatrick, John P.; Kogel, Albert J. van der; Schultheiss, Timothy E.
Dose-volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8-2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (alpha/beta = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage becoming evident about 6 months post-RT and increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare (<1%) when the maximum spinal cord dose is limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose-volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen.
Stirling, David P; Cummins, Karen; Mishra, Manoj; Teo, Wulin; Yong, V Wee; Stys, Peter
Improving neurological outcome after spinal cord injury is a major clinical challenge because axons, once severed, do not regenerate but 'dieback' from the lesion site. Although microglia, the immunocompetent cells of the brain and spinal cord respond rapidly to spinal cord injury, their role in subsequent injury or repair remains unclear. To assess the role of microglia in spinal cord white matter injury we used time-lapse two-photon and spectral confocal imaging of green fluorescent protein-labelled microglia, yellow fluorescent protein-labelled axons, and Nile Red-labelled myelin of living murine spinal cord and revealed dynamic changes in white matter elements after laser-induced spinal cord injury in real time. Importantly, our model of acute axonal injury closely mimics the axonopathy described in well-characterized clinically relevant models of spinal cord injury including contusive-, compressive- and transection-based models. Time-lapse recordings revealed that microglia were associated with some acute pathophysiological changes in axons and myelin acutely after laser-induced spinal cord injury. These pathophysiological changes included myelin and axonal spheroid formation, spectral shifts in Nile Red emission spectra in axonal endbulbs detected with spectral microscopy, and 'bystander' degeneration of axons that survived the initial injury, but then succumbed to secondary degeneration. Surprisingly, modulation of microglial-mediated release of neurotoxic molecules failed to protect axons and myelin. In contrast, sterile stimulation of microglia with the specific toll-like receptor 2 agonist Pam2CSK4 robustly increased the microglial response to ablation, reduced secondary degeneration of central myelinated fibres, and induced an alternative (mixed M1:M2) microglial activation profile. Conversely, Tlr2 knock out: Thy1 yellow fluorescent protein double transgenic mice experienced greater axonal dieback than littermate controls. Thus, promoting an alternative
Umezawa, Nobuo; Arisaka, Hirofumi; Sakuraba, Shigeki; Sugita, Takeo; Matsumoto, Akiko; Kaku, Yuki; Yoshida, Kazu-ichi; Kuwana, Shun-ichi
Orexins (hypocretins) play a crucial role in arousal, feeding, and endocrine function. We previously reported that orexin-B activated respiratory neurons in the isolated brainstem-spinal cords of neonatal rats. We herein determined whether orexin-B antagonized respiratory depression induced by sevoflurane, propofol, or remifentanil. We recorded C4 nerve bursts as an index of inspiratory activity in a brainstem-spinal cord preparation. The preparation was superfused with a solution equilibrated with 3% sevoflurane alone for 10 min and the superfusate was then switched to a solution containing sevoflurane plus orexin-B. Sevoflurane decreased the C4 burst rate and the integrated C4 amplitude. The C4 burst rate and amplitude were reversed by 0.5 μM orexin-B, but not by 0.1 μM orexin-B. The decrease induced in the C4 burst rate by 10 μM propofol or 0.01 μM remifentanil was significantly antagonized by 0.1 μM orexin-B. Respiratory depression induced by a higher concentration (0.1 μM) of remifentanil was not restored by 0.1 μM orexin-B. These results demonstrated that orexin-B antagonized respiratory depression induced by sevoflurane, propofol, or remifentanil.
Zhang, Chao; Wang, Chendan; Ren, Jianbo; Guo, Xiangjie; Yun, Keming
Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated whether morphine, a common opioid ligand, could affect glutamate-induced apoptosis in astrocytes. Primary cultured astrocytes were incubated with glutamate in the presence/absence of morphine. It was found that morphine could reduce glutamate-induced apoptosis of astrocytes. Furthermore, glutamate activated Ca(2+) release, thereby inducing endoplasmic reticulum (ER) stress in astrocytes, while morphine attenuated this deleterious effect. Using siRNA to reduce the expression of κ-opioid receptor, morphine could not effectively inhibit glutamate-stimulated Ca(2+) release in astrocytes, the protective effect of morphine on glutamate-injured astrocytes was also suppressed. These results suggested that morphine could protect astrocytes from glutamate-induced apoptosis via reducing Ca(2+) overload and ER stress pathways. In conclusion, this study indicated that excitotoxicity participated in the glutamate mediated apoptosis in astrocytes, while morphine attenuated this deleterious effect via regulating Ca(2+) release and ER stress.
Grau, James W.
The paper reviews research examining whether and how training can induce a lasting change in spinal cord function. A framework for the study of learning, and some essential issues in experimental design, are discussed. A core element involves delayed assessment under common conditions. Research has shown that brain systems can induce a lasting (memory-like) alteration in spinal function. Neurons within the lower (lumbosacral) spinal cord can also adapt when isolated from the brain by means of a thoracic transection. Using traditional learning paradigms, evidence suggests that spinal neurons support habituation and sensitization as well as Pavlovian and instrumental conditioning. At a neurobiological level, spinal systems support phenomena (e.g., long-term potentiation), and involve mechanisms (e.g., NMDA mediated plasticity, protein synthesis) implicated in brain-dependent learning and memory. Spinal learning also induces modulatory effects that alter the capacity for learning. Uncontrollable/unpredictable stimulation disables the capacity for instrumental learning and this effect has been linked to the cytokine tumor necrosis factor (TNF). Predictable/controllable stimulation enables learning and counters the adverse effects of uncontrollable simulation through a process that depends upon brain-derived neurotrophic factor (BDNF). Finally, uncontrollable, but not controllable, nociceptive stimulation impairs recovery after a contusion injury. A process-oriented approach (neurofunctionalism) is outlined that encourages a broader view of learning phenomena. PMID:23973905
Chen, Xiang Yang; Chen, Yi; Wang, Yu; Thompson, Aiko; Carp, Jonathan S.; Segal, Richard L.; Wolpaw, Jonathan R.
Spinal reflex conditioning changes reflex size, induces spinal cord plasticity, and modifies locomotion. Appropriate reflex conditioning can improve walking in rats after spinal cord injury (SCI). Reflex conditioning offers a new therapeutic strategy for restoring function in people with SCI. This approach can address the specific deficits of individuals with SCI by targeting specific reflex pathways for increased or decreased responsiveness. In addition, once clinically significant regeneration can be achieved, reflex conditioning could provide a means of re-educating the newly (and probably imperfectly) reconnected spinal cord. PMID:20590534
Background Experimental and clinical studies showed that intraoperative infusionof remifentanil has been associated with postoperative hyperalgesia. Previous reports suggested that spinal N-methyl-D-aspartate (NMDA) receptors may contribute to the development and maintenance of opioid-induced hyperalgesia. In the present study, we used a rat model of postoperative pain to investigate the role of tyrosine phosphorylation of NMDA receptor 2B (NR2B) subunit in spinal cord in the postoperative hyperalgesia induced by remifentanil and the intervention of pretreatment with ketamine. Results Intraoperative infusion of remifentanil (0.04 mg/kg, subcutaneous) significantly enhanced mechanical allodynia and thermal hyperalgesia induced by the plantar incision during the postoperative period (each lasting between 2 h and 48 h), which was attenuated by pretreatment with ketamine (10 mg/kg, subcutaneous). Correlated with the pain behavior changes, immunocytochemical and western blotting experiments in our study revealed that there was a marked increase in NR2B phosphorylation at Tyr1472 in the superficial dorsal horn after intraoperative infusion of remifentanil, which was attenuated by pretreatment with ketamine. Conclusions This study provides direct evidence that tyrosine phosphorylation of the NR2B at Tyr1472 in spinal dosal horn contributes to postoperative hyperalgesia induced by remifentanil and supports the potential therapeutic value of ketamine for improving postoperative hyperalgesia induced by remifentanil. PMID:20042082
Hou, Shaoping; Carson, David M; Wu, Di; Klaw, Michelle C; Houlé, John D; Tom, Veronica J
Dopamine (DA) neurons in the mammalian central nervous system are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine micturition center. Here we show that DA is produced in the rat spinal cord and modulates the bladder reflex. We observed numerous tyrosine hydroxylase (TH)(+) neurons in the autonomic nuclei and superficial dorsal horn in L6-S3 spinal segments. These neurons are dopamine-β-hydroxylase (DBH)(-) and some contain detectable dopamine decarboxylase (DDC), suggesting their capacity to produce DA. Interestingly, following a complete thoracic spinal cord injury (SCI) to interrupt supraspinal projections, more TH(+) neurons emerged in the lumbosacral spinal cord, coincident with a sustained, low level of DA expression there and a partially recovered micturition reflex. Non-selective blockade of spinal DA receptors reduced bladder activity whereas activation of spinal D2-like receptors increased bladder activity and facilitated voiding. Additionally, depletion of lumbosacral TH(+) neurons with 6-hydroxydopamine (6-OHDA) decreased bladder non-voiding contractions and voiding efficiency. Furthermore, injecting the transsynaptic neuronal tracer pseudorabies virus (PRV) into the bladder detrusor labeled TH(+) cells in the lumbosacral cord, confirming their involvement in spinal micturition reflex circuits. These results illustrate that DA is synthesized in the rat spinal cord; plasticity of lumbosacral TH(+) neurons following SCI may contribute to DA expression and modulate the spinal bladder reflex. Thus, spinally-derived DA and receptors could be a novel therapeutic target to improve micturition recovery after SCI.
Thielen, K.R.; Miller, G.M.
To determine the MR appearance of spinal cord multiple sclerosis (MS) plaques in patients presenting with myclopathy by using a high-field (1.5 T) imager. We studied 119 patients who underwent high-field (1.5 T) MR studies of the spinal cord for evaluation of myelopathy. All 119 patients were thought to have possible findings of spinal cord MS at the time of the MRI interpretation. Sixty-four plaques were studied in 47 patients with clinically definite MS and adequate quality MRI. Of these patients 68% had a single spinal cord plaque, 19% had two plaques, and 13% had three or more plaques. Sixty-two percent of the plaques occurred in the cervical spinal cord and most frequently involved the posterior (41%) and lateral (25%) aspects of the spinal cord. None of the 64 lesions involved the entire thickness of the spinal cord. The lesion length varied from 2 to 60 mm, with 84% of the lesions <15 mm in length. The spinal cord diameter was unchanged in 84% of plaques, enlarged at the level of the lesion in 14%, and atrophic in 2%. Just over half (55%) of the plaques enhanced with intravenously administered gadolinium. Of the patients who received synchronous head and spinal cord examinations on the same day, 24% had normal findings on the MR study of the head. Follow-up spinal cord studies were available in nine patients. New lesions developed in two patients, while previously described lesions resolved. In three patients only new lesions developed. In four patients no change occurred in the existing number of cord plaques. Spinal cord demyelinating plaques present as well-circumscribed foci of increased T2 signal that asymmetrically involve the spinal cord parenchyma. Knowledge of their usual appearance may prevent unnecessary biopsy. An MR examination of the head may confirm the imaging suggestion of spinal cord demyelinating disease, because up to 76% of patients have abnormal intracranial findings. 15 refs., 7 figs.
Prados, Ferran; Ashburner, John; Blaiotta, Claudia; Brosch, Tom; Carballido-Gamio, Julio; Cardoso, Manuel Jorge; Conrad, Benjamin N; Datta, Esha; Dávid, Gergely; Leener, Benjamin De; Dupont, Sara M; Freund, Patrick; Wheeler-Kingshott, Claudia A M Gandini; Grussu, Francesco; Henry, Roland; Landman, Bennett A; Ljungberg, Emil; Lyttle, Bailey; Ourselin, Sebastien; Papinutto, Nico; Saporito, Salvatore; Schlaeger, Regina; Smith, Seth A; Summers, Paul; Tam, Roger; Yiannakas, Marios C; Zhu, Alyssa; Cohen-Adad, Julien
An important image processing step in spinal cord magnetic resonance imaging is the ability to reliably and accurately segment grey and white matter for tissue specific analysis. There are several semi- or fully-automated segmentation methods for cervical cord cross-sectional area measurement with an excellent performance close or equal to the manual segmentation. However, grey matter segmentation is still challenging due to small cross-sectional size and shape, and active research is being conducted by several groups around the world in this field. Therefore a grey matter spinal cord segmentation challenge was organised to test different capabilities of various methods using the same multi-centre and multi-vendor dataset acquired with distinct 3D gradient-echo sequences. This challenge aimed to characterize the state-of-the-art in the field as well as identifying new opportunities for future improvements. Six different spinal cord grey matter segmentation methods developed independently by various research groups across the world and their performance were compared to manual segmentation outcomes, the present gold-standard. All algorithms provided good overall results for detecting the grey matter butterfly, albeit with variable performance in certain quality-of-segmentation metrics. The data have been made publicly available and the challenge web site remains open to new submissions. No modifications were introduced to any of the presented methods as a result of this challenge for the purposes of this publication.
Santos-Nogueira, Eva; López-Serrano, Clara; Hernández, Joaquim; Lago, Natalia; Astudillo, Alma M.; Balsinde, Jesús; Estivill-Torrús, Guillermo; de Fonseca, Fernando Rodriguez; Chun, Jerold
Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions that signals through six known G-protein-coupled receptors (LPA1–LPA6). A wide range of LPA effects have been identified in the CNS, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and development of neuropathic pain. However, little is known about the involvement of LPA in CNS pathologies. Herein, we demonstrate for the first time that LPA signaling via LPA1 contributes to secondary damage after spinal cord injury. LPA levels increase in the contused spinal cord parenchyma during the first 14 d. To model this potential contribution of LPA in the spinal cord, we injected LPA into the normal spinal cord, revealing that LPA induces microglia/macrophage activation and demyelination. Use of a selective LPA1 antagonist or mice lacking LPA1 linked receptor-mediated signaling to demyelination, which was in part mediated by microglia. Finally, we demonstrate that selective blockade of LPA1 after spinal cord injury results in reduced demyelination and improvement in locomotor recovery. Overall, these results support LPA–LPA1 signaling as a novel pathway that contributes to secondary damage after spinal cord contusion in mice and suggest that LPA1 antagonism might be useful for the treatment of acute spinal cord injury. SIGNIFICANCE STATEMENT This study reveals that LPA signaling via LPA receptor type 1 activation causes demyelination and functional deficits after spinal cord injury. PMID:26180199
Mourelo Fariña, M; Salvador de la Barrera, S; Montoto Marqués, A; Ferreiro Velasco, M E; Galeiras Vázquez, R
The aim of treatment in acute traumatic spinal cord injury is to preserve residual neurologic function, avoid secondary injury, and restore spinal alignment and stability. In this second part of the review, we describe the management of spinal cord injury focusing on issues related to short-term respiratory management, where the preservation of diaphragmatic function is a priority, with prediction of the duration of mechanical ventilation and the need for tracheostomy. Surgical assessment of spinal injuries based on updated criteria is discussed, taking into account that although the type of intervention depends on the surgical team, nowadays treatment should afford early spinal decompression and stabilization. Within a comprehensive strategy in spinal cord injury, it is essential to identify and properly treat patient anxiety and pain associated to spinal cord injury, as well as to prevent and ensure the early diagnosis of complications secondary to spinal cord injury (thromboembolic disease, gastrointestinal and urinary disorders, pressure ulcers).
As the biomedical engineering field expands, combination technologies are demonstrating enormous potential for treating human disease. In particular, intersections between the rapidly developing fields of gene therapy and tissue engineering hold promise to achieve tissue regeneration. Nonviral gene therapy uses plasmid DNA to deliver therapeutic proteins in vivo for extended periods of time. Tissue engineering employs biomedical materials, such as polymers, to support the regrowth of injured tissue. In this thesis, a combination strategy to deliver genes and drugs in a polymeric scaffold was applied to a spinal cord injury model. In order to develop a platform technology to treat spinal cord injury, several nonviral gene delivery systems and polymeric scaffolds were evaluated in vitro and in vivo. Nonviral vector trafficking was evaluated in primary neuronal culture to develop an understanding of the barriers to gene transfer in neurons and their supporting glia. Although the most efficient gene carrier in vitro differed from the optimal gene carrier in vivo, confocal and electron microscopy of these nonviral vectors provided insights into the interaction of these vectors with the nucleus. A novel pathway for delivering nanoparticles into the nuclei of neurons and Schwann cells via vesicle trafficking was observed in this study. Reporter gene expression levels were evaluated after direct and remote delivery to the spinal cord, and the optimal nonviral vector, dose, and delivery strategy were applied to deliver the gene encoding the basic fibroblast growth factor (bFGF) to the spinal cord. An injectable and biocompatible gel, composed of the amphiphillic polymer poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG) was evaluated as a drug and gene delivery system in vitro, and combined with the optimized nonviral gene delivery system to treat spinal cord injury. Plasmid DNA encoding the bFGF gene and the therapeutic NEP1--40 peptide
Zeng, Xiang; Ma, Yuan‐huan; Chen, Yuan‐feng; Qiu, Xue‐cheng; Wu, Jin‐lang; Ling, Eng‐Ang
Abstract Extracellular matrix (ECM) expression is temporally and spatially regulated during the development of stem cells. We reported previously that fibronectin (FN) secreted by bone marrow mesenchymal stem cells (MSCs) was deposited on the surface of gelatin sponge (GS) soon after culture. In this study, we aimed to assess the function of accumulated FN on neuronal differentiating MSCs as induced by Schwann cells (SCs) in three dimensional transwell co‐culture system. The expression pattern and amount of FN of differentiating MSCs was examined by immunofluorescence, Western blot and immunoelectron microscopy. The results showed that FN accumulated inside GS scaffold, although its mRNA expression in MSCs was progressively decreased during neural induction. MSC‐derived neuron‐like cells showed spindle‐shaped cell body and long extending processes on FN‐decorated scaffold surface. However, after blocking of FN function by application of monoclonal antibodies, neuron‐like cells showed flattened cell body with short and thick neurites, together with decreased expression of integrin β1. In vivo transplantation study revealed that autocrine FN significantly facilitated endogenous nerve fiber regeneration in spinal cord transection model. Taken together, the present results showed that FN secreted by MSCs in the early stage accumulated on the GS scaffold and promoted the neurite elongation of neuronal differentiating MSCs as well as nerve fiber regeneration after spinal cord injury. This suggests that autocrine FN has a dynamic influence on MSCs in a three dimensional culture system and its potential application for treatment of traumatic spinal cord injury. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1902–1911, 2016. PMID:26991461
Kuerten, Stefanie; Kostova-Bales, Dilyana A; Frenzel, Lukas P; Tigno, Justine T; Tary-Lehmann, Magdalena; Angelov, Doychin N; Lehmann, Paul V
Mechanism-oriented studies of EAE rely mostly on gene-modified mice on the C57BL/6 background. Here we report that MP4-induced EAE displays characteristic differences in CNS pathology as compared to MOG peptide 35-55-elicited disease. While in the latter, the topology of CNS infiltration remained unchanged throughout the disease, in MP4-induced EAE it was dynamic and stage-dependent shifting from the brain to the spinal cord and finally to the cerebellum. Unlike in the MOG peptide model, the frequencies and sizes of CNS lesions in MP4-induced disease showed a clear correlation with clinical disease severity. These characteristic features of MP4-induced EAE may contribute to modelling the complex spectrum of disease manifestations seen in MS.
Centeno, Maria V.; Mutso, Amelia; Millecamps, Magali; Apkarian, A.Vania
Sarcosine is a competitive inhibitor of glycine type 1 transporter. We hypothesized that it may have analgesic and anti-neuropathic efficacy by a dual action: affecting neurotransmission in the prefrontal cortex as well as within the spinal cord. In rats with spared nerve injury (SNI) oral sarcosine reduced mechanical sensitivity for the injured limb (anti-neuropathy or anti-allodynia) as well as for the uninjured limb (analgesia), showing better dose efficacy for the injured limb. Intrathecal administration of sarcosine was more effective in reducing mechanical sensitivity for the uninjured paw. In contrast, prefrontal cortex infusions of sarcosine acutely reduced mechanical sensitivity for the injured paw. Repeated daily oral sarcosine induced anti-neuropathy, observed only after days of repeated treatment; this long term effect disappeared a few days after treatment cessation. The findings indicate that manipulating glycine T1 transporter at multiple central sites can induce acute analgesia, as well as acute and long-term reduction in neuropathic pain behavior. Analgesic effects seem primarily mediated through spinal cord circuitry while anti-neuropathic effects through prefrontal cortex circuitry, most likely through distinct molecular pathways. The results suggest that such an approach may provide a novel venue for treating clinical pain conditions. PMID:19577367
Sun, Chunhui; Shao, Jing; Su, Le; Zhao, Jing; Bi, Jianzhong; Yang, Shaonan; Zhang, Shangli; Gao, Jiangang; Miao, Junying
The rate of neuronal differentiation of bone marrow stromal cells (BMSCs) in vivo is very low; therefore, it is necessary to elevate the number of BMSC-derived neurons to cure neurodegenerative diseases. We previously reported that tricyclodecane-9-yl-xanthogenate (D609), an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), induced BMSCs to differentiate into neuron-like cells in vitro. However, the neuronal type is not clear, and it is still unknown whether these neuron-like cells possess physiological properties of functional neurons and whether they can contribute to the recovery of neuron dysfunction. To answer these questions, we investigated their characteristics by detecting neuronal function-related neurotransmitters and calcium image. The results showed that these cells exhibited functional cholinergic neurons in vitro. Transplantation of these cholinergic neuron-like cells promoted the recovery of spinal cord-injured mice, and they were more effective than BMSCs. The number of cholinergic neurons was increased after injection with BMSC-derived cholinergic neuron-like cells, indicating their high differentiation rate in vivo. Moreover, the proportion of cholinergic neurons in host cells and secretion of acetylcholine were increased, and preservation of neurofilament was also observed in the lesion of mice implanted with BMSC-derived neurons, suggesting the neuronal protection of BMSC-derived neurons. Our findings provide both a simple method to induce the differentiation of BMSCs into cholinergic neuron-like cells and a putative strategy for the therapy of spinal cord injuries.
Sahgal, Arjun; Ma Lijun; Gibbs, Iris; Gerszten, Peter C.; Ryu, Sam; Soltys, Scott; Weinberg, Vivian; Wong Shun; Chang, Eric; Fowler, Jack; Larson, David A.
Purpose: Dosimetric data are reported for five cases of radiation-induced myelopathy after stereotactic body radiotherapy (SBRT) to spinal tumors. Analysis per the biologically effective dose (BED) model was performed. Methods and Materials: Five patients with radiation myelopathy were compared to a subset of 19 patients with no radiation myelopathy post-SBRT. In all patients, the thecal sac was contoured to represent the spinal cord, and doses to the maximum point, 0.1-, 1-, 2-, and 5-cc volumes, were analyzed. The mean normalized 2-Gy-equivalent BEDs (nBEDs), calculated using an alpha/beta value of 2 for late toxicity with units Gy 2/2, were compared using the t test and analysis of variance test. Results: Radiation myelopathy was observed at the maximum point with doses of 25.6 Gy in two fractions, 30.9 Gy in three fractions, and 14.8, 13.1, and 10.6 Gy in one fraction. Overall, there was a significant interaction between patient subsets and volume based on the nBED (p = 0.0003). Given individual volumes, a significant difference was observed for the mean maximum point nBED (p = 0.01). Conclusions: The maximum point dose should be respected for spine SBRT. For single-fraction SBRT 10 Gy to a maximum point is safe, and up to five fractions an nBED of 30 to 35 Gy 2/2 to the thecal sac also poses a low risk of radiation myelopathy.
De Leener, Benjamin; Lévy, Simon; Dupont, Sara M; Fonov, Vladimir S; Stikov, Nikola; Louis Collins, D; Callot, Virginie; Cohen-Adad, Julien
For the past 25 years, the field of neuroimaging has witnessed the development of several software packages for processing multi-parametric magnetic resonance imaging (mpMRI) to study the brain. These software packages are now routinely used by researchers and clinicians, and have contributed to important breakthroughs for the understanding of brain anatomy and function. However, no software package exists to process mpMRI data of the spinal cord. Despite the numerous clinical needs for such advanced mpMRI protocols (multiple sclerosis, spinal cord injury, cervical spondylotic myelopathy, etc.), researchers have been developing specific tools that, while necessary, do not provide an integrative framework that is compatible with most usages and that is capable of reaching the community at large. This hinders cross-validation and the possibility to perform multi-center studies. In this study we introduce the Spinal Cord Toolbox (SCT), a comprehensive software dedicated to the processing of spinal cord MRI data. SCT builds on previously-validated methods and includes state-of-the-art MRI templates and atlases of the spinal cord, algorithms to segment and register new data to the templates, and motion correction methods for diffusion and functional time series. SCT is tailored towards standardization and automation of the processing pipeline, versatility, modularity, and it follows guidelines of software development and distribution. Preliminary applications of SCT cover a variety of studies, from cross-sectional area measures in large databases of patients, to the precise quantification of mpMRI metrics in specific spinal pathways. We anticipate that SCT will bring together the spinal cord neuroimaging community by establishing standard templates and analysis procedures.
El-Kheir, Wael Abo; Gabr, Hala; Awad, Mohamed Reda; Ghannam, Osama; Barakat, Yousef; Farghali, Haithem A M A; El Maadawi, Zeinab M; Ewes, Ibrahim; Sabaawy, Hatem E
Spinal cord injuries (SCI) cause sensory loss and motor paralysis. They are normally treated with physical therapy, but most patients fail to recover due to limited neural regeneration. Here we describe a strategy in which treatment with autologous adherent bone marrow cells is combined with physical therapy to improve motor and sensory functions in early stage chronic SCI patients. In a phase I/II controlled single-blind clinical trial (clinicaltrials.gov identifier: NCT00816803), 70 chronic cervical and thoracic SCI patients with injury durations of at least 12 months were treated with either intrathecal injection(s) of autologous adherent bone marrow cells combined with physical therapy or with physical therapy alone. Patients were evaluated with clinical and neurological examinations using the American Spinal Injury Association (ASIA) Impairment Scale (AIS), electrophysiological somatosensory-evoked potential, magnetic resonance imaging (MRI), and functional independence measurements. Chronic cervical and thoracic SCI patients (15 AIS A and 35 AIS B) treated with autologous adherent bone marrow cells combined with physical therapy showed functional improvements over patients in the control group (10 AIS A and 10 AIS B) treated with physical therapy alone, and there were no long-term cell therapy-related side effects. At 18 months posttreatment, 23 of the 50 cell therapy-treated cases (46%) showed sustained functional improvement. Compared to those patients with cervical injuries, a higher rate of functional improvement was achieved in thoracic SCI patients with shorter durations of injury and smaller cord lesions. Therefore, when combined with physical therapy, autologous adherent bone marrow cell therapy appears to be a safe and promising therapy for patients with chronic SCI of traumatic origin. Randomized controlled multicenter trials are warranted.
Nowadays there are at present no efficient therapies for spinal cord injury (SCI), and new approaches have to be proposed. Recently, a new regenerative medicine strategy has been suggested using smart biomaterials able to carry and deliver cells and/or drugs in the damaged spinal cord. Among the wide field of emerging materials, research has been focused on hydrogels, three-dimensional polymeric networks able to swell and absorb a large amount of water. The present paper intends to give an overview of a wide range of natural, synthetic, and composite hydrogels with particular efforts for the ones studied in the last five years. Here, different hydrogel applications are underlined, together with their different nature, in order to have a clearer view of what is happening in one of the most sparkling fields of regenerative medicine. PMID:22816020
Liu, Jian; Yang, Xiaoyu; Jiang, Lianying; Wang, Chunxin; Yang, Maoguang
Plasticity changes of uninjured nerves can result in a novel neural circuit after spinal cord injury, which can restore sensory and motor functions to different degrees. Although processes of neural plasticity have been studied, the mechanism and treatment to effectively improve neural plasticity changes remain controversial. The present study reviewed studies regarding plasticity of the central nervous system and methods for promoting plasticity to improve repair of injured central nerves. The results showed that synaptic reorganization, axonal sprouting, and neurogenesis are critical factors for neural circuit reconstruction. Directed functional exercise, neurotrophic factor and transplantation of nerve-derived and non-nerve-derived tissues and cells can effectively ameliorate functional disturbances caused by spinal cord injury and improve quality of life for patients. PMID:25774179
Sandu, AM; Popescu, M; Iacobini, MA; Stoian, R; Neascu, C; Popa, F
The aim of this article is to analyze cardiac dysfunctions occurring after spinal cord injury (SCI). Cardiac dysfunctions are common complications following SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI. We reviewed epidemiology of cardiac disturbances after SCI, and neuroanatomy and pathophysiology of autonomic nervous system, sympathetic and parasympathetic. SCI causes disruption of descendent pathways from central control centers to spinal sympathetic neurons, originating into intermediolateral nuclei of T1–L2 spinal cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve. SCI associates significant cardiac dysfunction. Impairment of autonomic nervous control system, mostly in patients with cervical or high thoracic SCI, causes cardiac dysrrhythmias, especially bradycardia and, rarely, cardiac arrest, or tachyarrhytmias and hypotension. Specific complication dependent on the period of time after trauma like spinal shock and autonomic dysreflexia are also reviewed. Spinal shock occurs during the acute phase following SCI and is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe bradycardia and hypotension. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life–threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5–T6). Besides all this, additional cardiac complications, such as cardiac deconditioning and coronary heart disease may also occur. Proper prophylaxis, including nonpharmacologic and pharmacological strategies and cardiac rehabilitation diminish occurrence of the cardiac dysfunction following
Bao, Feng; DeWitt, Douglas S; Prough, Donald S; Liu, Danxia
To determine whether peroxynitrite at the concentration and duration present after spinal cord injury induces protein oxidation and nitration in vivo, the peroxynitrite donor 3-morpholinosydnonimine (SIN-1) was administered into the gray matter of the rat spinal cord for 5 hr. The cords were removed at 6, 12, 24, and 48 hr after SIN-1 exposure, immunohistochemically stained with antibodies to dinitrophenyl (DNP) and nitrotyrosine (Ntyr), markers of protein oxidation and nitration, respectively, and the immunostained neurons were counted. The percentages of DNP-positive (P = 0.023-0.002) and Ntyr-positive (P < 0.001 for all) neurons were significantly higher in the SIN-1-exposed groups than in the ACSF controls at each time, suggesting that peroxynitrite induced intracellular oxidation and nitration of proteins. The percentages of DNP- and Ntyr-positive neurons were not significantly different over time in either SIN-1- or ACSF-exposed groups (P = 0.20-1.00). The percentage of DNP-positive neurons was 7.6 +/- 3% to 12 +/- 4.2% at 6-24 hr, and it was 14 +/- 2% to 19 +/- 2% at 6-24 hr for Ntyr-positive neurons after SIN-1-exposure, whereas both ranged over 2-3% in ACSF controls. Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP, a broad-spectrum scavenger of reactive species) significantly reduced the percentages of DNP- and Ntyr-positive neurons (P = 0.04 and 0.002, respectively) compared to a SIN-1-exposed, untreated group at 24 hr after SIN-1 exposure. There were no significant differences between MnTBAP-treated and ACSF controls (P = 0.7 for DNP and 0.2 for Ntyr). These results further demonstrate peroxynitrite-induced protein oxidation and nitration and the efficiency of MnTBAP in scavenging peroxynitrite.
Ross, Christina L; Syed, Ishaq; Smith, Thomas L; Harrison, Benjamin S
Traumatic spinal cord injury (SCI) is typically the result of direct mechanical impact to the spine, leading to fracture and/or dislocation of the vertebrae along with damage to the surrounding soft tissues. Injury to the spinal cord results in disruption of axonal transmission of signals. This primary trauma causes secondary injuries that produce immunological responses such as neuroinflammation, which perpetuates neurodegeneration and cytotoxicity within the injured spinal cord. To date there is no FDA-approved pharmacological agent to prevent the development of secondary SCI and induce regenerative processes aimed at healing the spinal cord and restoring neurological function. An alternative method to electrically activate spinal circuits is the application of a noninvasive electromagnetic field (EMF) over intact vertebrae. The EMF method of modulating molecular signaling of inflammatory cells emitted in the extra-low frequency range of <100 Hz, and field strengths of <5 mT, has been reported to decrease inflammatory markers in macrophages, and increase endogenous mesenchymal stem cell (MSC) proliferation and differentiation rates. EMF has been reported to promote osteogenesis by improving the effects of osteogenic media, and increasing the proliferation of osteoblasts, while inhibiting osteoclast formation and increasing bone matrix in vitro. EMF has also been shown to increase chondrogenic markers and collagen and induce neural differentiation, while increasing cell viability by over 50%. As advances are made in stem cell technologies, stabilizing the cell line after differentiation is crucial to SCI repair. Once cell-seeded scaffolds are implanted, EMF may be applied outside the wound for potential continued adjunct treatment during recovery.
Kan, E M; Ling, E A; Lu, J
Spinal cord injury (SCI) damages axons and disrupts myelination interrupting sensory and motor neuronal transmission to and from the brain. Patients suffering from SCI although continue to survive, are often left chronically disabled and with no promise of a cure. Advances in stem cell biology has opened up doors for the use of human embryonic, adult neural and induced pluripotent stem cell strategies for SCI. Despite great promise from animal research, clinical trials have been limited and the jury is still out on its safety and efficacy. This review discusses the advantages and disadvantages of the various stem cell types, barriers hindering translation from animal to humans, and the need for established guidelines for standardization of clinical trials ensuring subsequent implementation. Ultimately, unrealistic expectations of stem cell therapy (SCT) as the elixir for SCI should be managed. The success of SCT for SCI lies in the network of research scientists, medical professionals and patients working cooperatively to build up a knowledge-intensive platform for a comprehensive risk-benefit assessment of SCT for SCI.
Lee, Thay Q; McMahon, Patrick J
After spinal cord injury, excessive burden falls on the upper extremity, especially the shoulder. Overall, 51% of persons with spinal cord injury have shoulder problems. Common shoulder problems in persons with spinal cord injury begin with muscle imbalance that can lead to glenohumeral instability, impingement disease, rotator cuff tears, and subsequent degenerative joint disease. These problems can be attributed to the functional demands placed on the shoulder that are specific to patients with spinal cord injury, including overhead activities, wheelchair use, and transfers. Despite preventive exercises, shoulder problems in persons with spinal cord injury remain a significant problem, causing pain and functional limitations. The biomechanics of the shoulder for persons with spinal cord injury resulting from changes in muscle plasticity will be elucidated. Specifically, the effects of scapular protraction that can result from muscle imbalance, the age-dependent properties of the anterior band of the inferior glenohumeral ligament, and the influence of the dynamic restraints around the shoulder will be addressed.
Galeiras Vázquez, R; Ferreiro Velasco, M E; Mourelo Fariña, M; Montoto Marqués, A; Salvador de la Barrera, S
Traumatic spinal cord injury requires a multidisciplinary approach both for specialized treatment of the acute phase and for dealing with the secondary complications. A suspicion or diagnosis of spinal cord injury is the first step for a correct management. A review is made of the prehospital management and characteristics of the acute phase of spinal cord injury. Respiratory monitoring for early selective intubation, proper identification and treatment of neurogenic shock are essential for the prevention of secondary spinal cord injury. The use of corticosteroids is currently not a standard practice in neuroprotective treatment, and hemodynamic monitoring and early surgical decompression constitute the cornerstones of adequate management. Traumatic spinal cord injury usually occurs as part of multiple trauma, and this can make diagnosis difficult. Neurological examination and correct selection of radiological exams prevent delayed diagnosis of spinal cord injuries, and help to establish the prognosis.
Meyer, Marc R; Haeusler, Martin
The discovery at Nariokotome of the Homo erectus skeleton KNM-WT 15000, with a narrow spinal canal, seemed to show that this relatively large-brained hominin retained the primitive spinal cord size of African apes and that brain size expansion preceded postcranial neurological evolution. Here we compare the size and shape of the KNM-WT 15000 spinal canal with modern and fossil taxa including H. erectus from Dmanisi, Homo antecessor, the European middle Pleistocene hominins from Sima de los Huesos, and Pan troglodytes. In terms of shape and absolute and relative size of the spinal canal, we find all of the Dmanisi and most of the vertebrae of KNM-WT 15000 are within the human range of variation except for the C7, T2, and T3 of KNM-WT 15000, which are constricted, suggesting spinal stenosis. While additional fossils might definitively indicate whether H. erectus had evolved a human-like enlarged spinal canal, the evidence from the Dmanisi spinal canal and the unaffected levels of KNM-WT 15000 show that unlike Australopithecus, H. erectus had a spinal canal size and shape equivalent to that of modern humans. Subadult status is unlikely to affect our results, as spinal canal growth is complete in both individuals. We contest the notion that vertebrae yield information about respiratory control or language evolution, but suggest that, like H. antecessor and European middle Pleistocene hominins from Sima de los Huesos, early Homo possessed a postcranial neurological endowment roughly commensurate to modern humans, with implications for neurological, structural, and vascular improvements over Pan and Australopithecus.
Curt, Armin; Friston, Karl; Thompson, Alan
Traumatic spinal cord injury is often disabling and recovery of function is limited. As a consequence of damage, both spinal cord and brain undergo anatomical and functional changes. Besides clinical measures of recovery, biomarkers that can detect early anatomical and functional changes might be useful in determining clinical outcome—during the course of rehabilitation and recovery—as well as furnishing a tool to evaluate novel treatment interventions and their mechanisms of action. Recent evidence suggests an interesting three-way relationship between neurological deficit and changes in the spinal cord and of the brain and that, importantly, noninvasive magnetic resonance imaging techniques, both structural and functional, provide a sensitive tool to lay out these interactions. This review describes recent findings from multimodal imaging studies of remote anatomical changes (i.e., beyond the lesion site), cortical reorganization, and their relationship to clinical disability. These developments in this field may improve our understanding of effects on the nervous system that are attributable to the injury itself and will allow their distinction from changes that result from rehabilitation (i.e., functional retraining) and from interventions affecting the nervous system directly (i.e., neuroprotection or regeneration). PMID:22730072
Lee, Sang Pyo; Lee, Kang Nyeong; Lee, Hang Lak; Jun, Dae Won; Yoon, Byung Chul; Choi, Ho Soon; Hwang, Se Jin; Lee, Seo Eun
Background/Aims DA-9701, a standardized extract of Pharbitis Semen and Corydalis Tuber, is a new prokinetic agent that exhibits an analgesic effect on the abdomen. We investigated whether DA-9701 affects visceral pain induced by colorectal distension (CRD) in rats. Methods A total of 21 rats were divided into three groups: group A (no CRD+no drug), group B (CRD+no drug), and group C (CRD+DA-9701). Expression of pain-related factors, substance P (SP), c-fos, and phosphorylated extracellular signal-regulated kinase (p-ERK) in the dorsal root ganglion (DRG) and spinal cord was determined by immunohistochemical staining and Western blotting. Results The proportions of neurons in the DRG and spinal cord expressing SP, c-fos, and p-ERK were higher in group B than in group A. In the group C, the proportion of neurons in the DRG and spinal cord expressing p-ERK was lower than that in group B. Western blot results for p-ERK in the spinal cord indicated a higher level of expression in group B than in group A and a lower level of expression in group C than in group B. Conclusions DA-9701 may decrease visceral pain via the downregulation of p-ERK in the DRG and spinal cord. PMID:24672654
Background Paclitaxel is an effective chemotherapeutic agent widely used for the treatment of solid tumors. The major dose-limiting toxicity of paclitaxel is peripheral neuropathy. The mechanisms underlying the development and maintenance of paclitaxel-induced peripheral neuropathy are still unclear, and there are no currently established effective treatments. Accumulating evidence in models of neuropathic pain in which peripheral nerves are lesioned has implicated spinal microglia and chemokines in pain hypersensitivity, but little is know about their roles in chemotherapy-induced peripheral neuropathy. In the present study, we investigated the role of CC-chemokine ligand 3 (CCL3) in the spinal cord in the development and maintenance of mechanical allodynia using a rat model of paclitaxel-induced neuropathy. Findings Repeated intravenous administration of paclitaxel induced a marked decrease in paw withdrawal threshold in response to mechanical stimulation (mechanical allodynia). In these rats, the number of microglia in the spinal dorsal horn (SDH) was significantly increased. Paclitaxel-treated rats showed a significant increase in the expression of mRNAs for CCL3 and its receptor CCR5 in the SDH. Intrathecal administration of a CCL3-neutralizing antibody not only attenuated the development of paclitaxel-induced mechanical allodynia but also reversed its maintenance. Paclitaxel also upregulated expression of purinoceptor P2X7 receptors (P2X7Rs), which have been implicated in the release of CCL3 from microglia, in the SDH. The selective P2X7R antagonist A438079 had preventive and reversal effects on paclitaxel-induced allodynia. Conclusions Our findings suggest a contribution of CCL3 and P2X7Rs in the SDH to paclitaxel-induced allodynia and may provide new therapeutic targets for paclitaxel-induced painful neuropathy. PMID:25127716
Hachmann, Jan T.; Calvert, Jonathan S.; Grahn, Peter J.; Drubach, Dina I.; Lee, Kendall H.; Lavrov, Igor A.
Spinal cord injury (SCI) remains a debilitating condition for which there is no cure. In addition to loss of somatic sensorimotor functions, SCI is also commonly associated with impairment of autonomic function. Importantly, cough dysfunction due to paralysis of expiratory muscles in combination with respiratory insufficiency can render affected individuals vulnerable to respiratory morbidity. Failure to clear sputum can aggravate both risk for and severity of respiratory infections, accounting for frequent hospitalizations and even mortality. Recently, epidural stimulation of the lower thoracic spinal cord has been investigated as novel means for restoring cough by evoking expiratory muscle contraction to generate large positive airway pressures and expulsive air flow. This review article discusses available preclinical and clinical evidence, current challenges and clinical potential of lower thoracic spinal cord stimulation (SCS) for restoring cough in individuals with SCI.
Spinal Cord Injury PRINCIPAL INVESTIGATOR: Eva G. Widerström-Noga, DDS, PhD CONTRACTING ORGANIZATION: University of Miami REPORT...AND SUBTITLE Experiences of Living with Pain after a Spinal Cord Injury 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-12-1-0465 5c. PROGRAM...after a spinal cord injury (SCI), with about two-thirds of persons with SCI reporting persistent pain despite available treatments. There is a risk
The permeability alteration of brain and spinal cord vasculature to horseradish peroxidase during experimental decompression sickness as compared to the alteration in permeability induced by hyperosmolar solution.
Lehtosalo, J; Panula, P; Laitinen, L A
The permeability of microvasculature in the cerebral cortex, neostriatum, and spinal cord to i.v. injected horseradish peroxidase (HRP) has been investigated in rats following experimental compression to 6.1 bars (abs.) air for 90 min, and subsequent decompression to the ambient pressure in 1 min. For comparison, 1 ml of 2.0 M urea was injected into the right common carotid artery of rats during 15 s. After exposure to compression-decompression, under the light microscope focal leaky areas were found in all the regions examined. The leakage was most prominent in the grey matter of the spinal cord, and the cerebral cortex. In decompressed rats, arterioles were most often the site of peroxidase extravasation, whereas extravasation of HRP was less frequently displayed by capillaries and venules. In urea-treated rats, capillaries and venules frequently displayed extravasation of HRP as well. Parenchymal cells accumulated the trace adjacent to the leaky areas. Under the electron microscope, the extravasation of HRP was associated with peroxidase-containing pleomorphic vesicular structures in the endothelium, both in decompressed and urea-injected rats. Moreover, in contrast to decompressed rats, the junctions between endothelial cells were penetrated by the trace in urea-treated rats. Accordingly, the results indicate that during decompression sickness the pathway for the extravasation of proteins is through vesicular transfer, whereas the injection of hyperosmolar urea induces extravasation, both through vesicular transfer and junctions between the endothelial cells.
Kobus-Bianchini, Karoline; Bourckhardt, Gilian Fernando; Ammar, Dib; Nazari, Evelise Maria; Müller, Yara Maria Rauh
Maternal hyperhomocysteinemia during pregnancy is associated with increased risk of NTD in the offspring. Our study investigated the effects of homocysteine (Hcy) on proliferation and neuronal differentiation of the spinal cord cells in a chick embryo model. Embryos were treated with 20μmol D-L Hcy/50μL saline solution at embryonic day 2 (E2) and analyzed at embryonic days 4 (E4) and 6 (E6). Control embryos received exclusively 50μL saline solution. We performed immunolocalization and flow cytometry analyses using antibodies anti-phosphohistone H3 (pH3), anti-proliferating cell nuclear antigen (PCNA), anti-β-tubulin III and anti-p53. Our results revealed that Hcy interferes in the proliferation of the neural cells, and that this effect is age-dependent and differed between Hcy-treated embryos with and without NTD. Also, Hcy induced a decrease of neuronal differentiation in the spinal cord at both embryonic ages. These findings contribute to clarifying the cellular bases of NTD genesis, under experimental hiperhomocysteinemia.
... in Adults What Are the Key Statistics About Brain and Spinal Cord Tumors? The American Cancer Society’s ... Spinal Cord Tumor Research and Treatment? More In Brain And Spinal Cord Tumors In Adults About Brain ...
Popa, F; Grigorean, VT; Onose, G; Sandu, AM; Popescu, M; Burnei, G; Strambu, V; Sinescu, C
The aim of this article is to analyze the vascular dysfunctions occurring after spinal cord injury (SCI). Vascular dysfunctions are common complications of SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI. Neuroanatomy and physiology of autonomic nervous system, sympathetic and parasympathetic, is reviewed. SCI implies disruption of descendent pathways from central centers to spinal sympathetic neurons, originating in intermediolateral nuclei of T1–L2 cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve. SCI associates significant vascular dysfunction. Spinal shock occurs during the acute phase following SCI and it is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe arterial hypotension and bradycardia. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life–threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5–T6). Arterial hypotension with orthostatic hypotension occurs in both acute and chronic phases. The etiology is multifactorial. We described a few factors influencing the orthostatic hypotension occurrence in SCI: sympathetic nervous system dysfunction, low plasma catecholamine levels, rennin–angiotensin–aldosterone activity, peripheral alpha–adrenoceptor hyperresponsiveness, impaired function of baroreceptors, hyponatremia and low plasmatic volume, cardiovascular deconditioning, morphologic changes in sympathetic neurons, plasticity within spinal circuits, and motor deficit leading to loss of skeletal muscle pumping activity. Additional associated cardiovascular concerns in SCI, such as
Moffie, D; Stefanko, S Z; Makkink, B
Description of 11 patients with congenital malformations of the spinal cord. Six of them were males, five females and the age varied from 7 to 70 years. Most of these cases produced clinical neurological signs indicating spinal cord disease in later life during an intercurrent disease. It was thought that changes in the bloodvessels and/or perfusion of the area of the spinal cord malformation was the ultimate cause of the neurological symptoms. An exact explanation of the origin of these developmental disturbances of the spinal cord remains unknown. Different hypotheses proposed in the literature, concerning these malformations, are not satisfactory.
Bican, Orhan; Minagar, Alireza; Pruitt, Amy A
The spinal cord controls the voluntary muscles of the trunk and limbs and receives sensory input from these areas. It extends from the medulla oblongata to the lower border of the first lumbar vertebra. A basic knowledge of spinal cord anatomy is essential for interpretation of clinical signs and symptoms and for understanding of pathologic processes involving the spinal cord. In this article, anatomic structures are correlated with relevant clinical signs and symptoms and a step-wise approach to spinal cord diagnosis is outlined.
Paul, Ian; Reichard, R Ross
Subacute combined degeneration (SCD) of the spinal cord is the most common neurologic manifestation of vitamin B12 (cobalamin) deficiency and is usually secondary to autoimmune gastritis, but may also be seen in malnutrition syndromes such as chronic alcoholism, strict vegetarianism, gastrectomy, and also in nitrous oxide abuse. Although traumatic spinal cord injury is routinely encountered in the medical examiner's office, medical causes of spinal cord abnormalities such as SCD should be considered in the appropriate clinical setting. We report a case of alcohol-associated SCD mimicking traumatic spinal cord injury.
Yuan, Qing; Dougherty, Lawrence; Margulies, Susan S.
Traumatic mechanical loading of the head-neck complex results cervical spinal cord injury when the distortion of the cord is sufficient to produce functional or structural failure of the cord's neural and/or vascular components. Characterizing cervical spinal cord deformation during physiological loading conditions is an important step to defining a comprehensive injury threshold associated with acute spinal cord injury. In this study, in vivo quasi- static deformation of the cervical spinal cord during flexion of the neck in human volunteers was measured using magnetic resonance (MR) imaging of motion with spatial modulation of magnetization (SPAMM). A custom-designed device was built to guide the motion of the neck and enhance more reproducibility. the SPAMM pulse sequence labeled the tissue with a series of parallel tagging lines. A single- shot gradient-recalled-echo sequence was used to acquire the mid-sagittal image of the cervical spine. A comparison of the tagged line pattern in each MR reference and deformed image pair revealed the distortion of the spinal cord. The results showed the cervical spinal cord elongates during head flexion. The elongation experienced by the spinal cord varies linearly with head flexion, with the posterior surface of the cord stretching more than the anterior surface. The maximal elongation of the cord is about 12 percent of its original length.
This book is a source of information about aspects of radiology of the spine and spinal column. It presents coverage of both normal and abnormal conditions. Contents: Spinal fractures and dislocations. Degenerative diseases of the spine. Gross anatomy of the spinal cord and meninges. Intraspinal mass lesions. Spinal dysraphism. Congenital anomalies. Tumors of the vertebral column, and more.
Neuronal networks within the spinal cord of mammals are responsible for generating various rhythmic movements, such as walking, running, swimming, and scratching. The ability to generate multiple rhythmic movements highlights the complexity and flexibility of the mammalian spinal circuitry. The present review describes features of some rhythmic motor behaviors generated by the mammalian spinal cord and discusses how the spinal circuitry is able to produce different rhythmic movements with their own sets of goals and demands.
Cheng, Hsinlin Thomas
Chronic pain is a prevalent and challenging problem for most medical practitioners. Due to complex pathological mechanisms involved in chronic pain, optimal treatment is still under development. The spinal cord is an important gateway for peripheral pain signals transmitted to the brain. In chronic pain states, painful stimuli trigger afferent fibers in the dorsal horn to release neuropeptides and neurotransmitters. These events induce multiple inflammatory and neuropathic processes in the spinal cord dorsal horn and trigger modification and plasticity of local neural circuits. As a result, ongoing noxious signals to the brain are amplified and prolonged, a phenomenon known as central sensitization. In this review, the molecular events associated with central sensitization as well as their clinical implications are discussed. PMID:20461476
Gabal, Abdelwahab M.
Purpose: In this study we report a percutaneous technique to achieve sclerosis of vertebral hemangioma and decompression of the spinal cord and nerve roots. Methods: Under CT guidance the affected vertebral body is punctured by a biopsy needle and sclerosant is injected directly into the tumor. In the case of large paravertebral extension, additional injection is given in the paravertebral soft tissue component to induce shrinkage of the whole tumor mass and release of the compressed spinal cord. Results: Using this technique we treated five patients in whom vertebral hemangioma gave rise to neurologic symptoms.In three patients, sclerotherapy was the only treatment given. In the other two patients, sclerotherapy was preceded by transcatheter embolization. Neither decompressive surgery, radiation therapy nor stabilization was required with this technique. Conclusion: Our experience with CT-guided intraosseous sclerotherapy has proved highly satisfactory.
Farrar, Matthew J.; Bernstein, Ida M.; Schlafer, Donald H.; Cleland, Thomas A.; Fetcho, Joseph R.; Schaffer, Chris B.
Understanding and treatment of spinal cord pathology is limited in part by a lack of longitudinal in vivo imaging strategies at the cellular level. We developed a chronically implanted spinal chamber and surgical procedure suitable for time-lapse in vivo multiphoton microscopy of mouse spinal cord without the need for repeat surgical procedures. Repeated imaging was routinely achieved for more than five weeks post-operatively with up to ten separate imaging sessions. We observed neither motor function deficit nor neuropathology in the spinal cord as a result of chamber implantation. Using this chamber we quantified microglia and afferent axon dynamics following a laser-induced spinal cord lesion and observed massive microglia infiltration within one day along with a heterogeneous dieback of axon stumps. By enabling chronic imaging studies over timescales ranging from minutes to months, our method offers an ideal platform for understanding cellular dynamics in response to injury and therapeutic interventions. PMID:22266542
Martini, Alessandra C; Forner, Stefânia; Koepp, Janice; Rae, Giles Alexander
Mitogen-activated protein kinases (MAPKs) have been implicated in central nervous system injuries, yet the roles within neurodegeneration following spinal cord injury (SCI) still remain partially elucidated. We aimed to investigate the changes in expression of the three MAPKs following SCI and the role of spinal c-jun-NH2-terminal kinase (JNK) in motor impairment following the lesion. SCI induced at the T9 level resulted in enhanced expression of phosphorylated MAPKs shortly after trauma. SCI increased spinal cord myeloperoxidase levels, indicating a local neutrophil infiltration, and elevated the number of spinal apoptotic cells. Intrathecal administration of a specific inhibitor of JNK phosphorylation, SP600125, given at 1 and 4h after SCI, reduced the p-JNK expression, the number of spinal apoptotic cells and many of the histological signs of spinal injury. Notably, restoration of locomotor performance was clearly ameliorated by SP600125 treatment. Altogether, the results demonstrate that SCI induces activation of spinal MAPKs and that JNK plays a major role in mediating the deleterious consequences of spinal injury, not only at the spinal level, but also those regarding locomotor function. Therefore, inhibition of JNK activation in the spinal cord shortly after trauma might constitute a feasible therapeutic strategy for the functional recovery from SCI.
Liu, Haichun; Yang, Kaiyun; Xin, Tao; Wu, Wenliang; Chen, Yunzhen
Spinal cord injury (SCI) is one of the most serious disorders in clinics, and the high disability rate and functional deficits are common issues in patients. Transplantation of bone-marrow-derived mesenchymal stromal cells (BMSCs) into the injured spinal cord is emerging as a novel method in the therapeutics of SCI; however, its application is limited by the poor survival rate of the transplanted cells and low differentiation rate into neurons. Our laboratory recently reported that electrical stimulation (ES) dramatically improves the survival rate of transplanted BMSCs and increases spinal cord functions in animals with spinal cord injury. In this paper, we asked whether implanted electro-acupuncture (iEA) can advance the beneficial effects from the ES treatment in animals with spinal cord injury. We showed that BMSCs transplantation alone resulted in significant functional recovery in animals. Interestingly, iEA with BMSCs treatment induced a significantly higher functional improvement in locomotor functions and SSEP compared to the BMSCs treatment alone. Additionally, we used molecular biology techniques and showed that BMSCs transplantation with iEA treatment significantly increased the number of surviving BMSCs compared to the BMSCs alone group. In conclusion, our experiment showed that the approach of coupling iEA electric stimulation and BMSCs transplantation remarkably promotes functional improvements in animals with spinal cord injury and holds promising potential to treat spinal cord injury in humans.
Shank, C D; Walters, B C; Hadley, M N
Acute traumatic spinal cord injury (SCI) is a devastating disease process affecting tens of thousands of people across the USA each year. Despite the increase in primary prevention measures, such as educational programs, motor vehicle speed limits, automobile running lights, and safety technology that includes automobile passive restraint systems and airbags, SCIs continue to carry substantial permanent morbidity and mortality. Medical measures implemented following the initial injury are designed to limit secondary insult to the spinal cord and to stabilize the spinal column in an attempt to decrease devastating sequelae. This chapter is an overview of the contemporary management of an acute traumatic SCI patient from the time of injury through the stay in the intensive care unit. We discuss initial triage, immobilization, and transportation of the patient by emergency medical services personnel to a definitive treatment facility. Upon arrival at the emergency department, we review initial trauma protocols and the evidence-based recommendations for radiographic evaluation of the patient's vertebral column. Finally, we outline closed cervical spine reduction and various aggressive medical therapies aimed at improving neurologic outcome.
It is generally accepted that locomotion in mammals, including humans, is based on the activity of neuronal circuits within the spinal cord (the central pattern generator, CPG). Afferent information from the periphery (i.e. the limbs) influences the central pattern and, conversely, the CPG selects appropriate afferent information according to the external requirement. Both the CPG and the reflexes that mediate afferent input to the spinal cord are under the control of the brainstem. There is increasing evidence that in central motor diseases, a defective utilization of afferent input, in combination with secondary compensatory processes, is involved in typical movement disorders, such as spasticity and Parkinson's disease. Recent studies indicate a plastic behavior of the spinal neuronal circuits following a central motor lesion. This has implications for any rehabilitative therapy that should be directed to take advantage of the plasticity of the central nervous system. The significance of this research is in a better understanding of the pathophysiology underlying movement disorders and the consequences for an appropriate treatment.
Li, Xiao-Qian; Zhang, Zai-Li; Tan, Wen-Fei; Sun, Xi-Jia; Ma, Hong
Toll-like receptor 4 (TLR4) is important for the pathogenesis of inflammatory reactions and the promotion of pain processing after ischemia/reperfusion (IR) in spinal cord. Recently, C-X-C chemokine ligand 12 (CXCL12) and its receptor, C-X-C chemokine receptor 4 (CXCR4), were demonstrated to be simultaneously critical for inflammatory reactions, thereby facilitating glial activation. However, whether CXCL12/CXCR4 expression can contribute to IR-induced inflammatory pain via spinal TLR4 remained unclear. A rat model was established by 8 min of aortic arch occlusion. The effects of CXCL12/CXCR4 expression and TLR4 activation on inflammatory hyperalgesia were investigated by pretreatments with CXCL12-neutralizing antibody, CXCR4 antagonist (AMD3100) and TLR4 antagonist (TAK-242) for 5 consecutive days before surgery. The results indicated that IR induced significant and sustained inflammatory pain, observed as decreases in paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), throughout the post-injury period. The increased levels of TLR4 and proinflammatory chemokine CXCL12, as well as its receptor, CXCR4, were closely correlated with the PWT and PWL trends. Double immunostaining further suggested that TLR4, which is mainly expressed on astrocytes and microglia, was closely co-localized with CXCL12 and CXCR4 in spinal dorsal horn. As expected, intrathecal pretreatment with the TLR4 antagonist, TAK-242 markedly ameliorated pain by inhibiting astrocytic and microglial activation, as shown by decreases in TLR4 immunoreactivity and the percentage of double-labeled cells. These protective effects were likely due in part to the reduced production of the downstream cytokines IL-1β and TNF-α, as well as for the recruitment of CXCL12 and CXCR4. Additionally, intrathecal pretreatment with CXCL12-neutralizing antibody and AMD3100 resulted in similar analgesic and anti-inflammatory effects as those receiving TAK-242 pretreatment. These results suggest that
Louisville, KY After spinal cord injury (SCI) patients commonly develop spasticity and contractures as secondary complications of “upper motor neuron...lesions. Physical therapists use stretching maneuvers to maintain extensibility of soft tissues and to manage spasticity . Previous studies in our lab
Spinal cord injury research has greatly expanded in recent years, but our understanding of the mechanisms that underlie the functional recovery that can occur over the weeks and months following the initial injury, is far from complete. To grasp the scope of the problem, it is important to begin by defining the sensorimotor pathways that might be involved by a spinal injury. This is done in the rodent and nonhuman primate, which are two of the most commonly used animal models in basic and translational spinal injury research. Many of the better known experimentally induced models are then reviewed in terms of the pathways they involve and the reorganization and recovery that have been shown to follow. The better understood neuronal mechanisms mediating such post-injury plasticity, including dendritic spine growth and axonal sprouting, are then examined. PMID:19307422
Powell, Aaron; Davidson, Loren
In this article, an overview is provided of pediatric spinal cord injury, organized by effects of this injury on various organ systems. Specific management differences between children and adults with spinal cord injury are highlighted. A detailed management approach is offered for particularly complex topics, such as spasticity and upper extremity reconstruction.
This manual is intended for young people with spinal cord injuries who are receiving rehabilitation services within the Spinal Cord Injury Unit at Shriners Hospital (San Francisco, California). An introduction describes the rehabilitation program, which includes family conferences, an individualized program, an independent living program,…
Roessler, Richard; And Others
This article describes experiences with Personal Achievement Skills (PAS), a group counseling process in a spinal cord injury project, emphasizing training in communication and goal setting in the context of group process. Issues in conducting such training and providing comprehensive service to the spinal cord injured are discussed in detail.…
Elective colostomy is an accepted method of bowel management for patients who have had a spinal cord injury (SCI). Approximately 2.4% of patients with SCI have a colostomy, and traditionally it is performed as a last resort several years after injury, and only if bowel complications persist when all other methods have failed. This is despite evidence that patients find a colostomy easier to manage and frequently report wishing it had been performed earlier. It was noticed in the author's spinal unit that increasing numbers of patients were requesting colostomy formation during inpatient rehabilitation following SCI. No supporting literature was found for this; it appears to be an emerging and untested practice. This article explores colostomy formation as a method of bowel management in patients with SCI, considers the optimal time for colostomy formation after injury and examines issues for health professionals.
Patte-Mensah, Christine; Meyer, Laurence; Mensah-Nyagan, Ayikoe Guy
During the whole life, the nervous system is continuously submitted to the actions of different categories of hormones, including steroids. Therefore, the interactions between hormonal compounds and neural tissues are subjected to intense investigations. While a majority of studies focus on the brain, the spinal cord (SC) has received little attention, although this structure is also an important part of the central nervous system, controlling motor and sensory functions. To point out the importance of interactions between hormones and the SC in the regulation of neurobiological activities, we recapitulated and discussed herein various key data, revealing that the pivotal role played by the SC in nociception and pain modulation, directly depends on the SC ability to metabolize and synthesize steroidal molecules. The paper suggests that future investigations aiming to develop effective strategies against chronic pain, must integrate regulatory effects exerted by hormonal steroids on the SC activity, as well as the actions of endogenous neurosteroids locally synthesized in spinal neural networks.
Zhang, Qian; Wang, Jianbo; Gu, Zhengsong; Zhang, Qing; Zheng, Hong
The current study aimed to investigate the effect of lycopene on the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) in a mouse model. Lycopene inhibited lipid peroxidation and oxidative DNA damage as a highly efficient antioxidant and free radical scavenger. Lycopene (4 mg/kg/d) was administrated immediately following SCI. The permeability of the BSCB and water content in the spinal cord tissue were evaluated. Additionally, levels of expression of tight junction proteins and heme oxygenase-1 (HO-1) were determined with Western blotting. An enzyme-linked immunosorbent assay analysis of spinal cord tissue homogenates was performed 48 h after SCI to evaluate the expression of inflammation-related cytokines. In addition, recovery of motor function was assessed 1 d, 2 d, 5 d, 10 d, and 15 d after SCI using the Basso Mouse Scale to score locomotion. Compared to the group with an untreated SCI, mice with an SCI treated with lycopene had significantly reduced spinal cord tissue water content and BSCB permeability. Furthermore, motor function of mice with an SCI was also greatly improved by lycopene administration. The expression of the proinflammatory factors TNF-α and NF-kB increased markedly 48 h after SCI, and their upregulation was significantly attenuated by lycopene treatment. The expression of molecules that protect tight junctions, zonula occluden-1 and claudin-5, was upregulated by lycopene treatment after SCI. Taken together, these results clearly indicate that lycopene attenuated SCI by promoting repair of the damaged BSCB, so lycopene is a novel and promising treatment for SCI in humans.
We have demonstrated no adverse effects of DFA on bladder function following spinal cord injury. However, the drug resulted in no improvement in...We demonstrated that 40 mg/kg DFA is the minimally effective dose to induce L-selectin shedding in a mouse model of spinal cord injury -We...using this paradigm for two injury severities, mild and severe, suggesting a robust therapeutic effect -We identified no adverse effects to animal
Khalatbary, Ali Reza
Polyphenols have been shown to have some of the neuroprotective effects against neurodegenerative diseases. These effects are attributed to a variety of biological activities, including free radical scavenging/antioxidant and anti-inflammatory and anti-apoptotic activities. In this regard, many efforts have been made to study the effects of various well-known dietary polyphenols on spinal cord injury (SCI) and to explore the mechanisms behind the neuroprotective effects. The aim of this paper is to present the mechanisms of neuroprotection of natural polyphenols used in animal models of SCI. PMID:24842137
Vargas, Maria Isabel; Barnaure, Isabelle; Gariani, Joanna; Boto, José; Pellaton, Alain; Dietemann, Jean-Louis; Kulcsar, Zsolt
The various imaging techniques used to depict vascular lesions of the spinal cord are described in this article with particular emphasis on magnetic resonance imaging (MRI), vascular sequences, and advantages of high-field MRI. Technical vascular protocols are discussed in computed tomography, MRI, and conventional angiography. The diverse magnetic resonance angiography protocols are presented as well as their findings, specificities, and pitfalls. A review of the vascular anatomy and the most common pathologies analyzed by magnetic resonance angiography and conventional angiography is described.
Kramer, John L K; Geisler, Fred; Ramer, Leanne; Plunet, Ward; Cragg, Jacquelyn J
Recovery from acute spinal cord injury (SCI) is characterized by extensive heterogeneity, resulting in uncertain prognosis. Reliable prediction of recovery in the acute phase benefits patients and their families directly, as well as improves the likelihood of detecting efficacy in clinical trials. This issue of heterogeneity is not unique to SCI. In fields such as traumatic brain injury, Parkinson's disease, and amyotrophic lateral sclerosis, one approach to understand variability in recovery has been to make clinical trial data widely available to the greater research community. We contend that the SCI community should adopt a similar approach in providing open access clinical trial data.
Chen, Kun; Zhang, Zhi-Fa; Liao, Ming-Feng; Yao, Wen-Long; Wang, Juan; Wang, Xue-Ren
Oxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors; however, neuropathic pain is one of the main limiting complications of OXL. The purpose of this study was to examine the underlying mechanisms by which neuropathic pain is induced by OXL in a rat model. Our results demonstrated that blocking spinal proteinase-activated receptor 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) attenuated pain responses evoked by mechanical stimulation and decreased the releases of substance P and CGRP in the superficial dorsal horn of the spinal cord. The attenuating effect on mechanical pain was significantly smaller in OXL-rats than that in control rats. Blocking PAR2 also attenuated a heightened cold sensitivity evoked by OXL; whereas blocking TRPV1 had little effects on OXL-evoked hypersensitive cold response. Our data also showed that OXL increased the protein expressions of PAR2 and TRPV1 in the superficial dorsal horn. In addition, blocking PAR2 decreased TRPV1 expression in OXL-rats. Overall, our data suggest that upregulated expression of PAR2 in the superficial dorsal horn contributes to mechanical hyperalgesia and cold hypersensitivity; whereas amplified TRPV1 plays a role in regulating mechanical hyperalgesia, but not cold hypersensitivity after administration of OXL. We further suggest that TRPV1 is likely one of the signaling pathways for PAR2 to play a role in regulating OXL-induced neuropathic pain.
Shin, Ji Cheol; Yu, Su Jin; Yang, Hea Eun; Yoon, Seo Yeon
Objective To evaluate the epidemiologic change of patients with spinal cord injury who were admitted to a Rehabilitation Hospital, Yonsei University College of Medicine, during 1987-1996 and 2004-2008. Methods Medical records of 629 patients with spinal cord injury admitted to the Rehabilitation Hospital, Yonsei University College of Medicine, from 2004 to 2008 were collected and reviewed retrospectively. Results The male-to-female ratio decreased to 2.86:1, the mean age at injury increased, nontraumatic etiology increased, traffic accident remained to be the most common in traumatic spinal cord injury, and falling increased significantly. Tumor was the most common etiology in nontraumatic spinal cord injury, tetraplegia and incomplete injuries occurred more than paraplegia and complete injuries, indwelling catheter was the most common voiding method, and the duration of hospitalization decreased. Conclusion Many trends changed in epidemiology of spinal cord injury. PMID:23525183
Li, R; Thode, S; Zhou, J; Richard, N; Pardinas, J; Rao, M S; Sah, D W
Human motoneuron cell lines will be valuable tools for spinal cord research and drug discovery. To create such cell lines, we immortalized NCAM(+)/neurofilament(+) precursors from human embryonic spinal cord with a tetracycline repressible v-myc oncogene. Clonal NCAM(+)/neurofilament(+) cell lines differentiated exclusively into neurons within 1 week. These neurons displayed extensive processes, exhibited immunoreactivity for mature neuron-specific markers such as tau and synaptophysin, and fired action potentials upon current injection. Moreover, a clonal precursor cell line gave rise to multiple types of spinal cord neurons, including ChAT(+)/Lhx3(+)/Lhx4(+) motoneurons and GABA(+) interneurons. These neuronal restricted precursor cell lines will expedite the elucidation of molecular mechanisms that regulate the differentiation, maturation and survival of specific subsets of spinal cord neurons, and the identification and validation of novel drug targets for motoneuron diseases and spinal cord injury.
Szarek, Dariusz; Marycz, Krzysztof; Lis, Anna; Zawada, Zbigniew; Tabakow, Paweł; Laska, Jadwiga; Jarmundowicz, Włodzimierz
Spinal cord injury (SCI) is a well-known devastating lesion that sadly is very resistant to all treatment attempts. This fact has stimulated the exploration of multiple regenerative strategies that are examined at both the basic and clinical level. For laboratory research, differentin vivomodels are used, but each has many important limitations. The main limitation of these models is the high level of animal suffering related to the inflicted neurologic injury. It has caused a growing tendency to limit the injury, but this, in turn, produces incomplete SCI models and uncertainties in the neuroregeneration interpretation. To overcome such limitations, a new experimental SCI model is proposed. Geckos have been extensively examined as a potential animal model of SCI. Their spinal cord extends into the tail and can be transected without causing the typical neurologic consequences observed in rat models. In this study, we compared the gecko tail SCI model with the rat model of thoracic SCI. Anatomic and histologic analyses showed comparability between the gecko and rat in diameter of spinal canal and spinal cord, as well as applicability of multiple staining techniques (hematoxylin and eosin, immunostaining, and scanning and transmission electron microscopy). We tested the suitability ofin vivostudy with 3 prototype implants for the reconstruction of SCI: a multichannel sponge, a multilaminar tube, and a gel cylinder. These were compared with a spinal cord excision (control). A 20-wk observation revealed no adverse effects of SCI on the animals' well-being. The animals were easily housed and observed. Histologic analysis showed growth of nervous tissue elements on implant surface and implant cellular colonization. The study showed that the gecko SCI model can be used as a primary model for the assessment of SCI treatment methods. It provides a platform for testing multiple solutions with limited animal suffering before performing tests on mammals. Detailed results of
Aloe, Luigi; Bianchi, Patrizia; De Bellis, Alberto; Soligo, Marzia; Rocco, Maria Luisa
The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an increased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deficits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells. PMID:25206755
Aichner, F; Poewe, W; Rogalsky, W; Wallnöfer, K; Willeit, J; Gerstenbrand, F
Experience with magnetic resonance imaging in 22 patients with diseases of the spinal cord is reported. Important additional diagnostic information as compared to conventional neuroradiological techniques (myelography, spinal CT) was gained especially in cases of hydrosyringomyelia, intraspinal tumour and multiple sclerosis. It is suggested that magnetic resonance imaging may become the method of choice in the diagnosis of structural spinal cord diseases. Images PMID:3936900
Bradesi, Sylvie; Karagiannides, Iordanes; Bakirtzi, Kyriaki; Joshi, Swapna Mahurkar; Koukos, Georgios; Iliopoulos, Dimitrios; Pothoulakis, Charalabos; Mayer, Emeran A.
Introduction Animal studies have shown that stress could induce epigenetic and transcriptomic alterations essential in determining the balance between adaptive or maladaptive responses to stress. We tested the hypothesis that chronic stress in rats deregulates coding and non-coding gene expression in the spinal cord, which may underline neuroinflammation and nociceptive changes previously observed in this model. Methods Male Wistar rats were exposed to daily stress or handled, for 10 days. At day 11, lumbar spinal segments were collected and processed for mRNA/miRNA isolation followed by expression profiling using Agilent SurePrint Rat Exon and Rat miRNA Microarray platforms. Differentially expressed gene lists were generated using the dChip program. Microarrays were analyzed using the Ingenuity Pathways Analysis (IPA) tool from Ingenuity Systems. Multiple methods were used for the analysis of miRNA-mRNA functional modules. Quantitative real time RT-PCR for Interleukin 6 signal transducer (gp130), the Signal Transducer And Activator Of Transcription 3 (STAT3), glial fibrillary acidic protein and mir-17-5p were performed to confirm levels of expression. Results Gene network analysis revealed that stress deregulated different inflammatory (IL-6, JAK/STAT, TNF) and metabolic (PI3K/AKT) signaling pathways. MicroRNA array analysis revealed a signature of 39 deregulated microRNAs in stressed rats. MicroRNA-gene network analysis showed that microRNAs are regulators of two gene networks relevant to inflammatory processes. Specifically, our analysis of miRNA-mRNA functional modules identified miR-17-5p as an important regulator in our model. We verified miR-17-5p increased expression in stress using qPCR and in situ hybridization. In addition, we observed changes in the expression of gp130 and STAT3 (involved in intracellular signaling cascades in response to gp130 activation), both predicted targets for miR-17-5p. A modulatory role of spinal mir17-5p in the modulation of
Taweel, Waleed Al; Seyam, Raouf
Neurogenic bladder dysfunction due to spinal cord injury poses a significant threat to the well-being of patients. Incontinence, renal impairment, urinary tract infection, stones, and poor quality of life are some complications of this condition. The majority of patients will require management to ensure low pressure reservoir function of the bladder, complete emptying, and dryness. Management typically begins with anticholinergic medications and clean intermittent catheterization. Patients who fail this treatment because of inefficacy or intolerability are candidates for a spectrum of more invasive procedures. Endoscopic managements to relieve the bladder outlet resistance include sphincterotomy, botulinum toxin injection, and stent insertion. In contrast, patients with incompetent sphincters are candidates for transobturator tape insertion, sling surgery, or artificial sphincter implantation. Coordinated bladder emptying is possible with neuromodulation in selected patients. Bladder augmentation, usually with an intestinal segment, and urinary diversion are the last resort. Tissue engineering is promising in experimental settings; however, its role in clinical bladder management is still evolving. In this review, we summarize the current literature pertaining to the pathology and management of neurogenic bladder dysfunction in patients with spinal cord injury. PMID:26090342
Campbell, Claudia M.; Buenaver, Luis F.; Raja, Srinivasa N.; Kiley, Kasey B.; Swedberg, Lauren; Wacnik, Paul W.; Cohen, Steven P.; Erdek, Michael A.; Williams, Kayode A.; Christo, Paul J.
Objective Spinal Cord Stimulation (SCS) has become a widely used treatment option for a variety of pain conditions. Substantial variability exists in the degree of benefit obtained from SCS and patient selection is a topic of expanding interest and importance. However, few studies have examined the potential benefits of dynamic Quantitative Sensory Testing (QST) to develop objective measures of SCS outcomes or as a predictive tool to help patient selection. Psychological characteristics have been shown to play an important role in shaping individual differences in the pain experience and may aid in predicting responses to SCS. Static laboratory pain-induction measures have also been examined in their capacity for predicting SCS outcomes. Methods The current study evaluated clinical, psychological and laboratory pain measures at baseline, during trial SCS lead placement, as well as one month and three months following permanent SCS implantation in chronic pain patients who received SCS treatment. Several QST measures were conducted, with specific focus on examination of dynamic models (central sensitization and conditioned pain modulation [CPM]) and their association with pain outcomes three months post SCS implantation. Results Results suggest few changes in QST over time. However, central sensitization and CPM at baseline were significantly associated with clinical pain at three months following SCS implantation, controlling for psycho/behavioral factors and pain at baseline. Specifically, enhanced central sensitization and reduced CPM were associated with less self-reported pain three months following SCS implantation. Conclusions These findings suggest a potentially important role for dynamic pain assessment in individuals undergoing SCS, and hint at potential mechanisms through which SCS may impart its benefit. PMID:25800088
Hillen, Brian K.; Jindrich, Devin L.; Abbas, James J.; Yamaguchi, Gary T.
Spinal cord injury (SCI) can lead to changes in muscle activation patterns and atrophy of affected muscles. Moderate levels of SCI are typically associated with foot drag during the swing phase of locomotion. Foot drag is often used to assess locomotor recovery, but the causes remain unclear. We hypothesized that foot drag results from inappropriate muscle coordination preventing flexion at the stance-to-swing transition. To test this hypothesis and to assess the relative contributions of neural and muscular changes on foot drag, we developed a two-dimensional, one degree of freedom ankle musculoskeletal model with gastrocnemius and tibialis anterior muscles. Anatomical data collected from sham-injured and incomplete SCI (iSCI) female Long-Evans rats as well as physiological data from the literature were used to implement an open-loop muscle dynamics model. Muscle insertion point motion was calculated with imposed ankle trajectories from kinematic analysis of treadmill walking in sham-injured and iSCI animals. Relative gastrocnemius deactivation and tibialis anterior activation onset times were varied within physiologically relevant ranges based on simplified locomotor electromyogram profiles. No-atrophy and moderate muscle atrophy as well as normal and injured muscle activation profiles were also simulated. Positive moments coinciding with the transition from stance to swing phase were defined as foot swing and negative moments as foot drag. Whereas decreases in activation delay caused by delayed gastrocnemius deactivation promote foot drag, all other changes associated with iSCI facilitate foot swing. Our results suggest that even small changes in the ability to precisely deactivate the gastrocnemius could result in foot drag after iSCI. PMID:25673734
Hillen, Brian K; Jindrich, Devin L; Abbas, James J; Yamaguchi, Gary T; Jung, Ranu
Spinal cord injury (SCI) can lead to changes in muscle activation patterns and atrophy of affected muscles. Moderate levels of SCI are typically associated with foot drag during the swing phase of locomotion. Foot drag is often used to assess locomotor recovery, but the causes remain unclear. We hypothesized that foot drag results from inappropriate muscle coordination preventing flexion at the stance-to-swing transition. To test this hypothesis and to assess the relative contributions of neural and muscular changes on foot drag, we developed a two-dimensional, one degree of freedom ankle musculoskeletal model with gastrocnemius and tibialis anterior muscles. Anatomical data collected from sham-injured and incomplete SCI (iSCI) female Long-Evans rats as well as physiological data from the literature were used to implement an open-loop muscle dynamics model. Muscle insertion point motion was calculated with imposed ankle trajectories from kinematic analysis of treadmill walking in sham-injured and iSCI animals. Relative gastrocnemius deactivation and tibialis anterior activation onset times were varied within physiologically relevant ranges based on simplified locomotor electromyogram profiles. No-atrophy and moderate muscle atrophy as well as normal and injured muscle activation profiles were also simulated. Positive moments coinciding with the transition from stance to swing phase were defined as foot swing and negative moments as foot drag. Whereas decreases in activation delay caused by delayed gastrocnemius deactivation promote foot drag, all other changes associated with iSCI facilitate foot swing. Our results suggest that even small changes in the ability to precisely deactivate the gastrocnemius could result in foot drag after iSCI.
Hu, Ji; Yu, Qijing; Xie, Lijie; Zhu, Hongfei
One of the principal functions of physical barriers between the blood and central nervous system protects system (i.e., blood brain barrier and blood-spinal cord barrier) is the protection from toxic and pathogenic agents in the blood. Disruption of blood-spinal cord barrier (BSCB) plays a key role in spinal cord ischemia-reperfusion injury (SCIRI). Following SCIRI, the permeability of the BSCB increases. Maintaining the integrity of the BSCB alleviates the spinal cord injury after spinal cord ischemia. This review summarizes current knowledge of the structure and function of the BSCB and its changes following SCIRI, as well as the prevention and cure of SCIRI and the role of the BSCB.
Elliott, Melanie B; Barr, Ann E; Kietrys, David M; Al-Shatti, Talal; Amin, Mamta; Barbe, Mary F
Performance of high repetition tasks with or without force is associated with peripheral tissue inflammation, decreased nerve function and motor dysfunction. Here, we examined whether a low repetition task with negligible force (LRNF) produces fewer tissue and behavioral pathologies than previously observed with high repetition tasks using our rat model of repetitive motion injury (RMI). Thirty-seven rats were randomized into control or LRNF groups, the latter reaching and grasping a 45 mg food pellet at a rate of 3 reaches/min. This task was performed in 4, 0.5 5 h sessions with 1.5 5 h rest periods for 3 days/week for up to 12 weeks. Examination of distal median nerve, forelimb flexor tendons and bones for ED1-positive cells (macrophages and osteoclasts) revealed increases in nerve and bone in week 12. The nerve also contained increased TNF-alpha expressing cells in week 12. Examination of spinal cord dorsal horns revealed increased immunoexpression of Substance P in week 8 and neurokinin-1 in weeks 8 and 12 in the superficial lamina. Motor behavioral analyses showed no changes in reach rate across weeks, slightly reduced task duration (a measurement of voluntary task participation) in week 12, but significantly increased extra arm movement reversals during reaching in week 8. These extra movement reversals were corrections for missed food pellets during a reach. Thus, performance of even a low repetition, negligible force upper extremity task for 3 months can induce mild peripheral tissue inflammation, neurochemical increases in spinal cord dorsal horns, and declines in fine motor control.
Gong, Gu; Yuan, Li-bang; Hu, Ling; Wu, Wei; Yin, Liang; Hou, Jing-li; Liu, Ying-hai; Zhou, Le-shun
Aim: To investigate the neuroprotective effect of glycyrrhizin (Gly) against the ischemic injury of rat spinal cord and the possible role of the nuclear protein high-mobility group box 1 (HMGB1) in the process. Methods: Male Sprague-Dawley rats were subjected to 45 min aortic occlusion to induce transient lumbar spinal cord ischemia. The motor functions of the animals were assessed according to the modified Tarlov scale. The animals were sacrificed 72 h after reperfusion and the lumbar spinal cord segment (L2–L4) was taken out for histopathological examination and Western blotting analysis. Serum inflammatory cytokine and HMGB1 levels were analyzed using ELISA. Results: Gly (6 mg/kg) administered intravenously 30 min before inducing the transient lumbar spinal cord ischemia significantly improved the hind-limb motor function scores, and reduced the number of apoptotic neurons, which was accompanied by reduced levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the plasma and injured spinal cord. Moreover, the serum HMGB1 level correlated well with the serum TNF-α, IL-1β and IL-6 levels during the time period of reperfusion. Conclusion: The results suggest that Gly can attenuate the transient spinal cord ischemic injury in rats via reducing inflammatory cytokines and inhibiting the release of HMGB1. PMID:22158106
Corona, Juan Carlos; Tapia, Ricardo
The mechanisms of motor neuron (MN) degeneration in amyotrophic lateral sclerosis (ALS) are unknown, but glutamate-mediated excitotoxicity may be involved. To examine directly this idea in vivo, we have used microdialysis in the rat lumbar spinal cord and showed that four- to fivefold increases in the concentration of endogenous extracellular glutamate during at least 1 h, by perfusion with the glutamate transport inhibitor L-2,4-trans-pyrrolidine-dicarboxylate, elicited no motor alterations or MN damage. Stimulation of glutamate release with 4-aminopyridine induced transitory ipsilateral hindlimb muscular twitches but no MN damage. In contrast, perfusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) did not modify glutamate levels but produced intense muscular spasms, followed by ipsilateral permanent hindlimb paralysis and a remarkable loss of MNs. These effects of AMPA were prevented by co-perfusion with the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline. Perfusion with NMDA or kainate produced no motor effects or MN damage. Thus, the elevation of endogenous extracellular glutamate in vivo due to blockade of its transport is innocuous for spinal MNs. Because this resistance is observed under the same experimental conditions in which MNs are highly vulnerable to AMPA, these results indicate that excitotoxicity due to this mechanism might not be an important factor in the pathogenesis of ALS.
Nesic, Olivera; Lee, Julieann; Ye, Zaiming; Unabia, Geda C.; Rafati, Danny; Hulsebosch, Claire E.; Perez-Polo, J. Regino
The effect of spinal cord injury (SCI) on the expression levels and distribution of water channel aquaporin 4 (AQP4) has not been studied. We have found AQP4 in gray and white matter astrocytes in both uninjured and injured rat spinal cords. AQP4 was detected in astrocytic processes that were tightly surrounding neurons and blood vessels, but more robustly in glia limitans externa and interna, which were forming an interface between spinal cord parenchyma and cerebrospinal fluid (CSF). Such spatial distribution of AQP4 suggests a critical role that astrocytes expressing AQP4 play in the transport of water from blood/CSF to spinal cord parenchyma and vice versa. SCI induced biphasic changes in astrocytic AQP4 levels, including its early down-regulation and subsequent persistent up-regulation. However, changes in AQP4 expression did not correlate well with the onset and magnitude of astrocytic activation, when measured as changes in GFAP expression levels. It appears that reactive astrocytes began expressing increased levels of AQP4 after migrating to the wound area (thoracic region) two weeks after SCI, and AQP4 remained significantly elevated for months after SCI. We also showed that increased levels of AQP4 spread away from the lesion site to cervical and lumbar segments, but only in chronically injured spinal cords. Although overall AQP4 expression levels increased in chronically-injured spinal cords, AQP4 immunolabeling in astrocytic processes forming glia limitans externa was decreased, which may indicate impaired water transport through glia limitans externa. Finally, we also showed that SCI-induced changes in AQP4 protein levels correlate, both temporally and spatially, with persistent increases in water content in acutely and chronically injured spinal cords. Although correlative, this finding suggests a possible link between AQP4 and impaired water transport/edema/syringomyelia in contused spinal cords. PMID:17074445
Cohen, A. H.; Mackler, S. A.; Selzer, M. E.
Axons in the larval sea lamprey can regenerate across the site of a spinal cord transection and form functioning synapses with some of their normal target neurons. The animals recover normal-appearing locomotion, but whether the regenerating axons and their synaptic connections are capable of playing a functional role during this behavior is unknown. To test this, ``fictive'' swimming was induced in the isolated spinal cord by the addition of D-glutamate to the bathing solution. Ventral root discharges of segments above and below a healed transection showed a high degree of phase-locking. This strongly suggests that the behavioral recovery is mediated by regenerated functional synaptic connections subserving intersegmental coordination of the central pattern generator for locomotion.
Taylor, T R; Dineen, R; White, B; Jaspan, T
Objectives This study included a series of middle-aged male and female patients who presented with chronic anterior hemicord dysfunction progressing to paraplegia. Imaging of anterior thoracic cord displacement by either a dural adhesion or a dural defect with associated cord herniation is presented. Methods This is a retrospective review of cases referred to a tertiary neuroscience centre over a 19-year period. Imaging series were classified by two experienced neuroradiologists against several criteria and correlated with clinical examination and/or findings at surgery. Results 16 cases were available for full review. Nine were considered to represent adhesions (four confirmed surgically) and four to represent true herniation (three confirmed surgically). In the three remaining cases the diagnosis was radiologically uncertain. Conclusion The authors propose “thoracic anterior spinal cord adhesion syndrome” as a novel term to describe this patient cohort and suggest appropriate clinicoradiological features for diagnosis. Several possible aetiologies are also suggested, with disc rupture and inflammation followed by disc resorption and dural pocket formation being a possible mechanism predisposing to herniation at the extreme end of a clinicopathological spectrum. PMID:22665931
... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Implanted spinal cord stimulator for pain relief... Implanted spinal cord stimulator for pain relief. (a) Identification. An implanted spinal cord stimulator for pain relief is a device that is used to stimulate electrically a patient's spinal cord to...
... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Implanted spinal cord stimulator for pain relief... Implanted spinal cord stimulator for pain relief. (a) Identification. An implanted spinal cord stimulator for pain relief is a device that is used to stimulate electrically a patient's spinal cord to...
... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Implanted spinal cord stimulator for pain relief... Implanted spinal cord stimulator for pain relief. (a) Identification. An implanted spinal cord stimulator for pain relief is a device that is used to stimulate electrically a patient's spinal cord to...
... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Implanted spinal cord stimulator for pain relief... Implanted spinal cord stimulator for pain relief. (a) Identification. An implanted spinal cord stimulator for pain relief is a device that is used to stimulate electrically a patient's spinal cord to...
... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Implanted spinal cord stimulator for pain relief... Implanted spinal cord stimulator for pain relief. (a) Identification. An implanted spinal cord stimulator for pain relief is a device that is used to stimulate electrically a patient's spinal cord to...
Leijnse, J N; D'Herde, K
In classic anatomic atlases, the spinal cord is standardly represented in its anatomical form with symmetrically emerging anterior and posterior roots, which at the level of the intervertebral foramen combine into the spinal nerves. The parts of the cord delimited by the boundaries of the roots are called segments or myelomeres. Associated with their regular repetitive appearance is the notion that the cord is segmentally organized. This segmental view is reinforced by clinical practice. Spinal cord roots innervate specific body parts. The level of cord trauma is diagnosed by the de-innervation symptoms of these parts. However, systemically, the case for a segmentally organized cord is not so clear. To date, developmental and genetic research points to a regionally rather than a segmentally organized cord. In the present study, to what degree the fila radicularia are segmentally implanted along the cord was investigated. The research hypothesis was that if the fila radicularia were non-segmentally implanted at the cord surface, it would be unlikely that the internal neuron stratum would be segmented. The visual segmented aspect of the myelomeres would then be the consequence of the necessary bundling of axons towards the vertebral foramen as the only exits of the vertebral canal, rather than of an underlying segment organization of the cord itself. To investigate the research hypothesis, the fila radicularia in the cervical-upper thoracic part of five spinal cords were detached from their spinal nerves and dissected in detail. The principal research question was if the fila radicularia are separated from their spinal nerves and dissected from their connective tissues up to the cord, would it be possible to reconstruct the original spinal segments from the morphology and interspaces of the fila? The dissections revealed that the anterior fila radicularia emerge from the cord at regular regionally modulated interspaces without systematic segmental delineations. The
ABSTRACT Essentially all spinal cord injured patients receive stretching therapies beginning within the first few weeks post-injury. Despite this fact...that stretching for short periods of time (4-5 weeks ) allows substantial recovery to occur once stretching is stopped, and both acute and chronic...4hours after one stretching session and then on Friday afternoon 3-4hours after the final stretching session of the week (the lowest scores). As seen
Hylands-White, Nicholas; Duarte, Rui V; Beeson, Paul; Mayhew, Stephen D; Raphael, Jon H
Pain is a subjective response that limits assessment. The purpose of this case report was to explore how the objectivity of the electroencephalographic response to thermal stimuli would be affected by concurrent spinal cord stimulation. A patient had been implanted with a spinal cord stimulator for the management of complex regional pain syndrome of both hands for 8 years. Following ethical approval and written informed consent we induced thermal stimuli using the Medoc PATHWAY Pain & Sensory Evaluation System on the right hand of the patient with the spinal cord stimulator switched off and with the spinal cord stimulator switched on. The patient reported a clinically significant reduction in thermal induced pain using the numerical rating scale (71.4 % reduction) with spinal cord stimulator switched on. Analysis of electroencephalogram recordings indicated the occurrence of contact heat evoked potentials (N2-P2) with spinal cord stimulator off, but not with spinal cord stimulator on. This case report suggests that thermal pain can be reduced in complex regional pain syndrome patients with the use of spinal cord stimulation and offers objective validation of the reported outcomes with this treatment.
Akman, Tarik; Yener, Ali Umit; Sehitoglu, Muserref Hilal; Yuksel, Yasemin; Cosar, Murat
Objective The main causes of spinal cord ischemia are a variety of vascular pathologies causing acute arterial occlusions. We investigated neuroprotective effects of kefir on spinal cord ischemia injury in rats. Methods Rats were divided into three groups : 1) sham operated control rats; 2) spinal cord ischemia group fed on a standard diet without kefir pretreatment; and 3) spinal cord ischemia group fed on a standard diet plus kefir. Spinal cord ischemia was performed by the infrarenal aorta cross-clamping model. The spinal cord was removed after the procedure. The biochemical and histopathological changes were observed within the samples. Functional assessment was performed for neurological deficit scores. Results The kefir group was compared with the ischemia group, a significant decrease in malondialdehyde levels was observed (p<0.05). Catalase and superoxide dismutase levels of the kefir group were significantly higher than ischemia group (p<0.05). In histopathological samples, the kefir group is compared with ischemia group, there was a significant decrease in numbers of dead and degenerated neurons (p<0.05). In immunohistochemical staining, hipoxia-inducible factor-1α and caspase 3 immunopositive neurons were significantly decreased in kefir group compared with ischemia group (p<0.05). The neurological deficit scores of kefir group were significantly higher than ischemia group at 24 h (p<0.05). Conclusion Our study revealed that kefir pretreatment in spinal cord ischemia/reperfusion reduced oxidative stress and neuronal degeneration as a neuroprotective agent. Ultrastructural studies are required in order for kefir to be developed as a promising therapeutic agent to be utilized for human spinal cord ischemia in the future. PMID:26113960
Cao, Xiaoyu C; Pappalardo, Laura W; Waxman, Stephen G; Tan, Andrew M
Neuropathic pain is a major complication of spinal cord injury, and despite aggressive efforts, this type of pain is refractory to available clinical treatment. Our previous work has demonstrated a structure-function link between dendritic spine dysgenesis on nociceptive sensory neurons in the intermediate zone, laminae IV/V, and chronic pain in central nervous system and peripheral nervous system injury models of neuropathic pain. To extend these findings, we performed a follow-up structural analysis to assess whether dendritic spine remodeling occurs on superficial dorsal horn neurons located in lamina II after spinal cord injury. Lamina II neurons are responsible for relaying deep, delocalized, often thermally associated pain commonly experienced in spinal cord injury pathologies. We analyzed dendritic spine morphometry and localization in tissue obtained from adult rats exhibiting neuropathic pain one-month following spinal cord injury. Although the total density of dendritic spines on lamina II neurons did not change after spinal cord injury, we observed an inverse relationship between the densities of thin- and mushroom-shaped spines: thin-spine density decreased while mushroom-spine density increased. These structural changes were specifically noted along dendritic branches within 150 µm from the soma, suggesting a possible adverse contribution to nociceptive circuit function. Intrathecal treatment with NSC23766, a Rac1-GTPase inhibitor, significantly reduced spinal cord injury-induced changes in both thin- and mushroom-shaped dendritic spines. Overall, these observations demonstrate that dendritic spine remodeling occurs in lamina II, regulated in part by the Rac1-signaling pathway, and suggests that structural abnormalities in this spinal cord region may also contribute to abnormal nociception after spinal cord injury.
Cao, Xiaoyu C; Pappalardo, Laura W; Waxman, Stephen G
Neuropathic pain is a major complication of spinal cord injury, and despite aggressive efforts, this type of pain is refractory to available clinical treatment. Our previous work has demonstrated a structure–function link between dendritic spine dysgenesis on nociceptive sensory neurons in the intermediate zone, laminae IV/V, and chronic pain in central nervous system and peripheral nervous system injury models of neuropathic pain. To extend these findings, we performed a follow-up structural analysis to assess whether dendritic spine remodeling occurs on superficial dorsal horn neurons located in lamina II after spinal cord injury. Lamina II neurons are responsible for relaying deep, delocalized, often thermally associated pain commonly experienced in spinal cord injury pathologies. We analyzed dendritic spine morphometry and localization in tissue obtained from adult rats exhibiting neuropathic pain one-month following spinal cord injury. Although the total density of dendritic spines on lamina II neurons did not change after spinal cord injury, we observed an inverse relationship between the densities of thin- and mushroom-shaped spines: thin-spine density decreased while mushroom-spine density increased. These structural changes were specifically noted along dendritic branches within 150 µm from the soma, suggesting a possible adverse contribution to nociceptive circuit function. Intrathecal treatment with NSC23766, a Rac1-GTPase inhibitor, significantly reduced spinal cord injury-induced changes in both thin- and mushroom-shaped dendritic spines. Overall, these observations demonstrate that dendritic spine remodeling occurs in lamina II, regulated in part by the Rac1-signaling pathway, and suggests that structural abnormalities in this spinal cord region may also contribute to abnormal nociception after spinal cord injury. PMID:28326929
Kumar, Hemant; Ropper, Alexander E; Lee, Soo-Hong; Han, Inbo
The blood-spinal cord barrier (BSCB) is a specialized protective barrier that regulates the movement of molecules between blood vessels and the spinal cord parenchyma. Analogous to the blood-brain barrier (BBB), the BSCB plays a crucial role in maintaining the homeostasis and internal environmental stability of the central nervous system (CNS). After spinal cord injury (SCI), BSCB disruption leads to inflammatory cell invasion such as neutrophils and macrophages, contributing to permanent neurological disability. In this review, we focus on the major proteins mediating the BSCB disruption or BSCB repair after SCI. This review is composed of three parts. Section 1. SCI and the BSCB of the review describes critical events involved in the pathophysiology of SCI and their correlation with BSCB integrity/disruption. Section 2. Major proteins involved in BSCB disruption in SCI focuses on the actions of matrix metalloproteinases (MMPs), tumor necrosis factor alpha (TNF-α), heme oxygenase-1 (HO-1), angiopoietins (Angs), bradykinin, nitric oxide (NO), and endothelins (ETs) in BSCB disruption and repair. Section 3. Therapeutic approaches discusses the major therapeutic compounds utilized to date for the prevention of BSCB disruption in animal model of SCI through modulation of several proteins.
Erol, İlknur; Özkale, Murat; Savaş, Tülin; Alkan, Özlem; Çekinmez, Melih; Erbay, Ayşe
Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system, that predominantly affects the spinal cord and the optic nerve. Its key features include transverse myelitis, commonly associated with extensive inflammation spanning three or more consecutive vertebral segments. Longitudinal extensive spinal cord lesions can also occur in systemic autoimmune diseases, infections, vascular and metabolic disorders, subsequent to irradiation, intramedullary tumors and paraneoplastic myelopathies. We present a case study of an 8-year-old girl seropositive for antibodies against the aquaporin 4 who displayed longitudinal extensive spinal cord lesions, that was initially misdiagnosed as an intramedullary tumor.
Nardone, Raffaele; Pikija, Slaven; Mutzenbach, J Sebastian; Seidl, Martin; Leis, Stefan; Trinka, Eugen; Sellner, Johann
Spinal cord infarction (SCI) is a rare but disabling disorder caused by a wide spectrum of conditions. Given the lack of randomized-controlled trials, contemporary treatment concepts are adapted from guidelines for cerebral ischemia, atherosclerotic vascular disease, and acute traumatic spinal cord injury. In addition, patients with SCI are at risk for several potentially life-threatening but preventable systemic and neurologic complications. Notably, there is emerging evidence from preclinical studies for the use of neuroprotection in acute ischemic injury of the spinal cord. In this review, we discuss the current state of the art for the therapy and prevention of SCI and highlight potential emerging treatment concepts awaiting translational adoption.
Baker, E R; Cardenas, D D; Benedetti, T J
We reviewed the experience with pregnancy in spinal cord-injured women at the University of Washington over the past 10 years. During that time, 11 women with spinal cord injury had 13 pregnancies. Infant outcome was uniformly good. No major obstetric complication occurred. The mothers experienced medical problems including urinary tract infection in ten and pyelonephritis in three. Autonomic hyperreflexia occurred in three of five subjects with lesions at or above the sixth thoracic vertebra. Pregnancy in the spinal cord-injured patient involves medical risk for the mother, but with careful management, an excellent outcome for both mother and infant may be anticipated.
Singh, Priyanka L.; Agarwal, Nitin; Barrese, James C.; Heary, Robert F.
Damage from spinal cord injury occurs in two phases – the trauma of the initial mechanical insult and a secondary injury to nervous tissue spared by the primary insult. Apart from damage sustained as a result of direct trauma to the spinal cord, the post-traumatic inflammatory response contributes significantly to functional motor deficits exacerbated by the secondary injury. Attenuating the detrimental aspects of the inflammatory response is a promising strategy to potentially ameliorate the secondary injury, and promote significant functional recovery. This review details how the inflammatory component of secondary injury to the spinal cord can be treated currently and in the foreseeable future. PMID:25624806
Cohen-Adad, J; Hoge, R D; Leblond, H; Xie, G; Beaudoin, G; Song, A W; Krueger, G; Doyon, J; Benali, H; Rossignol, S
Functional magnetic resonance imaging (fMRI) of the spinal cord has been the subject of intense research for the last ten years. An important motivation for this technique is its ability to detect non-invasively neuronal activity in the spinal cord related to sensorimotor functions in various conditions, such as after spinal cord lesions. Although promising results of spinal cord fMRI have arisen from previous studies, the poor reproducibility of BOLD activations and their characteristics remain a major drawback. In the present study we investigated the reproducibility of BOLD fMRI in the spinal cord of cats (N=9) by repeating the same stimulation protocol over a long period (approximately 2 h). Cats were anaesthetized with ketamine, and spinal cord activity was induced by electrical stimulation of cutaneous nerves of the hind limbs. As a result, task-related signals were detected in most cats with relatively good spatial specificity. However, BOLD response significantly varied within and between cats. This variability was notably attributed to the moderate intensity of the stimulus producing a low amplitude haemodynamic response, variation in end-tidal CO(2) during the session, low signal-to-noise ratio (SNR) in spinal fMRI time series and animal-specific vascular anatomy. Original contributions of the present study are: (i) first spinal fMRI experiment in ketamine-anaesthetized animals, (ii) extensive study of intra- and inter-subject variability of activation, (iii) characterisation of static and temporal SNR in the spinal cord and (iv) investigation on the impact of CO(2) end-tidal level on the amplitude of BOLD response.
Barman, Apurba; Sinha, Mithilesh K; Rao, P Bhaskar
Autonomic dysreflexia is a medical emergency in spinal cord injury. Majority of cases of autonomic dysreflexia are known to be induced by either bladder or bowel distension. Very few cases of recurrent postural autonomic dysreflexia, due to secondary spinal pathology, have been reported. Discovertebral or Andersson lesion, a recognized complication in Ankylosing Spondylitis, can give rise to similar kind of recurrent postural dysreflexic symptoms. Here, we report a case of Ankylosing Spondylitis with high level, complete spinal cord injury, where the patient was developing recurrent postural autonomic dysreflexia and its successful management. Andersson lesion in the lumbar spine below the level of injury was demonstrated in this case report.
Lin, Chia-Ching; Lai, Sih-Rong; Shao, Yu-Han; Chen, Chun-Lin; Lee, Kun-Ze
Respiratory impairment due to damage of the spinal respiratory motoneurons and interruption of the descending drives from brainstem premotor neurons to spinal respiratory motoneurons is the leading cause of morbidity and mortality following cervical spinal cord injury. The present study was designed to evaluate the therapeutic effectiveness of delayed transplantation of fetal spinal cord (FSC) tissue on respiratory function in rats with mid-cervical spinal cord injury. Embryonic day-14 rat FSC tissue was transplanted into a C4 spinal cord hemilesion cavity in adult male rats at 1 week postinjury. The histological results showed that FSC-derived grafts can survive, fill the lesion cavity, and differentiate into neurons and astrocytes at 8 weeks post-transplantation. Some FSC-derived graft neurons exhibited specific neurochemical markers of neurotransmitter (e.g., serotonin, noradrenalin, or acetylcholine). Moreover, a robust expression of glutamatergic and γ-aminobutyric acid-ergic fibers was observed within FSC-derived grafts. Retrograde tracing results indicated that there was a connection between FSC-derived grafts and host phrenic nucleus. Neurophysiological recording of the phrenic nerve demonstrated that phrenic burst amplitude ipsilateral to the lesion was significantly greater in injured animals that received FSC transplantation than in those that received buffer transplantation under high respiratory drives. These results suggest that delayed FSC transplantation may have the potential to repair the injured spinal cord and promote respiratory functional recovery after mid-cervical spinal cord injury.
Kuerten, Stefanie; Gruppe, Traugott L; Laurentius, Laura-Maria; Kirch, Christiane; Tary-Lehmann, Magdalena; Lehmann, Paul V; Addicks, Klaus
In this study we demonstrate that experimental autoimmune encephalomyelitis (EAE) induced by the MBP-PLP fusion protein MP4, MOG peptide 35-55, or PLP peptide 178-191 in C57BL/6 mice, respectively, displays distinct features of CNS pathology. Major differences between the three models resided in (i) the region-/tract-specificity and disseminated nature of spinal cord degeneration, (ii) the extent and kinetics of demyelination, and (iii) the involvement of motoneurons in the disease. In contrast, axonal damage was present in all models and to a similar extent, proposing this feature as a possible morphological correlate for the comparable chronic clinical course of the disease induced by the three antigens. The data suggest that the antigen targeted in autoimmune encephalomyelitis is crucial to the induction of differential histopathological disease manifestations. The use of MP4-, MOG:35-55-, and PLP:178-191-induced EAE on the C57BL/6 background can be a valuable tool when it comes to reproducing and studying the structural-morphological diversity of multiple sclerosis.
Pittner, Y; Dufour, J-F; David, G; Boibieux, A; Peyramond, D
We report the case of an atypical localization of a spinal cord "toxoplasmic abscess". The 46-year-old patient, HIV-1 positive, was admitted for acute urine retention and gait disorders. MRI revealed a T12-L1 medullary lesion suggesting a tumoral, inflammatory and infectious pathology. The radiological aspect and immunosuppression lead to the initiation of a treatment against Toxoplasma gondii, following the same treatment principles as for cerebral toxoplasmosis. The diagnosis can only be proved by data from autopsy or surgical biopsy, but toxoplasmosis PCR on CSF seems to be an interesting alternative to confirm the diagnosis. According to the literature, PCR is not sensitive enough as a diagnostic tool. Improvement after treatment supported the diagnosis confirmed by PCR.
Ho, Chester H.; Triolo, Ronald J.; Elias, Anastasia L.; Kilgore, Kevin L.; DiMarco, Anthony F.; Bogie, Kath; Vette, Albert H.; Audu, Musa; Kobetic, Rudi; Chang, Sarah R.; Chan, K. Ming; Dukelow, Sean; Bourbeau, Dennis J.; Brose, Steven W.; Gustafson, Kenneth J.; Kiss, Zelma; Mushahwar, Vivian K.
Synopsis Spinal cord injuries (SCI) can disrupt communications between the brain and the body, leading to a loss of control over otherwise intact neuromuscular systems. The use of electrical stimulation (ES) of the central and peripheral nervous system can take advantage of these intact neuromuscular systems to provide therapeutic exercise options, to allow functional restoration, and even to manage or prevent many medical complications following SCI. The use of ES for the restoration of upper extremity, lower extremity and truncal functions can make many activities of daily living a potential reality for individuals with SCI. Restoring bladder and respiratory functions and preventing pressure ulcers may significantly decrease the morbidity and mortality following SCI. Many of the ES devices are already commercially available and should be considered by all SCI clinicians routinely as part of the lifelong rehabilitation care plan for all eligible individuals with SCI. PMID:25064792
Ha, Kee-Yong; Kim, Sang-Il
Spinal cord injury (SCI) has been considered an incurable condition and it often causes devastating sequelae. In terms of the pathophysiology of SCI, reducing secondary damage is the key to its treatment. Various researches and clinical trials have been performed, and some of them showed promising results; however, there is still no gold standard treatment with sufficient evidence. Two therapeutic concepts for SCI are neuroprotective and neuroregenerative strategies. The neuroprotective strategy modulates the pathomechanism of SCI. The purpose of neuroprotective treatment is to minimize secondary damage following direct injury. The aim of neuroregenerative treatment is to enhance the endogenous regeneration process and to alter the intrinsic barrier. With advancement in biotechnology, cell therapy using cell transplantation is currently under investigation. This review discusses the pathophysiology of SCI and introduces the therapeutic candidates that have been developed so far. PMID:28261421
Chime, Chukwunonso; Arjun, Shiva; Reddy, Pavithra; Niazi, Masooma
Hepatocellular carcinoma (HCC) is the most common primary malignancy of liver. Distant metastasis to various organs is well known. Skeletal metastasis is also reported to various locations. Vertebral metastasis has been reported mostly to thoracic spine. However, cervical spinal cord involvement leading to cord compression has been reported very rarely in literature. We present a case of 58-year-old male with liver cirrhosis presenting as neck pain. Further work-up revealed metastatic HCC to cervical spinal cord resulting in acute cord compression. Patient has been treated with neurosurgical intervention. PMID:28299213
Nance, Jessica R.; Golomb, Meredith R.
Spinal cord infarction in children is a rare condition which is becoming more widely recognized. There are few reports in the pediatric literature characterizing etiology, diagnosis, treament and prognosis. The risk factors for pediatric ischemic spinal cord infarction include obstruction of blood flow associated with cardiovascular compromise or malformation, iatrogenic or traumatic vascular inujury, cerebellar herniation, thrombotic or embolic disease, infection, and vasculitis. In many children the cause of spinal cord ischemia in the absence of vertebral fracture is unknown. Imaging diagnosis of spinal cord ischemia is often difficult due to the small transverse area of the cord, cerebrospinal fluid artifact and inadequate resolution of MRI. Physical therapy is the most important treatment option. The prognosis is dependent on the level of spinal cord damage, early identification and reversal of ischemia, and follow-up with intensive physical therapy and medical support. In addition to summarizing the literature regarding spinal cord infarction in children without vertebral fracture, this review article adds two cases to the literature which highlight the difficulties and controversies in the management of this condition. PMID:17437902
Jia, Liu; Yu, Zou; Hui, Li; Yu-Guang, Guan; Xin-Fu, Zhou; Chao, You; Yanbin, Xiyang; Xi, Zhan; Jun, Wang; Xin-Hua, Heng; Xin-Hua, Hen; Ting-Hua, Wang
The changes of endogenous Fas/FasL in injured spinal cord, mostly in primates, are not well known. In this study, we investigated the temporal changes in the expression of Fas and FasL and explored their possible roles in the ventral horn of the spinal cord and associated precentral gyrus following T(11) spinal cord hemisection in the adult rhesus monkey. A significant functional improvement was seen with the time going on in monkeys subjected to cord hemisection. Apoptotic cells were also seen in the ventral horn of injured spinal cord with TUNEL staining, and a marked increase presents at 7 days post operation (dpo). Simultaneously, the number of Fas and FasL immunoreactive neurons in the spinal cords caudal and rostral to injury site and their intracellular optical density (OD) in the ipsilateral side of injury site at 7 dpo increased significantly more than that of control group and contralateral sides. This was followed by a decrease and returned to normal level at 60 dpo. No positive neurons were observed in precentral gyrus. The present results may provide some insights to understand the role of Fas/FasL in the spinal cord but not motor cortex with neuronal apoptosis and neuroplasticity in monkeys subjected to hemisection spinal cord injury.
Biering-Sørensen, Fin; Biering-Sørensen, Tor; Liu, Nan; Malmqvist, Lasse; Wecht, Jill Maria; Krassioukov, Andrei
A spinal cord injury (SCI) interferes with the autonomic nervous system (ANS). The effect on the cardiovascular system will depend on the extent of damage to the spinal/central component of ANS. The cardiac changes are caused by loss of supraspinal sympathetic control and relatively increased parasympathetic cardiac control. Decreases in sympathetic activity result in heart rate and the arterial blood pressure changes, and may cause arrhythmias, in particular bradycardia, with the risk of cardiac arrest in those with cervical or high thoracic injuries. The objective of this review is to give an update of the current knowledge related to the alterations in cardiac autonomic control following SCI. With this purpose the review includes the following subheadings: 2. Neuro-anatomical plasticity and cardiac control 2.1 Autonomic nervous system and the heart 2.2 Alteration in autonomic control of the heart following spinal cord injury 3. Spinal shock and neurogenic shock 3.1 Pathophysiology of spinal shock 3.2 Pathophysiology of neurogenic shock 4. Autonomic dysreflexia 4.1 Pathophysiology of autonomic dysreflexia 4.2 Diagnosis of autonomic dysreflexia 5. Heart rate/electrocardiography following spinal cord injury 5.1 Acute phase 5.2 Chronic phase 6. Heart rate variability 6.1 Time domain analysis 6.2 Frequency domain analysis 6.3 QT-variability index 6.4 Nonlinear (fractal) indexes 7. Echocardiography 7.1 Changes in cardiac structure following spinal cord injury 7.2 Changes in cardiac function following spinal cord injury 8. International spinal cord injury cardiovascular basic data set and international standards to document the remaining autonomic function in spinal cord injury.
Flynn, Jamie R.; Dunn, Lynda R.; Galea, Mary P.; Callister, Robin; Rank, Michelle M.
Abstract Following spinal cord injury (SCI), anatomical changes such as axonal sprouting occur within weeks in the vicinity of the injury. Exercise training enhances axon sprouting; however, the exact mechanisms that mediate exercised-induced plasticity are unknown. We studied the effects of exercise training after SCI on the intrinsic and synaptic properties of spinal neurons in the immediate vicinity (<2 segments) of the SCI. Male mice (C57BL/6, 9–10 weeks old) received a spinal hemisection (T10) and after 1 week of recovery, they were randomized to trained (treadmill exercise for 3 weeks) and untrained (no exercise) groups. After 3 weeks, mice were killed and horizontal spinal cord slices (T6–L1, 250 μm thick) were prepared for visually guided whole cell patch clamp recording. Intrinsic properties, including resting membrane potential, input resistance, rheobase current, action potential (AP) threshold and after-hyperpolarization (AHP) amplitude were similar in neurons from trained and untrained mice (n=67 and 70 neurons, respectively). Neurons could be grouped into four categories based on their AP discharge during depolarizing current injection; the proportions of tonic firing, initial bursting, single spiking, and delayed firing neurons were similar in trained and untrained mice. The properties of spontaneous excitatory synaptic currents (sEPSCs) did not differ in trained and untrained animals. In contrast, evoked excitatory synaptic currents recorded after dorsal column stimulation were markedly increased in trained animals (peak amplitude 78.9±17.5 vs. 42.2±6.8 pA; charge 1054±376 vs. 348±75 pA·ms). These data suggest that 3 weeks of treadmill exercise does not affect the intrinsic properties of spinal neurons after SCI; however, excitatory synaptic drive from dorsal column pathways, such as the corticospinal tract, is enhanced. PMID:23320512
Nanai, Beatrix; Lyman, Ronald; Bichsel, Pierre S
The purpose of this retrospective study was to describe the intraoperative appearance of various spinal cord conditions, and to investigate how intraoperative ultrasonography assisted in modification of surgical and postoperative treatment plans. Intraoperative ultrasonography (B-mode, and power Doppler mode) was used in 25 dogs undergoing spinal surgery. The neurologic conditions included cervical spondylomyelopathy, intervertebral disc (IVD) protrusion, IVD extrusion, spinal tumors, nerve sheath mass, granulomatous myelitis, and discospondylitis. All of these diagnoses were supported by histopathologic and/or cytologic evaluation. It was possible to visualize the spinal cord and the abnormal spinal tissue in all of the patients. Power Doppler imaging allowed assessment of the spinal cord microcirculation, and assisted in judgment of the degree of decompression. Ultrasound imaging directly impacted the surgical and the medical treatment plans in four patients. Owing to the intraoperative imaging, two hemilaminectomies were extended cranially and caudally, and additional disc spaces were fenestrated, one hemilaminectomy site was extended dorsally to retrieve the disc material from the opposite side, and one intramedullary cervical spinal cord lesion was discovered, aspirated, and consequently diagnosed as granulomatous inflammation, which altered the long-term medication protocol in that dog. This study suggests that intraoperative sonographic spinal cord imaging is a useful and viable technique.
Ohsawa, Masahiro; Kamei, Junzo
The supraspinal and spinal antinociceptive effects of several kappa-opioid receptor agonists were examined in diabetic and non-diabetic mice using the tail-flick assay. The antinociception induced by intrathecal (i.t.), but not intracerebroventricular (i.c.v.), CI-977, a highly selective kappa(1)-opioid receptor agonist, in diabetic mice was less than that in non-diabetic mice. The antinociceptive effects of ICI-199,441 and R-84760, high potency kappa(1)-opioid receptor agonists, given i.c.v., but not i.t., were attenuated in diabetic mice compared to those in non-diabetic mice. On the other hand, the antinociceptive effects of the new kappa-opioid receptor agonist TRK-820, which has high affinity for kappa(2)- and/or kappa(3)-opioid receptors, injected both i.c.v. and i.t. in diabetic mice were markedly less than those in non-diabetic mice. These results indicate that the antinociceptive effects of those kappa-opioid receptor agonists in diabetic mice are altered in a region-specific manner in the central nervous system (CNS). The dysfunction of kappa-opioid receptor subtypes in diabetic mice may underlie this CNS region-specific variation in the effects of these kappa-opioid receptor agonists.
Duan, Hongmei; Song, Wei; Zhao, Wen; Gao, Yudan; Yang, Zhaoyang; Li, Xiaoguang
During the whole life cycle of mammals, new neurons are constantly regenerated in the subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles. Thanks to emerging methodologies, great progress has been made in the characterization of spinal cord endogenous neural stem cells (ependymal cells) and identification of their role in adult spinal cord development. As recently evidenced, both the intrinsic and extrinsic molecular mechanisms of ependymal cells control the sequential steps of the adult spinal cord neurogenesis. This review introduces the concept of adult endogenous neurogenesis, the reaction of ependymal cells after adult spinal cord injury (SCI), the heterogeneity and markers of ependymal cells, the factors that regulate ependymal cells, and the niches that impact the activation or differentiation of ependymal cells.
Lu, Daniel C.; Niu, Tianyi; Alaynick, William A.
The spinal cord of vertebrate animals is comprised of intrinsic circuits that are capable of sensing the environment and generating complex motor behaviors. There are two major perspectives for understanding the biology of this complicated structure. The first approaches the spinal cord from the point of view of function and is based on classic and ongoing research in electrophysiology, adult behavior, and spinal cord injury. The second view considers the spinal cord from a developmental perspective and is founded mostly on gene expression and gain-of-function and loss-of-function genetic experiments. Together these studies have uncovered functional classes of neurons and their lineage relationships. In this review, we summarize our knowledge of developmental classes, with an eye toward understanding the functional roles of each group. PMID:26136656
... the Spinal Cord and Brain Stem Symptoms Diagnosis Treatment Medical Dictionary Also of Interest (Quiz) Horner Syndrome (Video) Overview of the Nervous System (News) Youth With Type 2 Diabetes Often Face Complications (News) Study Tracks Bleeding Risk ...
Oliynyk, M. S.; Gillies, G. T.; Oya, H.; Wilson, S.; Reddy, C. G.; Howard, M. A.
We have measured the forces that act on the electrode-bearing surface of an intradural neuromodulator designed to be in direct contact with the pial surface of the spinal cord, as part of our effort to develop a new method for treating intractable pain. The goal was to investigate the pressures produced by this device on the spinal cord and compare them with normal intrathecal pressure. For this purpose, we employed a dual-sensor arrangement that allowed us to measure the response of a custom-designed silicone spinal cord surrogate to the forces applied by the device. We found that the device had a mean compliance of ≈63 μN μm-1, and that over a 3 mm range of compression, the mid-span pressure it exerted on the spinal cord was ≈1.88 × 103 Pa = 14.1 mm Hg, which lies within the range of normal intrathecal pressure in humans.
... before the cancer is diagnosed and continue for months or years. Childhood brain and spinal cord tumors ... after treatment. Some cancer treatments cause side effects months or years after treatment has ended. These are ...
... before the cancer is diagnosed and continue for months or years. Childhood brain and spinal cord tumors ... after treatment. Some cancer treatments cause side effects months or years after treatment has ended. These are ...
Straley, Karin S.; Po Foo, Cheryl Wong
Abstract The highly debilitating nature of spinal cord injuries has provided much inspiration for the design of novel biomaterials that can stimulate cellular regeneration and functional recovery. Many experts agree that the greatest hope for treatment of spinal cord injuries will involve a combinatorial approach that integrates biomaterial scaffolds, cell transplantation, and molecule delivery. This manuscript presents a comprehensive review of biomaterial-scaffold design strategies currently being applied to the development of nerve guidance channels and hydrogels that more effectively stimulate spinal cord tissue regeneration. To enhance the regenerative capacity of these two scaffold types, researchers are focusing on optimizing the mechanical properties, cell-adhesivity, biodegradability, electrical activity, and topography of synthetic and natural materials, and are developing mechanisms to use these scaffolds to deliver cells and biomolecules. Developing scaffolds that address several of these key design parameters will lead to more successful therapies for the regeneration of spinal cord tissue. PMID:19698073
Martínez, Ernesto; Bolívar, Guillermo; Sánchez, Sandra; Carrascal, Edwin
We, herein, describe an HIV-positive patient with toxoplasmosis of the spinal cord. We also carried out a comprehensive literature review of this topic, with emphasis on the diagnostic tools and therapeutic approach. PMID:24892240
Ohta, Yuki; Takenaga, Mitsuko; Tokura, Yukie; Hamaguchi, Akemi; Matsumoto, Taro; Kano, Koichiro; Mugishima, Hideo; Okano, Hideyuki; Igarashi, Rie
Transplantation of mature adipocyte-derived cells (dedifferentiated fat cells) led to marked functional recovery from spinal cord injury (SCI)-induced motor dysfunction in rats. When mature adipocytes were isolated from rat adipose tissue and grown in ceiling culture, transformation into fibroblast-like cells without lipid droplets occurred. These fibroblast-like cells, termed dedifferentiated fat cells (DFAT), could proliferate and could also differentiate back into adipocytes. DFAT expressed neural markers such as nestin, betaIII tubulin, and GFAP. Allografting of DFAT into SCI-induced rats led to significant recovery from hindlimb dysfunction. Grafted cells were detected at the injection site, and some of these cells expressed betaIII tubulin. DFAT expressed neurotrophic factors such as BDNF and GDNF prior to transplantation, and grafted cells were also positive for these factors. Therefore, these neurotrophic factors derived from grafted DFAT might have contributed to the promotion of functional recovery. These findings also suggest that mature adipocytes could become a new source for cell replacement therapy to treat central nervous system disorders.
García, Elisa; Silva-García, Raúl; Mestre, Humberto; Flores, Nayeli; Martiñón, Susana; Calderón-Aranda, Emma S; Ibarra, Antonio
Immunization with neurally derived peptides (INDP) boosts the action of an autoreactive immune response that has been shown to induce neuroprotection in several neurodegenerative diseases, especially after spinal cord (SC) injury. This strategy provides an environment that promotes neuronal survival and tissue preservation. The mechanisms by which this autoreactive response exerts its protective effects is not totally understood at the moment. A recent study showed that INDP reduces lipid peroxidation. Lipid peroxidation is a neurodegenerative phenomenon caused by the increased production of reactive nitrogen species such as nitric oxide (NO). It is possible that INDP could be interfering with NO production. To test this hypothesis, we examined the effect of INDP on the amount of NO produced by glial cells when cocultured with autoreactive T cells. We also evaluated the amount of NO and the expression of the inducible form of nitric oxide synthase (iNOS) at the injury site of SC-injured animals. The neural-derived peptides A91 and Cop-1 were used to immunize mice and rats with SC injury. In vitro studies showed that INDP significantly reduces the production of NO by glial cells. This observation was substantiated by in vivo experiments demonstrating that INDP decreases the amount of NO and iNOS gene expression at the site of injury. The present study provides substantial evidence on the inhibitory effect of INDP on NO production, helpingour understanding of the mechanisms through which protective autoimmunity promotes neuroprotection.
Lee, Seung Heon; Lee, Kyu Chan; Choi, Jinho; Ahn, So Hyun; Lee, Seok Ho; Sung, Ki Hoon; Kil, Se Hee
Background. The aim of the study was to investigate whether biologically effective dose (BED) based on linear-quadratic model can be used to estimate spinal cord tolerance dose in spine stereotactic body radiation therapy (SBRT) delivered in 4 or more fractions. Patients and methods. Sixty-three metastatic spinal lesions in 47 patients were retrospectively evaluated. The most frequently prescribed dose was 36 Gy in 4 fractions. In planning, we tried to limit the maximum dose to the spinal cord or cauda equina less than 50% of prescription or 45 Gy2/2. BED was calculated using maximum point dose of spinal cord. Results. Maximum spinal cord dose per fraction ranged from 2.6 to 6.0 Gy (median 4.3 Gy). Except 4 patients with 52.7, 56.4, 62.4, and 67.9 Gy2/2, equivalent total dose in 2-Gy fraction of the patients was not more than 50 Gy2/2 (12.1–67.9, median 32.0). The ratio of maximum spinal cord dose to prescription dose increased up to 82.2% of prescription dose as epidural spinal cord compression grade increased. No patient developed grade 2 or higher radiation-induced spinal cord toxicity during follow-up period of 0.5 to 53.9 months. Conclusions. In fractionated spine SBRT, BED can be used to estimate spinal cord tolerance dose, provided that the dose per fraction to the spinal cord is moderate, e.g. < 6.0 Gy. It appears that a maximum dose of up to 45–50 Gy2/2 to the spinal cord is tolerable in 4 or more fractionation regimen. PMID:26029031
Wong, Kenneth H.; Choi, Jae; Wilson, William; Berry, Joel; Henderson, Fraser C., Sr.
Abnormal stretch and strain is a major cause of injury to the spinal cord and brainstem. Such forces can develop from age-related degeneration, congenital malformations, occupational exposure, or trauma such as sporting accidents, whiplash and blast injury. While current imaging technologies provide excellent morphology and anatomy of the spinal cord, there is no validated diagnostic tool to assess mechanical stresses exerted upon the spinal cord and brainstem. Furthermore, there is no current means to correlate these stress patterns with known spinal cord injuries and other clinical metrics such as neurological impairment. We have therefore developed the spinal cord stress injury assessment (SCOSIA) system, which uses imaging and finite element analysis to predict stretch injury. This system was tested on a small cohort of neurosurgery patients. Initial results show that the calculated stress values decreased following surgery, and that this decrease was accompanied by a significant decrease in neurological symptoms. Regression analysis identified modest correlations between stress values and clinical metrics. The strongest correlations were seen with the Brainstem Disability Index (BDI) and the Karnofsky Performance Score (KPS), whereas the weakest correlations were seen with the American Spinal Injury Association (ASIA) scale. SCOSIA therefore shows encouraging initial results and may have wide applicability to trauma and degenerative disease involving the spinal cord and brainstem.
Miele, Vincent J; Panjabi, Manohar M; Benzel, Edward C
The field of biomechanics combines the disciplines of biology and engineering, attempting to quantitatively describe the complicated properties of biological materials. These properties depend not only upon the inherent attributes of its constituents but also upon how the constituents are arranged relative to each other. Its importance in understanding spinal column and spinal cord pathology cannot be overemphasized. This chapter is a primer on the application of biomechanical principles to the normal and pathological spine. The basic concepts of biomechanics will first be reviewed followed by a review of the structural anatomy of the osteoligamentous spinal column and the biomechanics of injury. Relevant spinal cord anatomy will then be addressed as well as current biomechanical theories of spinal cord injury.
Fogelholm, R.; Haltia, M.; Andersson, L. C.
Radiation myelopathy is a well-known complication of irradiation therapy of neoplasms in the vicinity of the spinal cord. Most earlier authors have stressed the association of a normal myelogram and normal CSF protein level with this condition. One case of radiation myelopathy with a myelogram simulating intramedullary neoplasm and with extremely high CSF protein concentration is presented. Six months after myelography necropsy revealed severe atrophy of the previously thickened lower cervical spinal cord. The pathogenetic mechanisms are discussed. Images PMID:4443812
Treatment with the flavonoid quercetin starting 1 h after compression SCI in rats had a var- iable effect on improving locomotor function in that a...Kendall, E., Kamencic, H., Ghong, Z., Griebel, R.W., Juurlink, B.H., 2003. Quercetin promotes functional recovery following acute spinal cord injury. J...Neurotrauma 20 (6), 583-591. Schultke, E., Griebel, R.W., Juurlink, B.H., 2010a. Quercetin attenuates inflammatory pro- cesses after spinal cord
da Costa, Ronaldo C; Cook, Laurie B
Cystic lesions of the vertebral column and spinal cord are important differential diagnoses in dogs with signs of spinal cord disease. Synovial cysts are commonly associated with degenerative joint disease and usually affect the cervical and lumbosacral regions. Arachnoid diverticulum (previously known as cyst) is seen in the cervical region of large breed dogs and thoracolumbar region of small breed dogs. This article reviews the causes, diagnosis, and treatment of these and other, less common, cystic lesions.
Perruchoud, Christophe; Mariotti, Nicolas
Neuromodulation techniques modify the activity of the central or peripheral nervous system. Spinal cord stimulation is a reversible and minimally invasive treatment whose efficacy and cost effectiveness are recognized for the treatment of chronic neuropathic pain or ischemic pain. Spinal cord stimulation is not the option of last resort and should be considered among other options before prescribing long-term opioids or considering reoperation. The selection and regular follow-up of patients are crucial to the success of the therapy.
De Leener, Benjamin; Kadoury, Samuel; Cohen-Adad, Julien
Spinal cord segmentation provides measures of atrophy and facilitates group analysis via inter-subject correspondence. Automatizing this procedure enables studies with large throughput and minimizes user bias. Although several automatic segmentation methods exist, they are often restricted in terms of image contrast and field-of-view. This paper presents a new automatic segmentation method (PropSeg) optimized for robustness, accuracy and speed. The algorithm is based on the propagation of a deformable model and is divided into three parts: firstly, an initialization step detects the spinal cord position and orientation using a circular Hough transform on multiple axial slices rostral and caudal to the starting plane and builds an initial elliptical tubular mesh. Secondly, a low-resolution deformable model is propagated along the spinal cord. To deal with highly variable contrast levels between the spinal cord and the cerebrospinal fluid, the deformation is coupled with a local contrast-to-noise adaptation at each iteration. Thirdly, a refinement process and a global deformation are applied on the propagated mesh to provide an accurate segmentation of the spinal cord. Validation was performed in 15 healthy subjects and two patients with spinal cord injury, using T1- and T2-weighted images of the entire spinal cord and on multiecho T2*-weighted images. Our method was compared against manual segmentation and against an active surface method. Results show high precision for all the MR sequences. Dice coefficients were 0.9 for the T1- and T2-weighted cohorts and 0.86 for the T2*-weighted images. The proposed method runs in less than 1min on a normal computer and can be used to quantify morphological features such as cross-sectional area along the whole spinal cord.
Moshonkina, T R; Shapkova, E Yu; Sukhotina, I A; Emeljannikov, D V; Gerasimenko, Yu P
We analyzed the efficiency of percutaneous electrical stimulation of the spinal cord and serotonin receptor activation in rehabilitation of paralyzed patients. Four-week course of spinal cord electrical stimulation combined with mechanotherapy produced positive shifts in the status of chronically paralyzed patients. Serotonin receptor activation potentiated the effect of spinal cord stimulation and can be regarded as an additional neurorehabilitation option.
Etlin, Alex; Bráz, Joao M.; Kuhn, Julia A.; Wang, Xidao; Hamel, Katherine A.; Llewellyn-Smith, Ida J.
Spinal cord transplants of embryonic cortical GABAergic progenitor cells derived from the medial ganglionic eminence (MGE) can reverse mechanical hypersensitivity in the mouse models of peripheral nerve injury- and paclitaxel-induced neuropathic pain. Here, we used electrophysiology, immunohistochemistry, and electron microscopy to examine the extent to which MGE cells integrate into host circuitry and recapitulate endogenous inhibitory circuits. Whether the transplants were performed before or after nerve injury, the MGE cells developed into mature neurons and exhibited firing patterns characteristic of subpopulations of cortical and spinal cord inhibitory interneurons. Conversely, the transplanted cells preserved cortical morphological and neurochemical properties. We also observed a robust anatomical and functional synaptic integration of the transplanted cells into host circuitry in both injured and uninjured animals. The MGE cells were activated by primary afferents, including TRPV1-expressing nociceptors, and formed GABAergic, bicuculline-sensitive, synapses onto host neurons. Unexpectedly, MGE cells transplanted before injury prevented the development of mechanical hypersensitivity. Together, our findings provide direct confirmation of an extensive, functional synaptic integration of MGE cells into host spinal cord circuits. This integration underlies normalization of the dorsal horn inhibitory tone after injury and may be responsible for the prophylactic effect of preinjury transplants. SIGNIFICANCE STATEMENT Spinal cord transplants of embryonic cortical GABAergic interneuron progenitors from the medial ganglionic eminence (MGE), can overcome the mechanical hypersensitivity produced in different neuropathic pain models in adult mice. Here, we examined the properties of transplanted MGE cells and the extent to which they integrate into spinal cord circuitry. Using electrophysiology, immunohistochemistry, and electron microscopy, we demonstrate that MGE cells
Amezcua, L.; Lerner, A.; Ledezma, K.; Conti, D.; Law, M.; Weiner, L.; Langer-Gould, A.
Background Longitudinally extensive spinal cord lesions (LESCLs) are believed to occur predominantly with opticospinal multiple sclerosis (OSMS) and are associated with disability. Objective To describe the prevalence and patterns of spinal cord lesions in Hispanics with multiple sclerosis (MS) and OSMS and their association with disability. Methods Cross-sectional study of 164 patients with complete MRIs. Spinal cord was classified: LESCLs, scattered spinal cord lesions (sSCLs) or no spinal cord lesions (noSCLs). Clinical course was defined as classical MS or OSMS. Risk of disability (Expanded Disability Status Scale ≥4.0) was adjusted for age, disease duration and sex using logistic regression. Results 125/164(73%) MS patients had spinal cord lesions (sSCLs, 57%; LESCLs, 19%) but only 11(7%) had OSMS. LESCLs were associated with disability (p<0.0001), longer disease duration (p<0.0001) and MS (n=21 vs. n=10 OSMS; p<0.0001). LESCLs was associated with the greatest risk to disability (OR 7.3, 95% CIs1.9-26.5; p=0.003; sSCLs OR 2.5, 95% CIs0.9-7.1; p=0.09) compared with noSCLs. Conclusion LESCLs are more common than OSMS and are associated with worse disability even in patients with MS. These results suggest that LESCLs are a more important marker of disability in MS than OSMS and may be an early indicator of more aggressive disease in this population. PMID:23912723
Kong, Yazhuo; Eippert, Falk; Beckmann, Christian F.; Andersson, Jesper; Finsterbusch, Jürgen; Büchel, Christian; Tracey, Irene; Brooks, Jonathan C. W.
Spontaneous fluctuations in functional magnetic resonance imaging (fMRI) signals of the brain have repeatedly been observed when no task or external stimulation is present. These fluctuations likely reflect baseline neuronal activity of the brain and correspond to functionally relevant resting-state networks (RSN). It is not known however, whether intrinsically organized and spatially circumscribed RSNs also exist in the spinal cord, the brain’s principal sensorimotor interface with the body. Here, we use recent advances in spinal fMRI methodology and independent component analysis to answer this question in healthy human volunteers. We identified spatially distinct RSNs in the human spinal cord that were clearly separated into dorsal and ventral components, mirroring the functional neuroanatomy of the spinal cord and likely reflecting sensory and motor processing. Interestingly, dorsal (sensory) RSNs were separated into right and left components, presumably related to ongoing hemibody processing of somatosensory information, whereas ventral (motor) RSNs were bilateral, possibly related to commissural interneuronal networks involved in central pattern generation. Importantly, all of these RSNs showed a restricted spatial extent along the spinal cord and likely conform to the spinal cord’s functionally relevant segmental organization. Although the spatial and temporal properties of the dorsal and ventral RSNs were found to be significantly different, these networks showed significant interactions with each other at the segmental level. Together, our data demonstrate that intrinsically highly organized resting-state fluctuations exist in the human spinal cord and are thus a hallmark of the entire central nervous system. PMID:25472845
An objective of this research was to obtain evidence for the synthesis and release of newly discovered opioid peptides, such as dynorphin, in spinal cord and sensory neurons. Several specific antisera were used to visualize dynorphin and related peptides in spinal cord and dorsal root ganglion neurons in dissociated cell culture. Antisera specific for the midportion of the dynorphin molecule revealed a subpopulation of spinal cord neurons with dense immunoreactive dynorphin in cell perikarya, but none in their associated neurites. Antisera specific for either the amino or carboxy terminal sequences of the molecule produced intense immunoreactivity in both cell perikarya and neurites of spinal neurons. These data suggest the cleavage products of dynorphin and not the complete molecule are possible neurotransmitters in the spinal cord. Additional evidence in support of this hypothesis was derived from radioimmunoassays of these cells and their culture medium following depolarization induced by elevated extracellular potassium. Antisera against aspartate aminotransferase revealed no differentially elevated immunoreactive aspartate aminotransferase in tissue sections of spinal cord or dorsal root ganglia.
Goncalves, Maria B.; Malmqvist, Tony; Clarke, Earl; Hubens, Chantal J.; Grist, John; Hobbs, Carl; Trigo, Diogo; Risling, Mårten; Angeria, Maria; Damberg, Peter; Carlstedt, Thomas P.
Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor β (RARβ) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)–CNS transition of regrown axons. RARβ agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, in RARβ-agonist-treated neurons, PTEN activity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect of RARβ signaling, both neuronal and neuronal–glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs. SIGNIFICANCE STATEMENT Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Here, we identify a single target, neuronal retinoic acid receptor β (RARβ), which modulates these two aspects of the postinjury physiological response. Activation of RARβ in the neuron inactivates
Mika, J; Rojewska, E; Makuch, W; Korostynski, M; Luvisetto, S; Marinelli, S; Pavone, F; Przewlocka, B
Botulinum neurotoxin serotype A (BoNT/A) acts by cleaving synaptosome-associated-protein-25 (SNAP-25) in nerve terminals to inhibit neuronal release and shows long-lasting antinociceptive action in neuropathic pain. However, its precise mechanism of action remains unclear. Our study aimed to characterize BoNT/A-induced neuroimmunological changes after chronic constriction injury (CCI) of the sciatic nerve. In the ipsilateral lumbar spinal cords of CCI-exposed rats, the mRNA of microglial marker (complement component 1q, C1q), astroglial marker (glial fibrillary acidic protein, GFAP), and prodynorphin were upregulated, as measured by reverse transcription-polymerase chain reaction (RT-PCR). No changes appeared in mRNA for proenkephalin, pronociceptin, or neuronal and inducible nitric oxide synthase (NOS1 and NOS2, respectively). In the dorsal root ganglia (DRG), an ipsilateral upregulation of prodynorphin, pronociceptin, C1q, GFAP, NOS1 and NOS2 mRNA and a downregulation of proenkephalin mRNA were observed. A single intraplantar BoNT/A (75 pg/paw) injection induced long-lasting antinociception in this model. BoNT/A diminished the injury-induced ipsilateral spinal upregulation of C1q mRNA. In the ipsilateral DRG a significant decrease of C1q-positive cell activation and of the upregulation of prodynorphin, pronociceptin and NOS1 mRNA was also observed following BoNT/A admistration. BoNT/A also diminished the injury-induced upregulation of SNAP-25 expression in both structures. We provide evidence that BoNT/A impedes injury-activated neuronal function in structures distant from the injection site, which is demonstrated by its influence on NOS1, prodynorphin and pronociceptin mRNA levels in the DRG. Moreover, the silence of microglia/macrophages after BoNT/A administration could be secondary to the inhibition of neuronal activity, but this decrease in neuroimmune interactions could be the key to the long-lasting BoNT/A effect on neuropathic pain.
... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Implanted spinal cord stimulator for bladder....5850 Implanted spinal cord stimulator for bladder evacuation. (a) Identification. An implanted spinal... paraplegic patient who has a complete transection of the spinal cord and who is unable to empty his or...
... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Implanted spinal cord stimulator for bladder....5850 Implanted spinal cord stimulator for bladder evacuation. (a) Identification. An implanted spinal... paraplegic patient who has a complete transection of the spinal cord and who is unable to empty his or...
... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Implanted spinal cord stimulator for bladder....5850 Implanted spinal cord stimulator for bladder evacuation. (a) Identification. An implanted spinal... paraplegic patient who has a complete transection of the spinal cord and who is unable to empty his or...
... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Implanted spinal cord stimulator for bladder....5850 Implanted spinal cord stimulator for bladder evacuation. (a) Identification. An implanted spinal... paraplegic patient who has a complete transection of the spinal cord and who is unable to empty his or...
... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Implanted spinal cord stimulator for bladder....5850 Implanted spinal cord stimulator for bladder evacuation. (a) Identification. An implanted spinal... paraplegic patient who has a complete transection of the spinal cord and who is unable to empty his or...
bladder distention between spinal intact and spinal cord injury ...excitability of bladder afferent neurons in rats with spinal cord injury : a role of A-type voltage-gated potassium channels. 110th Annual Meeting AUA...Increased excitability of bladder afferent neurons in rats with spinal cord injury : a role of A-type voltage-gated potassium channels. 110th Annual
Yousef, O M; Appenzeller, P; Kornfeld, M
A 14-year-old girl experienced sudden onset of weakness progressing rapidly to paralysis. She died 7 days later from a massive pulmonary thromboembolus. Autopsy revealed extensive infarction of the spinal cord with a fibrocartilaginous embolus of the corresponding segment of the anterior spinal artery.
Hida, Kazutoshi; Yano, Syunsuke; Aoyama, Takeshi; Koyanagi, Izumi; Houkin, Kiyohiro
Study Design A retrospective study. Purpose The purpose of this study was to obtain useful information for establishing the guidelines for treating high-grade spinal cord gliomas. Overview of Literature The optimal management of high-grade spinal cord gliomas remains controversial. We report the outcomes of the surgical management of 14 high-grade spinal glioma. Methods We analyzed the outcomes of 14 patients with high-grade spinal cord gliomas who were surgically treated between 1989 and 2012. Survival was charted with the Kaplan-Meier plots and comparisons were made with the log-rank test. Results None of the patients with high-grade spinal cord gliomas underwent total resection. Subtotal resection was performed in two patients, partial resection was performed in nine patients, and open biopsy was performed in three patients. All patients underwent postoperative radiotherapy and six patients further underwent radiation cordotomy. The median survival time for patients with high-grade spinal cord gliomas was 15 months, with a 5-year survival rate of 22.2%. The median survival time for patients with World Health Organization grade III tumors was 25.5 months, whereas the median survival time for patients with glioblastoma multiforme was 12.5 months. Both univariate and multivariate Cox proportional hazards models demonstrated a significant effect only in the group that did not include cervical cord lesion as a factor associated with survival (p=0.04 and 0.03). Conclusions The surgical outcome of patients diagnosed with high-grade spinal cord gliomas remains poor. Notably, only the model which excluded cervical cord lesions as a factor significantly predicted survival. PMID:26713128
Smit, Christof A J; Legemate, Karin J A; de Koning, Anja; de Groot, Sonja; Stolwijk-Swuste, Janneke M; Janssen, Thomas W J
Pressure ulcers (PUs) are highly prevalent in people with spinal cord injury (SCI). Electrical stimulation (ES) activates muscles and might reduce risk factors. Our objectives were to study and compare the effects of two duty cycles during 3 h of ES-induced gluteal and hamstring activation on interface pressure distribution in sitting individuals with SCI and study the usability of a newly developed electrode garment (ES shorts). Ten individuals with SCI participated in this study, in which two ES protocols with different duty cycles (1:1 s vs 1:4 s on-off) were applied in counterbalanced order using a custom-made garment with built-in electrodes. Outcome variables included interface pressure of the ischial tuberosities (ITs) and pressure gradient. A questionnaire was used to determine usability of the ES shorts. In both protocols, ES caused a significant decrease in average IT pressure compared with rest (no ES); on average, 35% for protocol 1:4 and 13% for protocol 1:1. The ES on-off duty cycle of protocol 1:4 showed less muscle fatigue. In general, participants scored the usability of the ES shorts as satisfactory. In this study, the application of ES resulted in a significant decrease in IT pressure. The ES on-off duty cycle of 1:4 s is recommended because of the less fatiguing effect. ES of the hamstrings and gluteal muscles might be a promising method in preventing PUs, but further study is needed.
Maggio, Dominic M.; Singh, Amanpreet; Iorgulescu, J. Bryan; Bleicher, Drew H.; Ghosh, Mousumi; Lopez, Michael M.; Tuesta, Luis M.; Flora, Govinder; Dietrich, W. Dalton; Pearse, Damien D.
Inducible nitric oxide synthase (iNOS) is a potent mediator of oxidative stress during neuroinflammation triggered by neurotrauma or neurodegeneration. We previously demonstrated that acute iNOS inhibition attenuated iNOS levels and promoted neuroprotection and functional recovery after spinal cord injury (SCI). The present study investigated the effects of chronic iNOS ablation after SCI using inos-null mice. iNOS−/− knockout and wild-type (WT) control mice underwent a moderate thoracic (T8) contusive SCI. Locomotor function was assessed weekly, using the Basso Mouse Scale (BMS), and at the endpoint (six weeks), by footprint analysis. At the endpoint, the volume of preserved white and gray matter, as well as the number of dorsal column axons and perilesional blood vessels rostral to the injury, were quantified. At weeks two and three after SCI, iNOS−/− mice exhibited a significant locomotor improvement compared to WT controls, although a sustained improvement was not observed during later weeks. At the endpoint, iNOS−/− mice showed significantly less preserved white and gray matter, as well as fewer dorsal column axons and perilesional blood vessels, compared to WT controls. While short-term antagonism of iNOS provides histological and functional benefits, its long-term ablation after SCI may be deleterious, blocking protective or reparative processes important for angiogenesis and tissue preservation. PMID:28125047
Ohri, Sujata Saraswat; Mullins, Ashley; Hetman, Michal; Whittemore, Scott R
Activation of the endoplasmic reticulum stress response (ERSR) is a hallmark of various pathological diseases and/or traumatic injuries. Restoration of ER homeostasis can contribute to improvement in the functional outcome of these diseases. Using genetic and pharmacological inhibition of the PERK-CHOP arm of the ERSR, we recently demonstrated improvements in hindlimb locomotion after spinal cord injury (SCI) and implicated oligodendrocyte survival as a potential mechanism. Here, we investigated the contribution of stress-inducible PPP1R15A/GADD34, an ERSR signaling effector downstream of CHOP that dephosphorylates eIF2α, in the pathogenesis of SCI. We show that although genetic ablation of GADD34 protects oligodendrocyte precursor cells (OPCs) against ER stress-mediated cell death in vitro and results in differential ERSR attenuation in vivo after SCI, there is no improvement in hindlimb locomotor function. Guanabenz, a FDA approved antihypertensive drug, was recently shown to reduce the burden of misfolded proteins in the ER by directly targeting GADD34. Guanabenz protected OPCs from ER stress-mediated cell death in vitro and attenuated the ERSR in vivo after SCI. However, guanabenz administration failed to rescue the locomotor deficits after SCI. These data suggest that deletion of GADD34 alone is not sufficient to improve functional recovery after SCI.
Führmann, T; Tam, R Y; Ballarin, B; Coles, B; Elliott Donaghue, I; van der Kooy, D; Nagy, A; Tator, C H; Morshead, C M; Shoichet, M S
Transplantation of pluripotent stem cells and their differentiated progeny has the potential to preserve or regenerate functional pathways and improve function after central nervous system injury. However, their utility has been hampered by poor survival and the potential to form tumors. Peptide-modified biomaterials influence cell adhesion, survival and differentiation in vitro, but their effectiveness in vivo remains uncertain. We synthesized a peptide-modified, minimally invasive, injectable hydrogel comprised of hyaluronan and methylcellulose to enhance the survival and differentiation of human induced pluripotent stem cell-derived oligodendrocyte progenitor cells. Cells were transplanted subacutely after a moderate clip compression rat spinal cord injury. The hydrogel, modified with the RGD peptide and platelet-derived growth factor (PDGF-A), promoted early survival and integration of grafted cells. However, prolific teratoma formation was evident when cells were transplanted in media at longer survival times, indicating that either this cell line or the way in which it was cultured is unsuitable for human use. Interestingly, teratoma formation was attenuated when cells were transplanted in the hydrogel, where most cells differentiated to a glial phenotype. Thus, this hydrogel promoted cell survival and integration, and attenuated teratoma formation by promoting cell differentiation.
Bhatnagar, Tim; Liu, Jie; Yung, Andrew; Cripton, Peter A; Kozlowski, Piotr; Oxland, Thomas
The spinal cord undergoes physical deformation during traumatic spinal cord injury (TSCI), which results in biological damage. This study demonstrates a novel approach, using magnetic resonance imaging and image registration techniques, to quantify the three-dimensional deformation of the cervical spinal cord in an in vivo rat model. Twenty-four male rats were subjected to one of two clinically relevant mechanisms of TSCI (i.e. contusion and dislocation) inside of a MR scanner using a novel apparatus, enabling imaging of the deformed spinal cords. The displacement fields demonstrated qualitative differences between injury mechanisms. Three-dimensional Lagrangian strain fields were calculated, and the results from the contusion injury mechanism were deemed most reliable. Strain field error was assessed using a Monte Carlo approach, which showed that simulated normal strain error experienced a bias, whereas shear strain error did not. In contusion injury, a large region of dorso-ventral compressive strain was observed under the impactor which extended into the ventral region of the spinal cord. High tensile lateral strains under the impactor and compressive lateral strains in the lateral white matter were also observed in contusion. The ability to directly observe and quantify in vivo spinal cord deformation informs our knowledge of the mechanics of TSCI.
Liu, Zhi-Qiang; Xing, Shan-Shan; Zhang, Wei
Background Ischemic/reperfusion (I/R) injury of the spinal cord is a serious complication that can result from thoracoabdominal aortic surgery. Objective To investigate the neuroprotective effect of curcumin against I/R injury in a rabbit model. Methods A total of 36 rabbits were randomly divided into three groups: sham, I/R, and curcumin-treated group. Rabbits were subject to 30-min aortic occlusion to induce transient spinal cord ischemia. Neurological function was observed after reperfusion and spinal cord segment (L3–L5) was collected for histopathological evaluation. Malondialdehyde (MDA) and total superoxide dismutase (SOD) activity were also assayed. Results Rabbits in I/R group were induced to paraplegia. While after 48-hour treatment, compared with I/R group, curcumin significantly improved neurological function, reduced cell apoptosis and MDA levels as well as increased SOD activity (P < 0.05). Conclusions The results suggest that curcumin, at least in an animal model, can attenuate transient spinal cord ischemic injury potentially via reducing oxidative damage, which may provide a novel approach in the treatment of spinal cord ischemic injury. PMID:23809530
Pal, Ajay; Singh, Anand; Nag, Tapas C; Chattopadhyay, Parthaprasad; Mathur, Rashmi; Jain, Suman
Background Iron oxide nanoparticles (IONPs) can attenuate oxidative stress in a neutral pH environment in vitro. In combination with an external electromagnetic field, they can also facilitate axon regeneration. The present study demonstrates the in vivo potential of IONPs to recover functional deficits in rats with complete spinal cord injury. Methods The spinal cord was completely transected at the T11 vertebra in male albino Wistar rats. Iron oxide nanoparticle solution (25 μg/mL) embedded in 3% agarose gel was implanted at the site of transection, which was subsequently exposed to an electromagnetic field (50 Hz, 17.96 μT for two hours daily for five weeks). Results Locomotor and sensorimotor assessment as well as histological analysis demonstrated significant functional recovery and a reduction in lesion volume in rats with IONP implantation and exposure to an electromagnetic field. No collagenous scar was observed and IONPs were localized intracellularly in the immediate vicinity of the lesion. Further, in vitro experiments to explore the cytotoxic effects of IONPs showed no effect on cell survival. However, a significant decrease in H2O2-mediated oxidative stress was evident in the medium containing IONPs, indicating their free radical scavenging properties. Conclusion These novel findings indicate a therapeutic role for IONPs in spinal cord injury and other neurodegenerative disorders mediated by reactive oxygen species. PMID:23818782
Anwar, M. Akhtar; Al Shehabi, Tuqa S.; Eid, Ali H.
Spinal cord injury (SCI) and spinal infarction lead to neurological complications and eventually to paraplegia or quadriplegia. These extremely debilitating conditions are major contributors to morbidity. Our understanding of SCI has certainly increased during the last decade, but remains far from clear. SCI consists of two defined phases: the initial impact causes primary injury, which is followed by a prolonged secondary injury consisting of evolving sub-phases that may last for years. The underlying pathophysiological mechanisms driving this condition are complex. Derangement of the vasculature is a notable feature of the pathology of SCI. In particular, an important component of SCI is the ischemia-reperfusion injury (IRI) that leads to endothelial dysfunction and changes in vascular permeability. Indeed, together with endothelial cell damage and failure in homeostasis, ischemia reperfusion injury triggers full-blown inflammatory cascades arising from activation of residential innate immune cells (microglia and astrocytes) and infiltrating leukocytes (neutrophils and macrophages). These inflammatory cells release neurotoxins (proinflammatory cytokines and chemokines, free radicals, excitotoxic amino acids, nitric oxide (NO)), all of which partake in axonal and neuronal deficit. Therefore, our review considers the recent advances in SCI mechanisms, whereby it becomes clear that SCI is a heterogeneous condition. Hence, this leads towards evidence of a restorative approach based on monotherapy with multiple targets or combinatorial treatment. Moreover, from evaluation of the existing literature, it appears that there is an urgent requirement for multi-centered, randomized trials for a large patient population. These clinical studies would offer an opportunity in stratifying SCI patients at high risk and selecting appropriate, optimal therapeutic regimens for personalized medicine. PMID:27147970
Thomas, Aline M.; Palma, Jaime L.; Shea, Lonnie D.
The environment within the spinal cord after injury, which changes in the progression from the acute to chronic stages, limits the extent of regeneration. The delivery of inductive factors to promote regeneration following spinal cord injury has been promising, yet, few strategies are have are versatile to allow delivery during acute or chronic injury that would facilitate screening of candidate therapies. This report investigates the intrathecal delivery of lentiviruses for long-term expression of regenerative factors. Lentivirus-filled sponges were inserted into the intrathecal space surrounding the spinal cord, with transgene expression observed within multiple cell types that persists for 12 weeks for both intact and injured spinal cord, without any apparent damage to the spinal cord tissue. Sponges loaded with lentivirus encoding for Sonic hedgehog (Shh) were investigated for acute (delivered at 0 weeks) and chronic (at 4 weeks) injuries, and for multiple locations relative to the injury. In an acute model, sponges placed directly above the injury increased oligodendrocyte and decreased astrocyte presence. Sponges placed caudal to the injury had reduced impact on oligodendrocytes and astrocytes in the injury. In a chronic model, sponges increased oligodendrocyte and decreased astrocyte presence. Furthermore, the effect of Shh was shown to be mediated in part by reduction of Bmp signaling, monitored with an Msx2-sensitive reporter vector. The implantation of lentivirus-loaded biomaterials intrathecally provides the opportunity to induce the expression of a factor at a specified time without entering the spinal cord, and has the potential to promote gene delivery within the spinal cord, which can influence the extent of regeneration. PMID:25724274
Bazilevskaia, Z V; Golovnykh, L L; Kirkinskaia, T A
In a group of 520 patients with injury to the spine and spinal cord 125 died within 10 years. The highest fatality rate (76.0 +/0 3.8) is recorded in the first year after the injury. In the following 10 years the fatality rate was uniform and ranged between 1.6 and 4.1%. This value increases with the patient's age, the severity of the spinal cord injury, and the degree of damage to the spinal ligamento-bursal apparatus. Among the total number of injured, 76% have a survival period of more than 10 years.
Tsang, S W; Zhao, M; Wu, J; Sung, J J Y; Bian, Z-X
Visceral hyperalgesia is a multifactorial gastrointestinal disorder which featured with alterations of abdominal motility and/or gut sensitivity, and is believed to be triggered by environmental stressor or psychological factors. However, its etiology remains incompletely understood. In this study, we aimed to investigate whether nerve growth factor (NGF)-mediated neuronal plasticity is involved in neonatal maternal separation (NMS)-induced visceral hypersensitivity in adult rats, and whether NGF antagonist can attenuate or block such development. In our experiments, animals subjected to NMS were developed with visceral hyperalgesia at age of 8 weeks. The threshold for visceral pain among these NMS rats was remarkably lowered than that of the normal handling (NH) rats; however, the expression levels of NGF, c-fos, calcitonin gene-related peptide (CGRP), Substance P, and tyrosine kinases A (TrkA) were notably elevated in lumbosacral spinal cord and/or dorsal root ganglion (DRG) when comparing to those of the NH rats. Further, as intra-peritoneal administration of NGF (10 μl at 1 μg/kg/day) was given to NH rats during neonatal period, effects that comparable to NMS induction were observed in the adulthood. In contrast, when NMS rats were treated with NGF antagonist K252a (10 μl/day from postnatal days 2-14), which acts against tyrosine kinases, the neonatal stress-induced down-shifted visceral pain threshold was restored and neuronal activation, specifically NGF and neuropeptide production, was attenuated. In conclusion, our data strongly suggest that NGF triggers neuronal plasticity and plays a crucial role in NMS-induced visceral hypersensitivity in which NGF antagonism provides positive inhibition via blocking the tyrosine phosphorylation of TrkA.
Mathew, Bruce; Laden, Gerard
There is an increasing body of evidence that drainage of lumbar cerebrospinal fluid (CSF) improves functional neurological outcome after reperfusion injury to the spinal cord that occasionally follows aortic reconstructive surgery. This beneficial effect is considered owing to lowering of the CSF pressure thereby normalising spinal cord blood flow and reducing the 'secondary' cord injury caused by vascular congestion and cord swelling in the relatively confined spinal canal. Whilst lacking definitive proof, there are convincing randomised controlled trials (RCTs), cohort data and systematic reviews supporting this intervention. The therapeutic window for lumbar CSF drainage requires further elucidation; however, it appears to be days rather than hours post insult. We contend that the same benefit is likely to be achieved following other primary spinal cord injuries that cause cord swelling and elicit the 'secondary' injury. Traditionally the concept of CSF drainage has been considered more applicable to the brain as contained in a 'closed box' by lowering intracranial pressure (ICP) to improve cerebral perfusion pressure (CPP). The control of CPP is intended to limit 'secondary' brain injury and is a key concept of brain injury management. Using microdialysis in the spinal cords of trauma patients, it has been shown that intraspinal pressure (ISP) needs to be kept below 20 mmHg and spinal cord perfusion pressure (SCPP) above 70 mmHg to avoid biochemical evidence of secondary cord damage. Vasopressor have also been used in spinal cord injury to improve perfusion, however complications are common, typically cardiac in nature, and require very careful monitoring; the evidence supporting this approach is notably less convincing. Decompression illness (DCI) of the spinal cord is treated with recompression, hyperbaric oxygen, various medications designed to reduce the inflammatory response and fluid administration to normalise blood pressure and haematocrit. These
Progress in the care of people with spinal cord injury (SCI) spans every aspect, from research in neuroregeneration to pharmacologic interventions. This article focuses on advances in rehabilitation interventions, which have employed bioengineering, computerization, and advanced therapeutic techniques. These interventions are being applied to functional deficits of the bladder, bowel, upper extremities, and respiratory system, as well as to improvements in ambulation and mobility. Functional electrical stimulation (FES) is being used to augment the function of the lower extremities, the upper extremities (Freehand System), and the bowel and bladder (Vocare System). Tendon transfer is a reconstructive technique used to improve upper extremity function; it is sometimes combined with FES. Body weight-supported treadmill training is being used to improve ambulation in people with incomplete SCI, and advances in wheelchair technology are expanding options for mobility. Cushion design and pressure mapping are modalities being used to reduce the high risk for pressure ulcers in the SCI population. Research on shoulder stressors is being applied to transfer techniques, exercise regimens, adaptive equipment and wheelchair mechanics to minimize shoulder pain, another common complication. The effectiveness of rehabilitation interventions needs to be documented by evidence-based research. Researchers are focusing on the identification of outcomes measures that will form the basis for established standards of care for individuals with SCI. Perhaps the combination of conventional and newer therapies may enhance neurological recovery. Well-designed studies are needed before we can make this determination.
Bauman, William A; Cardozo, Christopher P
The pathophysiology, clinical considerations, and relevant experimental findings with regard to osteoporosis in individuals with spinal cord injury (SCI) will be discussed. The bone loss that occurs acutely after more neurologically motor complete SCI is unique for its sublesional skeletal distribution and rate, at certain skeletal sites approaching 1% of bone mineral density per week, and its resistance to currently available treatments. The areas of high bone loss include the distal femur, proximal tibia, and more distal boney sites. Evidence from a study performed in monozygotic twins discordant for SCI indicates that sublesional bone loss in the twin with SCI increases for several decades, strongly suggesting that the heightened net bone loss after SCI may persist for an extended period of time. The increased frequency of fragility fracture after paralysis will be discussed, and a few risk factors for such fractures after SCI will be examined. Because vitamin D deficiency, regardless of disability, is a relevant consideration for bone health, as well as an easily reversible condition, the increased prevalence of and treatment target values for vitamin D in this deficiency state in the SCI population will be reviewed. Pharmacological and mechanical approaches to preserving bone integrity in persons with acute and chronic SCI will be reviewed, with emphasis placed on efficacy and practicality. Emerging osteoanabolic agents that improve functioning of WNT/β-catenin signaling after paralysis will be introduced as therapeutic interventions that may hold promise.
Teasell, R.W.; Hsieh, T.J.; Aubut, JA. L.; Eng, J.J.; Krassioukov, A.; Tu, L.
Objective To systematically review the published literature on the treatment of deep venous thromboembolism post-spinal cord injury (SCI). Data Sources MEDLINE/Pubmed, CINAHL, EMBASE, and PsycINFO databases were searched for articles addressing the treatment of deep venous thromboembolism post-SCI. Randomized controlled trials (RCTs) were assessed for methodologic quality using the Physiotherapy Evidence Database Scale, while non-RCTs were assessed using the Downs and Black evaluation tool. Study Selection Studies included RCTs, non-RCTS, cohort, case-control, case series, pre-post, and postinterventional studies. Case studies were included only when no other studies were available. Data Extraction Data extracted included demographics, the nature of the study intervention, and study results. Data Synthesis Levels of evidence were assigned to the interventions using a modified Sackett scale. Conclusions Twenty-three studies met inclusion criteria. Thirteen studies examined various pharmacologic interventions for the treatment or prevention of deep venous thrombosis in SCI patients. There was strong evidence to support the use of low molecular weight heparin in reducing venous thrombosis events, and a higher adjusted dose of unfractionated heparin was found to be more effective than 5000 units administered every 12 hours, although bleeding complication was more common. Nonpharmacologic treatments were also reviewed, but again limited evidence was found to support these treatments. PMID:19236977
Nardone, Raffaele; Höller, Yvonne; Storti, Monica; Lochner, Piergiorgio; Tezzon, Frediano; Golaszewski, Stefan; Brigo, Francesco; Trinka, Eugen
A severe spinal cord involvement may rarely occur in patients with cirrhosis and other chronic liver diseases; this complication is usually associated with overt liver failure and surgical or spontaneous porto-systemic shunt. Hepatic myelopathy (HM) is characterized by progressive weakness and spasticity of the lower extremities, while sensory and sphincter disturbances have rarely been described and are usually less important. The diagnosis is assigned in the appropriate clinical setting on clinical grounds after the exclusion of other clinical entities leading to spastic paraparesis. Magnetic resonance imaging is often unremarkable; however, also intracerebral corticospinal tract abnormalities have been reported recently. The study of motor evoked potentials may disclose central conduction abnormalities even before HM is clinically manifest. HM responds poorly to blood ammonia-lowering and other conservative medical therapy. Liver transplantation represents a potentially definitive treatment for HM in patients with decompensated cirrhosis of Child-Pugh B and C grades. Other surgical treatment options in HM include surgical ligation, shunt reduction, or occlusion by interventional procedures.
Sezer, Nebahat; Akkuş, Selami; Uğurlu, Fatma Gülçin
Spinal cord injury (SCI) is a serious medical condition that causes functional, psychological and socioeconomic disorder. Therefore, patients with SCI experience significant impairments in various aspects of their life. The goals of rehabilitation and other treatment approaches in SCI are to improve functional level, decrease secondary morbidity and enhance health-related quality of life. Acute and long-term secondary medical complications are common in patients with SCI. However, chronic complications especially further negatively impact on patients’ functional independence and quality of life. Therefore, prevention, early diagnosis and treatment of chronic secondary complications in patients with SCI is critical for limiting these complications, improving survival, community participation and health-related quality of life. The management of secondary chronic complications of SCI is also important for SCI specialists, families and caregivers as well as patients. In this paper, we review data about common secondary long-term complications after SCI, including respiratory complications, cardiovascular complications, urinary and bowel complications, spasticity, pain syndromes, pressure ulcers, osteoporosis and bone fractures. The purpose of this review is to provide an overview of risk factors, signs, symptoms, prevention and treatment approaches for secondary long-term complications in patients with SCI. PMID:25621208
Partida, Elizabeth; Mironets, Eugene; Hou, Shaoping; Tom, Veronica J.
Both sensorimotor and autonomic dysfunctions often occur after spinal cord injury (SCI). Particularly, a high thoracic or cervical SCI interrupts supraspinal vasomotor pathways and results in disordered hemodynamics due to deregulated sympathetic outflow. As a result of the reduced sympathetic activity, patients with SCI may experience hypotension, cardiac dysrhythmias, and hypothermia post-injury. In the chronic phase, changes within the CNS and blood vessels lead to orthostatic hypotension and life-threatening autonomic dysreflexia (AD). AD is characterized by an episodic, massive sympathetic discharge that causes severe hypertension associated with bradycardia. The syndrome is often triggered by unpleasant visceral or sensory stimuli below the injury level. Currently the only treatments are palliative – once a stimulus elicits AD, pharmacological vasodilators are administered to help reduce the spike in arterial blood pressure. However, a more effective means would be to mitigate AD development by attenuating contributing mechanisms, such as the reorganization of intraspinal circuits below the level of injury. A better understanding of the neuropathophysiology underlying cardiovascular dysfunction after SCI is essential to better develop novel therapeutic approaches to restore hemodynamic performance. PMID:27073353
Spinal cord cell cultures contain several types of neurons. Two methods are described for enriching such cultures with motoneurons (defined here simply as cholinergic cells that are capable of innervating muscle). In the first method, 7-day embryonic chick spinal cord neurons were separated according to size by 1 g velocity sedimentation. It is assumed that cholinergic motoneurons are among the largest cells present at this stage. The spinal cords were dissociated vigorously so that 95-98% of the cells in the initial suspension were isolated from one another. Cells in leading fractions (large cell fractions: LCFs) contain about seven times as much choline acetyltransferase (CAT) activity per unit cytoplasm as do cells in trailing fractions (small cell fractions: SCFs). Muscle cultures seeded with LCFs develop 10-70 times as much CAT as cultures seeded with SCFs and six times as much CAT as cultures seeded with control (unfractionated) spinal cord cells. More than 20% of the large neurons in LCF-muscle cultures innervate nearby myotubes. In the second method, neurons were gently dissociated from 4-day embryonic spinal cords and maintained in vitro. This approach is based on earlier observations that cholinergic neurons are among the first cells to withdraw form the mitotic cycle in the developing chick embryo (Hamburger, V. 1948. J. Comp. Neurol. 88:221- 283; and Levi-Montalcini, R. 1950. J. Morphol. 86:253-283). 4-Day spinal cord-muscle cultures develop three times as much CAT as do 7-day spinal cord-muscle plates, prepared in the same (gentle) manner. More than 50% of the relatively large 4-day neurons innervate nearby myotubes. Thus, both methods are useful first steps toward the complete isolation of motoneurons. Both methods should facilitate study of the development of cholinergic neurons and of nerve-muscle synapse formation. PMID:566275
Abdelalim, Essam M.; Bellier, Jean-Pierre; Tooyama, Ikuo
Brain natriuretic peptide (BNP) exerts its functions through NP receptors. Recently, BNP has been shown to be involved in a wide range of functions. Previous studies reported BNP expression in the sensory afferent fibers in the dorsal horn (DH) of the spinal cord. However, BNP expression and function in the neurons of the central nervous system are still controversial. Therefore, in this study, we investigated BNP expression in the rat spinal cord in detail using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. RT-PCR analysis showed that BNP mRNA was present in the spinal cord and dorsal root ganglion (DRG). BNP immunoreactivity was observed in different structures of the spinal cord, including the neuronal cell bodies and neuronal processes. BNP immunoreactivity was observed in the DH of the spinal cord and in the neurons of the intermediate column (IC) and ventral horn (VH). Double-immunolabeling showed a high level of BNP expression in the afferent fibers (laminae I–II) labeled with calcitonin gene-related peptide (CGRP), suggesting BNP involvement in sensory function. In addition, BNP was co-localized with CGRP and choline acetyltransferase (ChAT) in the motor neurons of the VH. Together, these results indicate that BNP is expressed in sensory and motor systems of the spinal cord, suggesting its involvement in several biological actions on sensory and motor neurons via its binding to NP receptor-A (NPR-A) and/or NP receptor-B (NPR-B) at the spinal cord level. PMID:27994541
Davalos, Dimitrios; Akassoglou, Katerina
In vivo imaging using two-photon microscopy 1 in mice that have been genetically engineered to express fluorescent proteins in specific cell types 2-3 has significantly broadened our knowledge of physiological and pathological processes in numerous tissues in vivo4-7. In studies of the central nervous system (CNS), there has been a broad application of in vivo imaging in the brain, which has produced a plethora of novel and often unexpected findings about the behavior of cells such as neurons, astrocytes, microglia, under physiological or pathological conditions 8-17. However, mostly technical complications have limited the implementation of in vivo imaging in studies of the living mouse spinal cord. In particular, the anatomical proximity of the spinal cord to the lungs and heart generates significant movement artifact that makes imaging the living spinal cord a challenging task. We developed a novel method that overcomes the inherent limitations of spinal cord imaging by stabilizing the spinal column, reducing respiratory-induced movements and thereby facilitating the use of two-photon microscopy to image the mouse spinal cord in vivo. This is achieved by combining a customized spinal stabilization device with a method of deep anesthesia, resulting in a significant reduction of respiratory-induced movements. This video protocol shows how to expose a small area of the living spinal cord that can be maintained under stable physiological conditions over extended periods of time by keeping tissue injury and bleeding to a minimum. Representative raw images acquired in vivo detail in high resolution the close relationship between microglia and the vasculature. A timelapse sequence shows the dynamic behavior of microglial processes in the living mouse spinal cord. Moreover, a continuous scan of the same z-frame demonstrates the outstanding stability that this method can achieve to generate stacks of images and/or timelapse movies that do not require image alignment post
Thomovsky, Stephanie A; Chen, Annie V; Roberts, Greg R; Schmidt, Carrie E; Layton, Arthur W
Two 15-yr-old grizzly bear littermates were evaluated within 9 mo of each other with the symptom of acute onset of progressive paraparesis and proprioceptive ataxia. The most significant clinical examination finding was pelvic limb paresis in both bears. Magnetic resonance examinations of both bears showed cranial thoracic spinal cord compression. The first bear had left-sided extradural, dorsolateral spinal cord compression at T3-T4. Vertebral canal stenosis was also observed at T2-T3. Images of the second bear showed lateral spinal cord compression from T2-T3 to T4-T5. Intervertebral disk disease and associated spinal cord compression was also observed at T2-T3 and T3-T4. One grizzly bear continued to deteriorate despite reduced exercise, steroid, and antibiotic therapy. The bear was euthanized, and a necropsy was performed. The postmortem showed a spinal ganglion cyst that caused spinal cord compression at the level of T3-T4. Wallerian-like degeneration was observed from C3-T6. The second bear was prescribed treatment that consisted of a combination of reduced exercise and steroid therapy. He continued to deteriorate with these medical therapies and was euthanized 4 mo after diagnosis. A necropsy showed hypertrophy and protrusion of the dorsal longitudinal ligament at T2-T3 and T3-T4, with resulting spinal cord compression in this region. Wallerian-like degeneration was observed from C2-L1. This is one of few case reports that describes paresis in bears. It is the only case report, to the authors' knowledge, that describes spinal magnetic resonance imaging findings in a grizzly bear and also the only report that describes a cranial thoracic myelopathy in two related grizzly bears with neurologic signs.
Özdemir, Ümit Sinan; Nazıroğlu, Mustafa; Şenol, Nilgün; Ghazizadeh, Vahid
Oxidative stress and cytosolic Ca(2+) overload have important roles on apoptosis in dorsal root ganglion (DRG) neurons after spinal cord injury (SCI). Hypericum perforatum (HP) has an antioxidant property in the DRGs due to its ability to modulate NADPH oxidase and protein kinase C pathways. We aimed to investigate the protective property of HP on oxidative stress, apoptosis, and Ca(2+) entry through transient receptor potential melastatin 2 (TRPM2) and transient receptor potential vanilloid 1 (TRPV1) channels in SCI-induced DRG neurons of rats. Rats were divided into four groups as control, HP, SCI, and SCI + HP. The HP groups received 30 mg/kg HP for three concessive days after SCI induction. The SCI-induced TRPM2 and TRPV1 currents and cytosolic free Ca(2+) concentration were reduced by HP. The SCI-induced decrease in glutathione peroxidase and cell viability values were ameliorated by HP treatment, and the SCI-induced increase in apoptosis, caspase 3, caspase 9, cytosolic reactive oxygen species (ROS) production, and mitochondrial membrane depolarization values in DRG of SCI group were overcome by HP treatment. In conclusion, we observed a protective role of HP on SCI-induced oxidative stress, apoptosis, and Ca(2+) entry through TRPM2 and TRPV1 in the DRG neurons. Our findings may be relevant to the etiology and treatment of SCI by HP. Graphical Abstract Possible molecular pathways of involvement of Hypericum perforatum (HP) on apoptosis, oxidative stress, and calcium accumulation through TRPM2 and TRPV1 channels in DRG neurons of SCI-induced rats. The TRPM2 channel is activated by ADP-ribose and oxidative stress through activation of ADP-ribose pyrophosphate although it was inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and 2-aminoethyl diphenylborinate (2APB). The TRPV1 channel is activated by oxidative stress and capsaicin and it is blocked by capsazepine. Injury in the DRG can result in augmented ROS release, leading to Ca(2+) uptake through
Medin, Paul M.; Boike, Thomas P.
Clinical implementation of spinal radiosurgery has increased rapidly in recent years, but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970s. The influences of field length, dose rate, inhomogeneous dose distributions, and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in preclinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small- and large-animal models. Extensive investigation of inhomogeneous dose distributions in the rat has demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Preclinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose-volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data are sparse, but results from guinea pig, rat, and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.
Jung, Sun-Young; Seo, Tae-Beom; Kim, Dae-Young
Spinal cord injury (SCI) disrupts both axonal pathways and segmental spinal cord circuity, resulting in permanent neurological deficits. Physical exercise is known to increase the expression of neurotrophins for improving the injured spinal cord. In the present study, we investigated the effects of treadmill exercise on locomotor function in relation with brain-derived neurotrophic factor (BDNF) expression after SCI. The rats were divided into five groups: control group, sham operation group, sham operation and exercise group, SCI group, and SCI and exercise group. The laminectomy was performed at the T9–T10 level. The exposed dorsal surface of the spinal cord received contusion injury (10 g × 25 mm) using the impactor. Treadmill exercise was performed 6 days per a week for 6 weeks. In order to evaluate the locomotor function of animals, Basso-Beattie-Bresnahan (BBB) locomotor scale was conducted once a week for 6 weeks. We examined BDNF expression and axonal sprouting in the injury site of the spinal cord using Western blot analysis and immunofluorescence staining. SCI induced loss of locomotor function with decreased BDNF expression in the injury site. Treadmill exercise increased the score of BBB locomotor scale and reduced cavity formation in the injury site. BDNF expression and axonal sprouting within the trabecula were further facilitated by treadmill exercise in SCI-exposed rats. The present study provides the evidence that treadmill exercise may facilitate recovery of locomotor function through axonal regeneration via BDNF expression following SCI. PMID:27656624
Background Glutamergic excitotoxicity has been shown to play a deleterious role in the pathophysiology of spinal cord injury (SCI). The aim of this study was to investigate the neuroprotective effect of dizocilpine maleate, MK801 (2 mg/Kg, 30 min and 6 hours after injury) in a mice model of SCI. The spinal cord trauma was induced by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. Results Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration and apoptosis. In this study we clearly demonstrated that administration of MK801 attenuated all inflammatory parameters. In fact 24 hours after injury, the degree of spinal cord inflammation and tissue injury (evaluated as histological score), infiltration of neutrophils, NF-κB activation, iNOS, cytokines levels (TNF-α and IL-1β), neurotrophin expression were markedly reduced by MK801 treatment. Moreover, in a separate set of experiments, we have demonstrated that MK801 treatment significantly improved the recovery of locomotory function. Conclusions Blockade of NMDA by MK801 lends support to the potential importance of NMDA antagonists as therapeutic agents in the treatment of acute spinal cord injury. PMID:21492450
Liu, Chien-Cheng; Gao, Yong-Jing; Luo, Hao; Berta, Temugin; Xu, Zhen-Zhong; Ji, Ru-Rong; Tan, Ping-Heng
It is well known that interferons (IFNs), such as type-I IFN (IFN-α) and type-II IFN (IFN-γ) are produced by immune cells to elicit antiviral effects. IFNs are also produced by glial cells in the CNS to regulate brain functions. As a proinflammatory cytokine, IFN-γ drives neuropathic pain by inducing microglial activation in the spinal cord. However, little is known about the role of IFN-α in regulating pain sensitivity and synaptic transmission. Strikingly, we found that IFN-α/β receptor (type-I IFN receptor) was expressed by primary afferent terminals in the superficial dorsal horn that co-expressed the neuropeptide CGRP. In the spinal cord IFN-α was primarily expressed by astrocytes. Perfusion of spinal cord slices with IFN-α suppressed excitatory synaptic transmission by reducing the frequency of spontaneous excitatory postsynaptic current (sEPSCs). IFN-α also inhibited nociceptive transmission by reducing capsaicin-induced internalization of NK-1 and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial dorsal horn neurons. Finally, spinal (intrathecal) administration of IFN-α reduced inflammatory pain and increased pain threshold in naïve rats, whereas removal of endogenous IFN-α by a neutralizing antibody induced hyperalgesia. Our findings suggest a new form of neuronal-glial interaction by which IFN-α, produced by astrocytes, inhibits nociceptive transmission in the spinal cord. PMID:27670299
Nitzken, Matthew; Bajaj, Nihit; Aslan, Sevda; Gimel’farb, Georgy; Ovechkin, Alexander
Surface Electromyography (EMG) is a standard method used in clinical practice and research to assess motor function in order to help with the diagnosis of neuromuscular pathology in human and animal models. EMG recorded from trunk muscles involved in the activity of breathing can be used as a direct measure of respiratory motor function in patients with spinal cord injury (SCI) or other disorders associated with motor control deficits. However, EMG potentials recorded from these muscles are often contaminated with heart-induced electrocardiographic (ECG) signals. Elimination of these artifacts plays a critical role in the precise measure of the respiratory muscle electrical activity. This study was undertaken to find an optimal approach to eliminate the ECG artifacts from EMG recordings. Conventional global filtering can be used to decrease the ECG-induced artifact. However, this method can alter the EMG signal and changes physiologically relevant information. We hypothesize that, unlike global filtering, localized removal of ECG artifacts will not change the original EMG signals. We develop an approach to remove the ECG artifacts without altering the amplitude and frequency components of the EMG signal by using an externally recorded ECG signal as a mask to locate areas of the ECG spikes within EMG data. These segments containing ECG spikes were decomposed into 128 sub-wavelets by a custom-scaled Morlet Wavelet Transform. The ECG-related sub-wavelets at the ECG spike location were removed and a de-noised EMG signal was reconstructed. Validity of the proposed method was proven using mathematical simulated synthetic signals and EMG obtained from SCI patients. We compare the Root-mean Square Error and the Relative Change in Variance between this method, global, notch and adaptive filters. The results show that the localized wavelet-based filtering has the benefit of not introducing error in the native EMG signal and accurately removing ECG artifacts from EMG signals
Newton, Victoria L.; Guck, Jonathan D.; Cotter, Mary A.
Spinal glial cell activation and cytokine secretion have been implicated in the etiology of neuropathic pain in a number of experimental models, including diabetic neuropathy. In this study, streptozotocin- (STZ-) induced diabetic rats were either untreated or treated with gabapentin (50 mg/kg/day by gavage for 2 weeks, from 6 weeks after STZ). At 8 weeks after STZ, hypersensitivity was confirmed in the untreated diabetic rats as a reduced response threshold to touch, whilst mechanical thresholds in gabapentin-treated diabetic rats were no different from controls. Diabetes-associated thermal hypersensitivity was also ameliorated by gabapentin. We performed a cytokine profiling array in lumbar spinal cord samples from control and diabetic rats. This revealed an increase in L-selectin, an adhesion molecule important for neutrophil transmigration, in the spinal cord of diabetic rats but not diabetic rats treated with gabapentin. Furthermore, we found an increase in the number of neutrophils present in the parenchyma of the spinal cord, which was again ameliorated in gabapentin-treated diabetic rats. Therefore, we suggest that dysregulated spinal L-selectin and neutrophil infiltration into the spinal cord could contribute to the pathogenesis of painful diabetic neuropathy. PMID:28293643
Attenuation of hyperalgesia responses via the modulation of 5-hydroxytryptamine signalings in the rostral ventromedial medulla and spinal cord in a 6-hydroxydopamine-induced rat model of Parkinson’s disease
Wang, Chen-Tao; Mao, Cheng-Jie; Zhang, Xiao-Qi; Zhang, Cai-Yi; Lv, Dong-Jun; Yang, Ya-Ping; Xia, Kai-Lin; Liu, Jun-Yi; Wang, Fen; Hu, Li-Fang; Xu, Guang-Yin
Background Although pain is one of the most distressing non-motor symptoms among patients with Parkinson’s disease, the underlying mechanisms of pain in Parkinson’s disease remain elusive. The aim of the present study was to investigate the role of serotonin (5-hydroxytryptamine) in the rostral ventromedial medulla (RVM) and spinal cord in pain sensory abnormalities in a 6-hydroxydopamine-treated rat model of Parkinson’s disease. Methods The rotarod test was used to evaluate motor function. The radiant heat test and von Frey test were conducted to evaluate thermal and mechanical pain thresholds, respectively. Immunofluorescence was used to examine 5-hydroxytryptamine neurons and fibers in the rostral ventromedial medulla and spinal cord. High-performance liquid chromatography was used to determine 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels. Results The duration of running time on the rotarod test was significantly reduced in 6-hydroxydopamine-treated rats. Nociceptive thresholds of both mechanical and heat pain were reduced compared to sham-treated rats. In addition to the degeneration of cell bodies and fibers in the substantia nigra pars compacta, the number of rostral ventromedial medulla 5-hydroxytryptamine neurons and 5-hydroxytryptamine fibers in the spinal dorsal horn was dramatically decreased. 5-Hydroxytryptamine concentrations in both the rostral ventromedial medulla and spinal cord were reduced. Furthermore, the administration of citalopram significantly attenuated pain hypersensitivity. Interestingly, Intra-rostral ventromedial medulla (intra-RVM) microinjection of 5,7-dihydroxytryptamine partially reversed pain hypersensitivity of 6-hydroxydopamine-treated rats. Conclusions These results suggest that the decreased 5-hydroxytryptamine contents in the rostral ventromedial medulla and spinal dorsal horn may be involved in hyperalgesia in the 6-hydroxydopamine-induced rat model of Parkinson’s disease. PMID:28326933
Humanes-Valera, Desiré; Alonso-Calviño, Elena; Yague, Josué G.; Moxon, Karen A.; Oliviero, Antonio
Spinal cord injury can produce extensive long-term reorganization of the cerebral cortex. Little is known, however, about the sequence of cortical events starting immediately after the lesion. Here we show that a complete thoracic transection of the spinal cord produces immediate functional reorganization in the primary somatosensory cortex of anesthetized rats. Besides the obvious loss of cortical responses to hindpaw stimuli (below the level of the lesion), cortical responses evoked by forepaw stimuli (above the level of the lesion) markedly increase. Importantly, these increased responses correlate with a slower and overall more silent cortical spontaneous activity, representing a switch to a network state of slow-wave activity similar to that observed during slow-wave sleep. The same immediate cortical changes are observed after reversible pharmacological block of spinal cord conduction, but not after sham. We conclude that the deafferentation due to spinal cord injury can immediately (within minutes) change the state of large cortical networks, and that this state change plays a critical role in the early cortical reorganization after spinal cord injury. PMID:20519527
Chen, Evan; Rauscher, Alexander; Kozlowski, Piotr; Yung, Andrew
The spinal cord is an integral part of the nervous system responsible for sensory, motor, and reflex control crucial to all bodily function. Due to its non-invasive nature, MRI is well matched for characterizing and imaging of spinal cord, and is used extensively for clinical applications. Recent developments in magnetic resonance imaging (MRI) at high field (7T) using phase represents a new approach of characterizing spinal cord myelin. Theory suggests that microstructure differences in myelinated white matter (WM) and non-myelinated gray matter (GM) affect MR phase, measurable frequency shifts. Data from pilot experiments using a multi-gradient echo (MGE) sequence to image rat spinal cords placed parallel to main magnetic field B0 has shown frequency shifts between not only between WM and GM, but also between specific WM tracts of the dorsal column, including the fasciculus gracilis, fasciculus cuneatus, and corticospinal tract. Using MGE, frequency maps at multiple echo times (TE) between 4ms and 22ms show a non-linear relationship between WM frequency, contrary to what was previously expected. These results demonstrate the effectiveness of MGE in revealing new information about spinal cord tissue microstructure, and lays important groundwork for in-vivo and human studies.
Dawley, Ellen M; O Samson, Shoji; Woodard, Kenton T; Matthias, Kathryn A
Adult urodele amphibians possess extensive regenerative abilities, including lens, jaws, limbs, and tails. In this study, we examined the cellular events and time course of spinal cord regeneration in a species, Plethodon cinereus, that has the ability to autotomize its tail as an antipredator strategy. We propose that this species may have enhanced regenerative abilities as further coadaptations with this antipredator strategy. We examined the expression of nestin, vimentin, and glial fibrillary acidic protein (GFAP) after autotomy as markers of neural precursor cells and astroglia; we also traced the appearance of new neurons using 5-bromo-2'-deoxyuridine/neuronal nuclei (BrdU/NeuN) double labeling. As expected, the regenerating ependymal tube was a major source of new neurons; however, the spinal cord cranial to the plane of autotomy showed significant mitotic activity, more extensive than what is reported for other urodeles that cannot autotomize their tails. In addition, this species shows upregulation of nestin, vimentin, and GFAP within days after tail autotomy; further, this expression is upregulated within the spinal cord cranial to the plane of autotomy, not just within the extending ependymal tube, as reported in other urodeles. We suggest that enhanced survival of the spinal cord cranial to autotomy allows this portion to participate in the enhanced recovery and regeneration of the spinal cord.
Abud, Edsel M; Ichiyama, Ronaldo M; Havton, Leif A; Chang, Huiyi H
After spinal cord injury (SCI), the neurogenic bladder is observed to develop asynchronous bladder and external urethral sphincter (EUS) contractions in a condition known as detrusor-sphincter dyssnergia (DSD). Activation of the EUS spinal controlling center located at the upper lumbar spinal cord may contribute to reduce EUS dyssynergic contractions and decrease urethral resistance during voiding. However, this mechanism has not been well studied. This study aimed at evaluating the effects of epidural stimulation (EpS) over the spinal EUS controlling center (L3) in combination with a serotonergic receptor agonist on EUS relaxation in naive rats and chronic (6-8 wk) T8 SCI rats. Cystometrogram and EUS electromyography (EMG) were obtained before and after the intravenous administration of 5HT-1A receptor agonist and antagonist. The latency, duration, frequency, amplitude, and area under curve of EpS-evoked EUS EMG responses were analyzed. EpS on L3 evoked an inhibition of EUS tonic contraction and an excitation of EUS intermittent bursting/relaxation correlating with urine expulsion in intact rats. Combined with a 5HT-1A receptor agonist, EpS on L3 evoked a similar effect in chronic T8 SCI rats to reduce urethral contraction (resistance). This study examined the effect of facilitating the EUS spinal controlling center to switch between urine storage and voiding phases by using EpS and a serotonergic receptor agonist. This novel approach of applying EpS on the EUS controlling center modulates EUS contraction and relaxation as well as reduces urethral resistance during voiding in chronic SCI rats with DSD.
Manxiu, Ma; Zhao, Can; Xi, Yue; Yang, Zhao-Yang; Li, Xiao-Guang
The effects of traumatic spinal cord injury (SCI) on the changes in the central nervous system (CNS) over time may depend on the dynamic interaction between the structural integrity of the spinal cord and the capacity of the brain plasticity. Functional magnetic resonance imaging (fMRI) was used in a longitudinal study on five rhesus monkeys to observe cerebral activation during upper limb somatosensory tasks in healthy animals and after unilateral thoracic SCI. The changes in the spinal cord diameters were measured, and the correlations among time after the lesion, structural changes in the spinal cord, and primary somatosensory cortex (S1) reorganization were also determined. After SCI, activation of the upper limb in S1 shifted to the region which generally dominates the lower limb, and the rostral spinal cord transverse diameter adjacent to the lesion exhibited obvious atrophy, which reflects the SCI-induced changes in the CNS. A significant correlation was found among the time after the lesion, the spinal cord atrophy, and the degree of contralateral S1 reorganization. The results indicate the structural changes in the spinal cord and the dynamic reorganization of the cerebral activation following early SCI stage, which may help to further understand the neural plasticity in the CNS. PMID:24490171
Douglas, M.A.; Parks, L.C.; Bebin, J.
Hyperthermia is a new method of treatment receiving increasing clinical attention in cancer therapy. Its efficacy has been well demonstrated in animals, but its indications, contraindications, and appropriate place in cancer therapy have yet to be defined. We report three cases of acute myelopathy in patients undergoing hyperthermia after spinal-cord irradiation within the preceding two months. Post-mortem examination in one case revealed findings similar to those seen in myelopathy resulting from long-term irradiation. Several neurologic side effects have been reported previously with total-body hyperthermia - most commonly peripheral neuropathy, but not myelopathy. The mechanism of action of hyperthermia in cancer therapy (with or without prior irradiation) is unknown. The experience reported suggests that in some patients hyperthermia may potentiate radiation-induced damage to the spinal cord or otherwise interact to cause acute spinal-cord necrosis.
Sufianova, G Z; Usov, L A; Sufianov, A A; Perelomov, Iu P; Raevskaia, L Iu; Shapkin, A G
Possibilities of the neuroprotector therapy using adenosine and cyclopentyladenosine (CPA), an adenosine receptor agonist, were studied on a model of spinal cord injury by compression in rats (most closely reproducing the analogous clinical pathological process in humans). The model was induced by slow, graded compression of the spinal cord at the thoracic level. Adenosine and CPA were introduced 60 min before injury by subcutaneous injections in a dose of 300 and 2.5 micrograms/kg, respectively. The protective effect was judged by comparing the neurological, electromyographic, and histopathological changes in animals with the model injury and in the control group (adenosine and CPA background). The A1-agonist CPA injections produced a pronounced, statistically significant neuroprotector effect on the given spinal cord injury model in rats. The neuroprotective effect of adenosine was significant but not as strong. It is concluded that it is expedient to use A-agonists in clinics.
Kim, Moonhang; Park, So Ra; Choi, Byung Hyune
This review presents a summary of various types of scaffold biomaterials used alone or together with therapeutic drugs and cells to regenerate spinal cord injury (SCI). The inhibitory environment and loss of axonal connections after SCI give rise to critical obstacles to regeneration of lost tissues and neuronal functions. Biomaterial scaffolds can provide a bridge to connect lost tissues, an adhesion site for implanted or host cells, and sustained release of therapeutic drugs in the injured spinal cord. In addition, they not only provide a structural platform, but can play active roles by inhibiting apoptosis of cells, inflammation and scar formation, and inducing neurogenesis, axonal growth and angiogenesis. Many synthetic and natural biomaterial scaffolds have been extensively investigated and tested in vitro and in animal SCI models for these purposes. We summarized the literature on the biomaterials commonly used for spinal cord regeneration in terms of historical backgrounds and current approaches.
Zhou, Chuan; Chan, Heang-Ping; Dong, Qian; He, Bo; Wei, Jun; Hadjiiski, Lubomir M.; Couriel, Daniel
We are developing an automated method for the identification of the spinal cord and the vertebras on spinal MR images, which is an essential step for computerized analysis of bone marrow diseases. The spinal cord segment was first enhanced by a newly developed hierarchical multiscale tubular (HMT) filter that utilizes the complementary hyper- and hypo- intensities in the T1-weighted (T1W) and STIR MRI sequences. An Expectation-Maximization (EM) analysis method was then applied to the enhanced tubular structures to extract candidates of the spinal cord. The spinal cord was finally identified by a maximum-likelihood registration method by analysis of the features extracted from the candidate objects in the two MRI sequences. Using the identified spinal cord as a reference, the vertebras were localized based on the intervertebral disc locations extracted by another HMT filter applied to the T1W images. In this study, 5 and 30 MRI scans from 35 patients who were diagnosed with multiple myeloma disease were collected retrospectively with IRB approval as training and test set, respectively. The vertebras manually outlined by a radiologist were used as reference standard. A total of 422 vertebras were marked in the 30 test cases. For the 30 test cases, 100% (30/30) of the spinal cords were correctly segmented with 4 false positives (FPs) mistakenly identified on the back muscles in 4 scans. A sensitivity of 95.0% (401/422) was achieved for the identification of vertebras, and 5 FPs were marked in 4 scans with an average FP rate of 0.17 FPs/scan.
Valente, Maurizio; Krstajic, Nikola; Biella, Gabriele E. M.
Despite the continuous improvement in medical imaging technology, visualizing the spinal cord poses severe problems due to structural or incidental causes, such as small access space and motion artifacts. In addition, positional guidance on the spinal cord is not commonly available during surgery, with the exception of neuronavigation techniques based on static pre-surgical data and of radiation-based methods, such as fluoroscopy. A fast, bedside, intraoperative real-time imaging, particularly necessary during the positioning of endoscopic probes or tools, is an unsolved issue. The objective of our work, performed on experimental rats, is to demonstrate potential intraoperative spinal cord imaging and probe guidance by optical coherence tomography (OCT). Concurrently, we aimed to demonstrate that the electromagnetic OCT irradiation exerted no particular effect at the neuronal and synaptic levels. OCT is a user-friendly, low-cost and endoscopy-compatible photonics-based imaging technique. In particular, by using a Fourier-domain OCT imager, operating at 850 nm wavelength and scanning transversally with respect to the spinal cord, we have been able to: 1) accurately image tissue structures in an animal model (muscle, spine bone, cerebro-spinal fluid, dura mater and spinal cord), and 2) identify the position of a recording microelectrode approaching and inserting into the cord tissue 3) check that the infrared radiation has no actual effect on the electrophysiological activity of spinal neurons. The technique, potentially extendable to full three-dimensional image reconstruction, shows prospective further application not only in endoscopic intraoperative analyses and for probe insertion guidance, but also in emergency and adverse situations (e.g. after trauma) for damage recognition, diagnosis and fast image-guided intervention. PMID:27050096
Myers, Scott A.; Andres, Kariena R.; Hagg, Theo; Whittemore, Scott R.
CD36 is a pleiotropic receptor involved in several pathophysiological conditions, including cerebral ischemia, neurovascular dysfunction and atherosclerosis, and recent reports implicate its involvement in the endoplasmic reticulum stress response (ERSR). We hypothesized that CD36 signaling contributes to the inflammation and microvascular dysfunction following spinal cord injury. Following contusive injury, CD36−/− mice demonstrated improved hindlimb functional recovery and greater white matter sparing than CD36+/+ mice. CD36−/− mice exhibited a reduced macrophage, but not neutrophil, infiltration into the injury epicenter. Fewer infiltrating macrophages were either apoptotic or positive for the ERSR marker, phospho-ATF4. CD36−/− mice also exhibited significant improvements in injury heterodomain vascularity and function. These microvessels accumulated less of the oxidized lipid product 4-hydroxy-trans-2-nonenal (4HNE) and exhibited a reduced ERSR, as detected by vascular phospho-ATF4, CHOP and CHAC-1 expression. In cultured primary endothelial cells, deletion of CD36 diminished 4HNE-induced phospho-ATF4 and CHOP expression. A reduction in phospho-eIF2α and subsequent increase in KDEL-positive, ER-localized proteins suggest that 4HNE-CD36 signaling facilitates the detection of misfolded proteins upstream of eIF2α phosphorylation, ultimately leading to CHOP-induced apoptosis. We conclude that CD36 deletion modestly, but significantly, improves functional recovery from spinal cord injury by enhancing vascular function and reducing macrophage infiltration. These phenotypes may, in part, stem from reduced ER stress-induced cell death within endothelial and macrophage cells following injury. PMID:24690303
Priori, Alberto; Ciocca, Matteo; Parazzini, Marta; Vergari, Maurizio; Ferrucci, Roberta
Two neuromodulatory techniques based on applying direct current (DC) non-invasively through the skin, transcranial cerebellar direct current stimulation (tDCS) and transcutaneous spinal DCS, can induce prolonged functional changes consistent with a direct influence on the human cerebellum and spinal cord. In this article we review the major experimental works on cerebellar tDCS and on spinal tDCS, and their preliminary clinical applications. Cerebellar tDCS modulates cerebellar motor cortical inhibition, gait adaptation, motor behaviour, and cognition (learning, language, memory, attention). Spinal tDCS influences the ascending and descending spinal pathways, and spinal reflex excitability. In the anaesthetised mouse, DC stimulation applied under the skin along the entire spinal cord may affect GABAergic and glutamatergic systems. Preliminary clinical studies in patients with cerebellar disorders, and in animals and patients with spinal cord injuries, have reported beneficial effects. Overall the available data show that cerebellar tDCS and spinal tDCS are two novel approaches for inducing prolonged functional changes and neuroplasticity in the human cerebellum and spinal cord, and both are new tools for experimental and clinical neuroscientists. PMID:24907311
He, Qin-Qin; Xiong, Liu-Lin; Liu, Fei; He, Xiang; Feng, Guo-Ying; Shang, Fei-Fei; Xia, Qing-Jie; Wang, You-Cui; Qiu, De-Lu; Luo, Chao-Zhi; Liu, Jia; Wang, Ting-Hua
Neuroregeneration and apoptosis are two important pathophysiologic changes after spinal cord injury (SCI), but their underlying mechanisms remain unclear. MicroRNAs (miRNAs) play a crucial role in the regulation of neuroregeneration and neuronal apoptosis, research areas that have been greatly expanded in recent years. Here, using miRNA arrays to profile miRNA transcriptomes, we demonstrated that miR-127-3p was significantly down-regulated after spinal cord transection (SCT). Then, bioinformatics analyses and experimental detection showed that miR-127-3p exhibited specific effects on the regulation of neurite outgrowth and the induction of neuronal apoptosis by regulating the expression of the mitochondrial membrane protein mitoNEET. Moreover, knockdown of MitoNEET leaded to neuronal loss and apoptosis in primary cultured spinal neurons. This study therefore revealed that miR-127-3p, which targets mitoNEET, plays a vital role in regulating neurite outgrowth and neuronal apoptosis after SCT. Thus, modificatioin of the mitoNEET expression, such as mitoNEET activition may provide a new strategy for the treatment of SCI in preclinical trials. PMID:27748416
Skutschas, Pavel P; Baleeva, Nataly V
The development of spinal cord supports (bony thickenings which extend into the vertebral canal of vertebrae) in primitive (Salamandrella keyserlingii) and derived (Lissotriton vulgaris) salamanders were described. The spinal cord supports develop as the protuberances of periostal bone of the neural arches in the anteroproximal part of the septal collagenous fibers which connect a transverse myoseptum with the notochord and spinal cord, in the septal bundle inside the vertebral canal. Spinal cord supports were also found in some teleostean (Salmo salar, Oncorhynchus mykiss) and dipnoan (Protopterus sp.) fishes. The absence of the spinal cord supports in vertebrates with cartilaginous vertebrae (lampreys, chondrichthyan, and chondrostean fishes) corresponds to the fact that the spinal cord supports are bone structures. The absence of the spinal cord supports in frogs correlates with the lack of the well developed septal bundles inside the vertebral canal. The spinal cord supports are, presumably, a synapomorphic character for salamanders which originated independently of those observed in teleostean and dipnoan fishes.
... AFFAIRS Proposed Information Collection (Spinal Cord Injury Patient Care Survey) Activity: Comment Request... spinal cord patients' satisfaction with VA rehabilitation and health care system. Affected Public... of automated collection techniques or the use of other forms of information technology. Title:...
Fenrich, Keith K.; Weber, Pascal; Rougon, Genevieve; Debarbieux, Franck
Experimental autoimmune encephalomyelitis (EAE) in adult rodents is the standard experimental model for studying autonomic demyelinating diseases such as multiple sclerosis. Here we present a low-cost and reproducible glass window implantation protocol that is suitable for intravital microscopy and studying the dynamics of spinal cord cytoarchitecture with subcellular resolution in live adult mice with EAE. Briefly, we surgically expose the vertebrae T12-L2 and construct a chamber around the exposed vertebrae using a combination of cyanoacrylate and dental cement. A laminectomy is performed from T13 to L1, and a thin layer of transparent silicone elastomer is applied to the dorsal surface of the exposed spinal cord. A modified glass cover slip is implanted over the exposed spinal cord taking care that the glass does not directly contact the spinal cord. To reduce the infiltration of inflammatory cells between the window and spinal cord, anti-inflammatory treatment is administered every 2 days (as recommended by ethics committee) for the first 10 days after implantation. EAE is induced only 2-3 weeks after the cessation of anti-inflammatory treatment. Using this approach we successfully induced EAE in 87% of animals with implanted windows and, using Thy1-CFP-23 mice (blue axons in dorsal spinal cord), quantified axonal loss throughout EAE progression. Taken together, this protocol may be useful for studying the recruitment of various cell populations as well as their interaction dynamics, with subcellular resolution and for extended periods of time. This intravital imaging modality represents a valuable tool for developing therapeutic strategies to treat autoimmune demyelinating diseases such as EAE. PMID:24378439
Fenrich, Keith K; Weber, Pascal; Rougon, Genevieve; Debarbieux, Franck
Experimental autoimmune encephalomyelitis (EAE) in adult rodents is the standard experimental model for studying autonomic demyelinating diseases such as multiple sclerosis. Here we present a low-cost and reproducible glass window implantation protocol that is suitable for intravital microscopy and studying the dynamics of spinal cord cytoarchitecture with subcellular resolution in live adult mice with EAE. Briefly, we surgically expose the vertebrae T12-L2 and construct a chamber around the exposed vertebrae using a combination of cyanoacrylate and dental cement. A laminectomy is performed from T13 to L1, and a thin layer of transparent silicone elastomer is applied to the dorsal surface of the exposed spinal cord. A modified glass cover slip is implanted over the exposed spinal cord taking care that the glass does not directly contact the spinal cord. To reduce the infiltration of inflammatory cells between the window and spinal cord, anti-inflammatory treatment is administered every 2 days (as recommended by ethics committee) for the first 10 days after implantation. EAE is induced only 2-3 weeks after the cessation of anti-inflammatory treatment. Using this approach we successfully induced EAE in 87% of animals with implanted windows and, using Thy1-CFP-23 mice (blue axons in dorsal spinal cord), quantified axonal loss throughout EAE progression. Taken together, this protocol may be useful for studying the recruitment of various cell populations as well as their interaction dynamics, with subcellular resolution and for extended periods of time. This intravital imaging modality represents a valuable tool for developing therapeutic strategies to treat autoimmune demyelinating diseases such as EAE.
André-Obadia, N; Mauguière, F
Evoked potentials (EPs) are useful to evaluate the functional impairment of motor and somatosensory pathways in spinal cord tumors. Conduction through pyramidal tracts is evaluated by motor EPs (MEPs) elicited by transcranial stimulation, magnetic for awake patients or electric in the operating room. Somatosensory EPs (SEPs) and laser EPs (LEPs) are complementary procedures to explore conduction in dorsal columns and spinothalamic tracts, respectively. MEPs as well as SEPs show conduction abnormalities in about 60% of cases with a sensitivity that increases up to 70% when both procedures are carried out. Abnormalities are observed in the absence of any clinical sign in respectively 7% and 15% of cases for MEPs and SEPs. Multilevel stimulations for SEPs recordings permit to detect segmental dysfunction in 70% in case of cervical TIM, even in the absence of clinical signs. LEPs are useful in specific clinical situations: they allow a dermatomal stimulation and are correlated to segmental thermoalgic anaesthesia. Electrophysiological testing plays an important role in the diagnostic and therapeutic strategy: before surgery, MEPs and SEPs objectively evaluate the functional impairment directly related to the lesion. They also help by permitting a follow-up, either before surgery when the surgical decision is delayed because of a good clinical tolerance of the lesion, or after operation to evaluate the functional evolution. Intraoperative monitoring of MEPs and SEPs allows informing the surgeon about the impact on each surgical manipulation. No prospective randomized study has been performed to date to compare clinical evolution after surgery with or without monitoring. Nevertheless, a wide consensus became established in favor of monitoring to limit the risk of postoperative definite deficit and to permit an optimal surgical resection without risk when responses are preserved.
Second cervical segment spinal cord hemisection (C2Hx) results in ipsilateral hemidiaphragm paralysis. However, the intact latent crossed phrenic pathway can restore function spontaneously over time or immediately following drug administration. WGA bound fluorochromes were administered to identify nuclei associated with diaphragm function in both the acute and chronic C2Hx models. WGA is unique in that it undergoes receptor mediated endocytosis and is transsynaptically transported across select physiologically active synapses. Comparison of labeling in the acutely injured to the chronically injured rat provided an anatomical map of spinal and supraspinal injury induced synaptic plasticity. The plasticity occurs over time in the chronic C2Hx model in an effort to adapt to the loss of hemidiaphragm function. Utilizing the selectivity of WGA, a nanoconjugate was developed to target drug delivery to nuclei involved in diaphragm function post C2Hx in an effort to restore lost function. Theophylline was selected due to its established history as a respiratory stimulant. Theophylline was attached to gold nanoparticles by a transient bond designed to degrade intracellularly. The gold nanoparticles were then permanently attached to WGA-HRP. Following intradiaphragmatic injection, the WGA portion was identified in the ipsilateral phrenic nuclei and bilaterally in the rVRGs. The location of WGA should reflect the location of the AuNP since the peptide bond between them is permanent. The effectiveness of the nanoconjugate was verified with EMG analysis of the diaphragm and recordings from the phrenic nerves. All doses administered in the acute C2Hx model resulted in resorted hemidiaphragm and phrenic nerve activity. A dose of 0.14mg/kg had a significantly higher percent recovery on day 3, whereas 0.03mg/kg was significantly higher on day 14. The change in most effective dose over time is likely due to the availability or concentration of the drug and location of drug release
Sengul, Gulgun; Fu, YuHong; Yu, You; Paxinos, George
The projections from the spinal cord to the cerebellar cortex were studied using retrograde neuronal tracers. Thus far, no study has shown the detailed topographic mapping of the projections from the spinal neuron clusters to the cerebellar cortex regions for experimental animals, and there are no studies for the mouse. Tracers Fluoro-Gold and cholera toxin B were injected into circumscribed regions of the cerebellar cortex, and retrogradely labeled spinal cord neurons were mapped throughout the spinal cord. Spinal projections to the cerebellar cortex were mainly from five neuronal columns--central cervical nucleus, dorsal nucleus, lumbar and sacral precerebellar nuclei, and lumbar border precerebellar cells--and from scattered neurons located in the deep dorsal horn and laminae 6-8. The spinocerebellar projections to the cortex were mainly to the vermis. All five precerebellar cell columns projected to both anterior and posterior parts of the cerebellar cortex. Results of this study provide an amendment to the known rostral and caudal boundaries of the precerebellar cell columns in the mouse. Scattered precerebellar neurons in the most caudal deep dorsal horn and laminae 6-8 projected exclusively to the anterior part of the cerebellar cortex. In this study, no labeled spinal neurons were found to project to the lobules 6 and 7 of the cerebellar vermis, the flocculus, and the paraflocculus. Spinocerebellar neurons were located bilaterally, but the majority of the projections were contralateral for the central cervical nucleus, and ipsilateral for the remaining spinal precerebellar neuronal clusters.
Stroman, Patrick W; Bosma, Rachael L; Tsyben, Anastasia
Previous functional MRI studies of normal sensory function in the human spinal cord, including right-to-left symmetry of activity, have been influenced by order effects between repeated studies. In this study, we apply thermal sensory stimulation to four dermatomes within each functional MRI time-series acquisition. Each of the four dermatomes receives a unique stimulation paradigm, such that the four paradigms form a linearly independent set, enabling detection of each individual stimulus response. Functional MRI data are shown spanning the cervical spinal cord and brainstem in 10 healthy volunteers. Results of general linear model analysis demonstrate consistent patterns of activity within the spinal cord segments corresponding to each dermatome, and a high degree of symmetry between right-side and left-side stimulation. Connectivity analyses also demonstrate consistent areas of activity and connectivity between spinal cord and brainstem regions corresponding to known anatomy. However, right-side and left-side responses are not at precisely the same rostral-caudal positions, but are offset by several millimeters, with left-side responses consistently more caudal than right-side responses. The results confirm that distinct responses to multiple interleaved sensory stimuli can be distinguished, enabling studies of sensory responses within the spinal cord without the confounding effects of comparing sequential studies.
Denervation of the spinal cord below the level of injury leads to complications producing malnutrition. Nutritional status affects mortality and pathology of injured subjects and it has been reported that two thirds of individuals enrolled in rehabilitation units are malnourished. Therefore, the aim should be either to maintain an optimal nutritional status, or supplement these subjects in order to overcome deficiencies in nutrients or prevent obesity. This paper reviews methods of nutritional assessment and describes the physiopathological mechanisms of malnutrition based on the assumption that spinal cord injured subjects need to receive adequate nutrition to promote optimal recovery, placing nutrition as a first line treatment and not an afterthought in the rehabilitation of spinal cord injury. PMID:22870169
Fu, Juanjuan; Deng, Lingxiao; Li, Jianan
The exercise training is an effective therapy for spinal cord injury which has been applied to clinic. Traditionally, the exercise training has been considered to improve spinal cord function only through enhancement, compensation, and replacement of the remaining function of nerve and muscle. Recently, accumulating evidences indicated that exercise training can improve the function in different levels from end-effector organ such as skeletal muscle to cerebral cortex through reshaping skeletal muscle structure and muscle fiber type, regulating physiological and metabolic function of motor neurons in the spinal cord and remodeling function of the cerebral cortex. We compiled published data collected in different animal models and clinical studies into a succinct review of the current state of knowledge. PMID:28050288
Hoh, Daniel J.; Mercier, Lynne M.; Hussey, Shaunn P.; Lane, Michael A.
Respiratory dysfunction is one of the most devastating consequences of cervical spinal cord injury (SCI) with impaired breathing being a leading cause of morbidity and mortality in this population. However, there is mounting experimental and clinical evidence for moderate spontaneous respiratory recovery, or “plasticity”, after some spinal cord injuries. Pre-clinical models of respiratory dysfunction following SCI have demonstrated plasticity at neural and behavioral levels that result in progressive recovery of function. Temporal changes in respiration after human SCI have revealed some functional improvements suggesting plasticity paralleling that seen in experimental models – a concept that has been previously under-appreciated. While the extent of spontaneous recovery remains limited, it is possible that enhancing or facilitating neuroplastic mechanisms may have significant therapeutic potential. The next generation of treatment strategies for SCI and related respiratory dysfunction should aim to optimize these recovery processes of the injured spinal cord for lasting functional restoration. PMID:23891679
Garudadri, Suresh; Gallarda, Benjamin; Pfaff, Samuel; Alaynick, William
Development of neural circuitries and locomotion can be studied using neonatal rodent spinal cord central pattern generator (CPG) behavior. We demonstrate a method to fabricate suction electrodes that are used to examine CPG activity, or fictive locomotion, in dissected rodent spinal cords. The rodent spinal cords are placed in artificial cerebrospinal fluid and the ventral roots are drawn into the suction electrode. The electrode is constructed by modifying a commercially available suction electrode. A heavier silver wire is used instead of the standard wire given by the commercially available electrode. The glass tip on the commercial electrode is replaced with a plastic tip for increased durability. We prepare hand drawn electrodes and electrodes made from specific sizes of tubing, allowing consistency and reproducibility. Data is collected using an amplifier and neurogram acquisition software. Recordings are performed on an air table within a Faraday cage to prevent mechanical and electrical interference, respectively.
Reintegration of Service-Members and Veterans with Spinal Cord Injury PRINCIPAL INVESTIGATOR: Seth D. Messinger...SUBTITLE Developing a Meaningful Life: Social Reintegration of Service- Social Reintegration of Service Me Members and Veterans with Spinal Cord...communities and cultural identities that is key to long-term success . 15. SUBJECT TERMS Spinal Cord Injury, Community Reintegration , Qualitative
Ferrero, Paolo; Grimaldi, Roberto; Massa, Riccardo; Chiribiri, Amedeo; De Luca, Anna; Castellano, Maddalena; Cardano, Paola; Trevi, Gian Paolo
Spinal cord stimulation is currently used to treat refractory angina. Some concerns may arise about the possible interaction concerning the spinal cord stimulator in patients already implanted with a pacemaker or a cardioverter defibrillator. We are going to describe the successful implantation of a spinal cord stimulator in a patient previously implanted with a cardioverter defibrillator.
... AFFAIRS Agency Information Collection (Spinal Cord Injury Patient Care Survey) Under OMB Review AGENCY.... 2900-New (VA Form 10-0515).'' SUPPLEMENTARY INFORMATION: Title: Spinal Cord Injury Patient Care Survey... Collection. Abstract: Information collected on VA Form 10-0515 will be used to determine spinal cord...
Wang, Jian-wei; Yang, Jun-feng; Ma, Yong; Hua, Zhen; Guo, Yang; Gu, Xiao-lin; Zhang, Ya-feng
The mechanism involved in neural regeneration after spinal cord injury is unclear. The myelin-derived protein Nogo-A, which is specific to the central nervous system, has been identified to negatively affect the cytoskeleton and growth program of axotomized neurons. Studies have shown that Nogo-A exerts immediate and chronic inhibitory effects on neurite outgrowth. In vivo, inhibitors of Nogo-A have been shown to lead to a marked enhancement of regenerative axon extension. We established a spinal cord injury model in rats using a free-falling weight drop device to subsequently investigate Nogo-A expression. Nogo-A mRNA and protein expression and immunoreactivity were detected in spinal cord tissue using real-time quantitative PCR, immunohistochemistry and western blot analysis. At 24 hours after spinal cord injury, Nogo-A protein and mRNA expression was low in the injured group compared with control and sham-operated groups. The levels then continued to drop further and were at their lowest at 3 days, rapidly rose to a peak after 7 days, and then gradually declined again after 14 days. These changes were observed at both the mRNA and protein level. The transient decrease observed early after injury followed by high levels for a few days indicates Nogo-A expression is time dependent. This may contribute to the lack of regeneration in the central nervous system after spinal cord injury. The dynamic variation of Nogo-A should be taken into account in the treatment of spinal cord injury. PMID:25883620
Machi, J; Sigel, B; Menoni, R; Jafar, J J; Beitler, J C; Crowell, R M
B-mode real-time ultrasound using 5 or 7.5 MHz transducer has been employed during 21 operations for brain pathology and spinal cord lesions. Ultrasonic scanning was performed at the following operations: 10 brain tumors (4 glioblastomas multiforme, 2 astrocytomas, 1 medulloblastoma, 2 metastatic tumors), 2 brain cysts (arachnoid, epidermoid), 1 tuberculous abscess, 3 cerebral hematomas: 2 spinal cord tumors (malignant melanoma, glioma), 2 syringomyelias, 1 posterior longitudinal ligament thickening. Operative ultrasound was useful prior to dural incisions and particularly for subcortical lesions. In addition, ultrasound provided assistance at spinal cord surgery. Our experience has been reviewed and summarized in this report in terms of specific usefulness of assistance of this method which has proven helpful to the neurosurgeons. The types of assistance provided by operative ultrasonography include: Location of dural incision. Localization of brain and spinal cord lesions prior to biopsy. Diagnosis which has not been made preoperatively (e.g. necrosis or cystic area in tumor). Consistency of each lesion (e.g. solid or cystic, necrosis, loculation). Size, extent and depth of brain tumor, cyst, abscess and hematoma. Presence and extent of spinal cord syrinx. Relation of tumor to spinal cord and dura. Access route for biopsy and drainage (avoiding critical areas such as motor strip). Exclusion of bleeding or hematoma following biopsy. Confirmation of the effectiveness of drainage or resection of lesions. Relationship between pathology and surrounding anatomic structures. A number of important assistance by the utilization of ultrasound during neurological surgery have been identified.(ABSTRACT TRUNCATED AT 250 WORDS)
Smith, AC; Parrish, TB; Hoggarth, MA; McPherson, JG; Tysseling, VM; Wasielewski, M; Kim, HE; Hornby, TG; Elliott, JM
Study Design: This research utilized a cross-sectional design with control group inclusion. Objectives: Preliminary evidence suggests that a portion of the patient population with chronic whiplash may have sustained spinal cord damage. Our hypothesis is that in some cases of chronic whiplash-associated disorders (WAD), observed muscle weakness in the legs will be associated with local signs of a partial spinal cord injury of the cervical spine. Setting: University based laboratory in Chicago, IL, USA. Methods: Five participants with chronic WAD were compared with five gender/age/height/weight/body mass index (BMI) control participants. For a secondary investigation, the chronic WAD group was compared with five unmatched participants with motor incomplete spinal cord injury (iSCI). Spinal cord motor tract integrity was assessed using magnetization transfer imaging. Muscle fat infiltration (MFI) was quantified using fat/water separation magnetic resonance imaging. Central volitional muscle activation of the plantarflexors was assessed using a burst superimposition technique. Results: We found reduced spinal cord motor tract integrity, increased MFI of the neck and lower extremity muscles and significantly impaired voluntary plantarflexor muscle activation in five participants with chronic WAD. The lower extremity structural changes and volitional weakness in chronic WAD were comparable to participants with iSCI. Conclusion: The results support the position that a subset of the chronic whiplash population may have sustained partial damage to the spinal cord. Sponsorship: NIH R01HD079076-01A1, NIH T32 HD057845 and the Foundation for Physical Therapy Promotion of Doctoral Studies program. PMID:27630770
Amezcua, L; Lerner, A; Ledezma, K; Conti, D; Law, M; Weiner, L; Langer-Gould, A
Longitudinally extensive spinal cord lesions (LESCLs) are believed to occur predominantly with opticospinal multiple sclerosis (OSMS) and are associated with disability. The purpose of this study is to describe the prevalence and patterns of spinal cord lesions in Hispanics with multiple sclerosis (MS) and OSMS and their association with disability. A cross-sectional study of 164 patients with complete MRIs was used. In each case the spinal cord was classified: LESCLs, scattered spinal cord lesions (sSCLs) or no spinal cord lesions (noSCLs). Clinical course was defined as classical MS or OSMS. Risk of disability (Expanded Disability Status Scale ≥4.0) was adjusted for age, disease duration and sex using logistic regression. A total of 125/164 (73 %) MS patients had spinal cord lesions (sSCLs, 57 %; LESCLs, 19 %), but only 11 (7 %) had OSMS. LESCLs were associated with disability (p < 0.0001), longer disease duration (p < 0.0001) and MS (n = 21 vs. n = 10 OSMS; p < 0.0001). LESCLs were also associated with the greatest risk to disability (OR 7.3, 95 % CIs 1.9-26.5; p = 0.003; sSCLs OR 2.5, 95 % CIs 0.9-7.1; p = 0.09) compared with noSCLs. LESCLs are more common than OSMS and are associated with worse disability even in patients with MS. These results suggest that LESCLs are a more important marker of disability in MS than OSMS and may be an early indicator of more aggressive disease in this population.
Chou, An-Kuo; Yang, Ming-Chang; Tsai, Hung-Pei; Chai, Chee-Yin; Tai, Ming-Hong; Kwan, Aij-Li; Hong, Yi-Ren
Neuropathic pain due to peripheral nerve injury may be associated with abnormal central nerve activity. Glial cell-line-derived neurotrophic factor (GDNF) can help attenuate neuropathic pain in different animal models of nerve injury. However, whether GDNF can ameliorate neuropathic pain in the spinal cord dorsal horn (SCDH) in constriction-induced peripheral nerve injury remains unknown. We investigated the therapeutic effects of adenoviral-mediated GDNF on neuropathic pain behaviors, microglial activation, pro-inflammatory cytokine expression and programmed cell death in a chronic constriction injury (CCI) nerve injury animal model. In this study, neuropathic pain was produced by CCI on the ipsilateral SCDH. Mechanical allodynia was examined with von Frey filaments and thermal sensitivity was tested using a plantar test apparatus post-operatively. Target proteins GDNF-1, GDNFRa-1, MMP2, MMP9, p38, phospho-p38, ED1, IL6, IL1β, AIF, caspase-9, cleaved caspase-9, caspase-3, cleaved caspase-3, PARP, cleaved PARP, SPECTRIN, cleaved SPECTRIN, Beclin-1, PKCσ, PKCγ, iNOS, eNOS and nNOS were detected. Microglial activity was measured by observing changes in immunoreactivity with OX-42. NeuN and TUNEL staining were used to reveal whether apoptosis was attenuated by GDNF. Results showed that administrating GDNF began to attenuate both allodynia and thermal hyperalgesia at day 7. CCI-rats were found to have lower GDNF and GDNFRa-1 expression compared to controls, and GDNF re-activated their expression. Also, GDNF significantly down-regulated CCI-induced protein expression except for MMP2, eNOS and nNOS, indicating that the protective action of GDNF might be associated with anti-inflammation and prohibition of microglia activation. Immunocytochemistry staining showed that GDNF reduced CCI-induced neuronal apoptosis. In sum, GDNF enhanced the neurotrophic effect by inhibiting microglia activation and cytokine production via p38 and PKC signaling. GDNF could be a good
Neuropathic pain constitutes a significant portion of chronic pain. Patients with neuropathic pain are usually more heavily burdened than patients with nociceptive pain. They suffer more often from insomnia, anxiety, and depression. Moreover, analgesic medication often has an insufficient effect on neuropathic pain. Spinal cord stimulation constitutes a therapy alternative that, to date, remains underused. In the last 10 to 15 years, it has undergone constant technical advancement. This review gives an overview of the present practice of spinal cord stimulation for chronic neuropathic pain and current developments such as high-frequency stimulation and peripheral nerve field stimulation. PMID:25429237
The World Health Organization together with the Iceland Ministry of Health and Social Security sponsored a conference entitled 'Human Spinal Cord Injury: New and Emerging Approaches to Treatment' held on May 31-June 2, 2001 in Reykjavik, Iceland. To help catalyze the development of new paradigms to address spinal cord injury, the conference's overall goal was to bring in a diversity of perspectives, ranging from state-of-the-art stem cell biology to the ancient wisdom of Eastern Medicine. The purpose of this paper is to summarize the presentations of the conference's 26 speakers.
Jeon, Young Hoon
Spinal cord stimulation has become a widely used and efficient alternative for the management of refractory chronic pain that is unresponsive to conservative therapies. Technological improvements have been considerable and the current neuromodulation devices are both extremely sophisticated and reliable in obtaining good results for various clinical situations of chronic pain, such as failed back surgery syndrome, complex regional pain syndrome, ischemic and coronary artery disease. This technique is likely to possess a savings in costs compared with alternative therapy strategies despite its high initial cost. Spinal cord stimulation continues to be a valuable tool in the treatment of chronic disabling pain.
Steward, Oswald; Willenberg, Rafer
For over a century, axon regeneration has been considered the Holy Grail for spinal cord injury (SCI) repair. Although there are other factors that could contribute to improving function, restoring the long motor and sensory tracts that are interrupted by SCI has the greatest potential for actually reversing paralysis, restoring the brain's control of autonomic functions mediated by sympathetic and parasympathetic circuits of the spinal cord and restoring sensation. Accordingly and in keeping with the overall theme of this special issue, this review focuses narrowly on rodent SCI models for studies of axon regeneration.
Kaser-Eichberger, Alexandra; Schroedl, Falk; Bieler, Lara; Trost, Andrea; Bogner, Barbara; Runge, Christian; Tempfer, Herbert; Zaunmair, Pia; Kreutzer, Christina; Traweger, Andreas; Reitsamer, Herbert A.; Couillard-Despres, Sebastien
Under physiological conditions, lymphatic vessels are thought to be absent from the central nervous system (CNS), although they are widely distributed within the rest of the body. Recent work in the eye, i.e., another organ regarded as alymphatic, revealed numerous cells expressing lymphatic markers. As the latter can be involved in the response to pathological conditions, we addressed the presence of cells expressing lymphatic markers within the spinal cord by immunohistochemistry. Spinal cord of young adult Fisher rats was scrutinized for the co-expression of the lymphatic markers PROX1 and LYVE-1 with the cell type markers Iba1, CD68, PGP9.5, OLIG2. Rat skin served as positive control for the lymphatic markers. PROX1-immunoreactivity was detected in many nuclei throughout the spinal cord white and gray matter. These nuclei showed no association with LYVE-1. Expression of LYVE-1 could only be detected in cells at the spinal cord surface and in cells closely associated with blood vessels. These cells were found to co-express Iba1, a macrophage and microglia marker. Further, double labeling experiments using CD68, another marker found in microglia and macrophages, also displayed co-localization in the Iba1+ cells located at the spinal cord surface and those apposed to blood vessels. On the other hand, PROX1-expressing cells found in the parenchyma were lacking Iba1 or PGP9.5, but a significant fraction of those cells showed co-expression of the oligodendrocyte lineage marker OLIG2. Intriguingly, following spinal cord injury, LYVE-1-expressing cells assembled and reorganized into putative pre-vessel structures. As expected, the rat skin used as positive controls revealed classical lymphatic vessels, displaying PROX1+ nuclei surrounded by LYVE-1-immunoreactivity. Classical lymphatics were not detected in adult rat spinal cord. Nevertheless, numerous cells expressing either LYVE-1 or PROX1 were identified. Based on their localization and overlapping expression with
Kaser-Eichberger, Alexandra; Schroedl, Falk; Bieler, Lara; Trost, Andrea; Bogner, Barbara; Runge, Christian; Tempfer, Herbert; Zaunmair, Pia; Kreutzer, Christina; Traweger, Andreas; Reitsamer, Herbert A; Couillard-Despres, Sebastien
Under physiological conditions, lymphatic vessels are thought to be absent from the central nervous system (CNS), although they are widely distributed within the rest of the body. Recent work in the eye, i.e., another organ regarded as alymphatic, revealed numerous cells expressing lymphatic markers. As the latter can be involved in the response to pathological conditions, we addressed the presence of cells expressing lymphatic markers within the spinal cord by immunohistochemistry. Spinal cord of young adult Fisher rats was scrutinized for the co-expression of the lymphatic markers PROX1 and LYVE-1 with the cell type markers Iba1, CD68, PGP9.5, OLIG2. Rat skin served as positive control for the lymphatic markers. PROX1-immunoreactivity was detected in many nuclei throughout the spinal cord white and gray matter. These nuclei showed no association with LYVE-1. Expression of LYVE-1 could only be detected in cells at the spinal cord surface and in cells closely associated with blood vessels. These cells were found to co-express Iba1, a macrophage and microglia marker. Further, double labeling experiments using CD68, another marker found in microglia and macrophages, also displayed co-localization in the Iba1+ cells located at the spinal cord surface and those apposed to blood vessels. On the other hand, PROX1-expressing cells found in the parenchyma were lacking Iba1 or PGP9.5, but a significant fraction of those cells showed co-expression of the oligodendrocyte lineage marker OLIG2. Intriguingly, following spinal cord injury, LYVE-1-expressing cells assembled and reorganized into putative pre-vessel structures. As expected, the rat skin used as positive controls revealed classical lymphatic vessels, displaying PROX1+ nuclei surrounded by LYVE-1-immunoreactivity. Classical lymphatics were not detected in adult rat spinal cord. Nevertheless, numerous cells expressing either LYVE-1 or PROX1 were identified. Based on their localization and overlapping expression with
injury . They will supervise the creation of the cervical spine injuries , care of the animals, sacrifice and perfusion fixation, and, after completion...cord injury . They will supervise the creation of the cervical spine injuries , care of the animals, sacrifice and perfusion fixation, and, after...AWARD NUMBER: W81XWH-10-1-0715 TITLE: Magnetic Resonance Characterization of Axonal Response to Spinal Cord Injury PRINCIPAL INVESTIGATOR
Groothuis, Jan T; Rongen, Gerard A; Deinum, Jaap; Pickkers, Peter; Danser, A H Jan; Geurts, Alexander C H; Smits, Paul; Hopman, Maria T E
Autonomic dysreflexia is a hypertensive episode in spinal cord-injured individuals induced by exaggerated sympathetic activity and thought to be alpha-adrenergic mediated. alpha-Adrenoceptor antagonists have been a rational first choice; nevertheless, calcium channel blockers are primarily used in autonomic dysreflexia management. However, alpha-adrenoceptor blockade may leave a residual vasoconstrictor response to sympathetic nonadrenergic transmission unaffected. The aim was to assess the alpha-adrenergic contribution and, in addition, the role of supraspinal control to leg vasoconstriction during exaggerated sympathetic activity provoked by autonomic dysreflexia in spinal cord-injured individuals and by a cold pressure test in control individuals. Upper leg blood flow was measured using venous occlusion plethysmography during supine rest and during exaggerated sympathetic activity in 6 spinal cord-injured individuals and 7 able-bodied control individuals, without and with phentolamine (alpha-adrenoceptor antagonist) and nicardipine (calcium channel blocker) infusion into the right femoral artery. Leg vascular resistance was calculated. In spinal cord-injured individuals, phentolamine significantly reduced the leg vascular resistance increase during autonomic dysreflexia (8+/-5 versus 24+/-13 arbitrary units; P=0.04) in contrast to nicardipine (15+/-10 versus 24+/-13 arbitrary units; P=0.12). In controls, phentolamine completely abolished the leg vascular resistance increase during a cold pressure test (1+/-2 versus 18+/-14 arbitrary units; P=0.02). The norepinephrine increase during phentolamine infusion was larger (P=0.04) in control than in spinal cord-injured individuals. These results indicate that the leg vascular resistance increase during autonomic dysreflexia in spinal cord-injured individuals is not entirely alpha-adrenergic mediated and is partly explained by nonadrenergic transmission, which may, in healthy subjects, be suppressed by supraspinal
Muresanu, Dafin F; Sharma, Aruna; Lafuente, José V; Patnaik, Ranjana; Tian, Z Ryan; Nyberg, Fred; Sharma, Hari S
Previous studies from our laboratory showed that topical application of growth hormone (GH) induced neuroprotection 5 h after spinal cord injury (SCI) in a rat model. Since nanodelivery of drugs exerts superior neuroprotective effects, a possibility exists that nanodelivery of GH will induce long-term neuroprotection after a focal SCI. SCI induces GH deficiency that is coupled with insulin-like growth factor-1 (IGF-1) reduction in the plasma. Thus, an exogenous supplement of GH in SCI may enhance the IGF-1 levels in the cord and induce neuroprotection. In the present investigation, we delivered TiO2-nanowired growth hormone (NWGH) after a longitudinal incision of the right dorsal horn at the T10-11 segments in anesthetized rats and compared the results with normal GH therapy on IGF-1 and GH contents in the plasma and in the cord in relation to blood-spinal cord barrier (BSCB) disruption, edema formation, and neuronal injuries. Our results showed a progressive decline in IGF-1 and GH contents in the plasma and the T9 and T12 segments of the cord 12 and 24 h after SCI. Marked increase in the BSCB breakdown, as revealed by extravasation of Evans blue and radioiodine, was seen at these time points after SCI in association with edema and neuronal injuries. Administration of NWGH markedly enhanced the IGF-1 levels and GH contents in plasma and cord after SCI, whereas normal GH was unable to enhance IGF-1 or GH levels 12 or 24 h after SCI. Interestingly, NWGH was also able to reduce BSCB disruption, edema formation, and neuronal injuries after trauma. On the other hand, normal GH was ineffective on these parameters at all time points examined. Taken together, our results are the first to demonstrate that NWGH is quite effective in enhancing IGF-1 and GH levels in the cord and plasma that may be crucial in reducing pathophysiology of SCI.
de Rivero Vaccari, Juan Pablo; Lotocki, George; Marcillo, Alex E; Dietrich, W Dalton; Keane, Robert W
Vigorous immune responses are induced in the immune privileged CNS by injury and disease, but the molecular mechanisms regulating innate immunity in the CNS are poorly defined. The inflammatory response initiated by spinal cord injury (SCI) involves activation of interleukin-1beta (IL-1beta) that contributes to secondary cell death. In the peripheral immune response, the inflammasome activates caspase-1 to process proinflammatory cytokines, but the regulation of trauma-induced inflammation in the CNS is not clearly understood. Here we show that a molecular platform [NALP1 (NAcht leucine-rich-repeat protein 1) inflammasome] consisting of caspase-1, caspase-11, ASC (apoptosis-associated speck-like protein containing a caspase-activating recruitment domain), and NALP1 is expressed in neurons of the normal rat spinal cord and forms a protein assembly with the X-linked inhibitor of apoptosis protein (XIAP). Moderate cervical contusive SCI induced processing of IL-1beta, IL-18, activation of caspase-1, cleavage of XIAP, and promoted assembly of the multiprotein complex. Anti-ASC neutralizing antibodies administered to injured rats entered spinal cord neurons via a mechanism that was sensitive to carbenoxolone. Therapeutic neutralization of ASC reduced caspase-1 activation, XIAP cleavage, and interleukin processing, resulting in significant tissue sparing and functional improvement. Thus, rat spinal cord neurons contain a caspase-1, pro-ILbeta, and pro-IL-18 activating complex different from the human NALP1 inflammasome that constitutes an important arm of the innate CNS inflammatory response after SCI.
Lukovic, Dunja; Moreno-Manzano, Victoria; Lopez-Mocholi, Eric; Rodriguez-Jiménez, Francisco Javier; Jendelova, Pavla; Sykova, Eva; Oria, Marc; Stojkovic, Miodrag; Erceg, Slaven
Spinal cord injury (SCI) results in neural loss and consequently motor and sensory impairment below the injury. There are currently no effective therapies for the treatment of traumatic SCI in humans. Various animal models have been developed to mimic human SCI. Widely used animal models of SCI are complete or partial transection or experimental contusion and compression, with both bearing controversy as to which one more appropriately reproduces the human SCI functional consequences. Here we present in details the widely used procedure of complete spinal cord transection as a faithful animal model to investigate neural and functional repair of the damaged tissue by exogenous human transplanted cells. This injury model offers the advantage of complete damage to a spinal cord at a defined place and time, is relatively simple to standardize and is highly reproducible. PMID:25860664
Moon, Lawrence D. F.
Extensive research is ongoing that concentrates on finding therapies to enhance CNS regeneration after spinal cord injury (SCI) and to cure paralysis. This review sheds light on the role of the FGFR pathway in the injured spinal cord and discusses various therapies that use FGFR activating ligands to promote regeneration after SCI. We discuss studies that use peripheral nerve grafts or Schwann cell grafts in combination with FGF1 or FGF2 supplementation. Most of these studies show evidence that these therapies successfully enhance axon regeneration into the graft. Further they provide evidence for partial recovery of sensory function shown by electrophysiology and motor activity evidenced by behavioural data. We also present one study that indicates that combination with additional, synergistic factors might further drive the system towards functional regeneration. In essence, this review summarises the potential of nerve and cell grafts combined with FGF1/2 supplementation to improve outcome even after severe spinal cord injury. PMID:28197342
Seiko, Yasuda; Kozo, Ishikawa; Yoshihiro, Matsumoto; Toru, Ariyoshi; Hironori, Sasaki; Yuika, Ida; Yasutake, Iwanaga; Hae-Kyu, Kim; Osamu, Nakanishi; Toshizo, Ishikawa
Aims. Hyperalgesia following tissue injury is induced by plasticity in neurotransmission. Few investigators have considered the ascending input which activates the superficial of spinal cord. The aim was to examine neurotransmission and nociceptive processing in the spinal cord after mustard-oil (MO) injection. Both in vitro and in vivo autoradiographs were employed for neuronal activity and transmission in discrete spinal cord regions using the (14)C-2-deoxyglucose method and (3)H-phorbol 12,13-dibutyrate ((3)H-PDBu) binding sites. Methods. To quantify the hyperalgesia evoked by MO, the flinching was counted for 60 min after MO (20%, 50 μL) injection in Wistar rats. Simultaneous determination of (14)C-2-deoxyglucose and (3)H-PDBu binding was used for a direct observation of neuronal/metabolic changes and intracellular signaling in the spinal cord. Results. MO injection evoked an increase in flinching for 60 min. LSCGU significantly increased in the Rexed I-II with (3)H-PDBu binding in the ipsilateral side of spinal cord. Discussion. We clearly demonstrated that the hyperalgesia is primarily relevant to increased neuronal activation with PKC activation in the Rexed I-II of the spinal cord. In addition, functional changes such as "neuronal plasticity" may result in increased neuronal excitability and a central sensitization.
Seiko, Yasuda; Kozo, Ishikawa; Yoshihiro, Matsumoto; Toru, Ariyoshi; Hironori, Sasaki; Yuika, Ida; Yasutake, Iwanaga; Hae-Kyu, Kim; Osamu, Nakanishi; Toshizo, Ishikawa
Aims. Hyperalgesia following tissue injury is induced by plasticity in neurotransmission. Few investigators have considered the ascending input which activates the superficial of spinal cord. The aim was to examine neurotransmission and nociceptive processing in the spinal cord after mustard-oil (MO) injection. Both in vitro and in vivo autoradiographs were employed for neuronal activity and transmission in discrete spinal cord regions using the 14C-2-deoxyglucose method and 3H-phorbol 12,13-dibutyrate (3H-PDBu) binding sites. Methods. To quantify the hyperalgesia evoked by MO, the flinching was counted for 60 min after MO (20%, 50 μL) injection in Wistar rats. Simultaneous determination of 14C-2-deoxyglucose and 3H-PDBu binding was used for a direct observation of neuronal/metabolic changes and intracellular signaling in the spinal cord. Results. MO injection evoked an increase in flinching for 60 min. LSCGU significantly increased in the Rexed I-II with 3H-PDBu binding in the ipsilateral side of spinal cord. Discussion. We clearly demonstrated that the hyperalgesia is primarily relevant to increased neuronal activation with PKC activation in the Rexed I-II of the spinal cord. In addition, functional changes such as “neuronal plasticity” may result in increased neuronal excitability and a central sensitization. PMID:27335874
Jutzeler, Catherine R.; Huber, Eveline; Callaghan, Martina F.; Luechinger, Roger; Curt, Armin; Kramer, John L. K.; Freund, Patrick
Traumatic spinal cord injury (SCI) has been shown to trigger structural atrophic changes within the spinal cord and brain. However, the relationship between structural changes and magnitude of neuropathic pain (NP) remains incompletely understood. Voxel-wise analysis of anatomical magnetic resonance imaging data provided information on cross-sectional cervical cord area and volumetric brain changes in 30 individuals with chronic traumatic SCI and 31 healthy controls. Participants were clinically assessed including neurological examination and pain questionnaire. Compared to controls, individuals with SCI exhibited decreased cord area, reduced grey matter (GM) volumes in anterior cingulate cortex (ACC), left insula, left secondary somatosensory cortex, bilateral thalamus, and decreased white matter volumes in pyramids and left internal capsule. The presence of NP was related with smaller cord area, increased GM in left ACC and right M1, and decreased GM in right primary somatosensory cortex and thalamus. Greater GM volume in M1 was associated with amount of NP. Below-level NP-associated structural changes in the spinal cord and brain can be discerned from trauma-induced consequences of SCI. The directionality of these relationships reveals specific changes across the neuroaxis (i.e., atrophic changes versus increases in volume) and may provide substrates of underlying neural mechanisms in the development of NP. PMID:26732942
Holly, Langston T.; Blaskiewicz, Donald; Wu, Aiguo; Feng, Cameron; Ying, Zhe; Gomez-Pinilla, Fernando
Object The pathogenesis of cervical spondylotic myelopathy (CSM) is related to both primary mechanical and secondary biological injury. The authors of this study explored a novel, noninvasive method of promoting neuroprotection in myelopathy by using curcumin to minimize oxidative cellular injury and the capacity of omega-3 fatty acids to support membrane structure and improve neurotransmission. Methods An animal model of CSM was created using a nonresorbable expandable polymer placed in the thoracic epidural space, which induced delayed myelopathy. Animals that underwent placement of the expandable polymer were exposed to either a diet rich in docosahexaenoic acid and curcumin (DHA-Cur) or a standard Western diet (WD). Twenty-seven animals underwent serial gait testing, and spinal cord molecular assessments were performed after the 6-week study period. Results At the conclusion of the study period, gait analysis revealed significantly worse function in the WD group than in the DHA-Cur group. Levels of brain-derived neurotrophic factor (BDNF), syntaxin-3, and 4-hydroxynonenal (4-HNE) were measured in the thoracic region affected by compression and lumbar enlargement. Results showed that BDNF levels in the DHA-Cur group were not significantly different from those in the intact animals but were significantly greater than in the WD group. Significantly higher lumbar enlargement syntaxin-3 in the DHA-Cur animals combined with a reduction in lipid peroxidation (4-HNE) indicated a possible healing effect on the plasma membrane. Conclusions Data in this study demonstrated that DHA-Cur can promote spinal cord neuroprotection and neutralize the clinical and biochemical effects of myelopathy. PMID:22735048
Liang, H; Bácskai, T; Paxinos, G
The present study investigated the vestibulospinal system which originates from the spinal vestibular nucleus (SpVe) with both retrograde and anterograde tracer injections. We found that fluoro-gold (FG) labeled neurons were found bilaterally with a contralateral predominance after FG injections into the upper lumbar cord. Anterogradely labeled fibers from the rostral SpVe traveled in the medial part of the ventral funiculus ipsilaterally and the dorsolateral funiculus bilaterally in the cervical cord. They mainly terminated in laminae 5-8, and 10 of the ipsilateral spinal cord. The contralateral side had fewer fibers and they were found in laminae 6-8, and 10. In the thoracic cord, fibers were also found to terminate in bilateral intermediolateral columns. In the lumbar and lower cord, fibers were mainly found in the dorsolateral funiculus bilaterally and they terminated predominantly in laminae 3-7 contralaterally. Anterogradely labeled fibers from the caudal SpVe did not travel in the medial part of the ventral funiculus but in the dorsolateral funiculus bilaterally. They mainly terminated in laminae 3-8 and 10 contralaterally. The present study is the first to describe the termination of vestibulospinal fibers arising from the SpVe in the spinal cord. It will lay the anatomical foundation for those who investigate the physiological role of vestibulospinal fibers and potentially target these fibers during rehabilitation after stroke, spinal cord injury, or vestibular organ injury.
Ding, Wen-Ge; Yan, Wei-hong; Wei, Zhao-Xiang; Liu, Jin-Bo
In the present study, we examined intraosseous blood vessel parameters of the tibial metaphysis in mice using microcomputed tomography (µCT) to investigate the relationship between post-nerve-injury osteoporosis and local intraosseous blood vessel volume and number. Mice were randomly divided into groups receiving spinal cord injury (SCI), sciatic nerve resection group (NX), or intact controls (30 mice/group). Four weeks after surgery, mice were perfused with silicone and the distribution of intraosseous blood vessels analyzed by μCT. The bone density, μCT microstructure, biomechanical properties, and the immunohistochemical and biochemical indicators of angiogenesis were also measured. The SCI group showed significantly reduced tibial metaphysis bone density, μCT bone microstructure, tibial biomechanical properties, indicators of angiogenesis, and intraosseous blood vessel parameters compared to the NX group. Furthermore, the spinal cord-injured mice exhibited significantly decreased intraosseous blood vessel volume and number during the development of osteoporosis. In conclusion, these data suggest that decreased intraosseous blood vessel volume and number may play an important role in the development of post-nerve-injury osteoporosis.
Laing, Andrew C; Brenneman, Elora C; Yung, Andrew; Liu, Jie; Kozlowski, Piotr; Oxland, Thomas
Rat models are commonly used to investigate the pathophysiological pathways and treatment outcomes after spinal cord injury (SCI). The high incidence of fall-induced SCI in older adults has created a need for aging models of SCI in rats to investigate potential age-related differences in SCI severity and outcomes. The aims of this study were to determine the influences of age and vertebral level on the geometries of the cervical spinal cord and spinal column in a rat model. Three young (3 months) and three aged (12 months) Fischer 344 rats were imaged in a high field (7 T) small-animal magnetic resonance imaging system. All spinal cord geometry variables (including depth, width, and axial cross-sectional area) and one spinal canal variable (depth) were significantly larger in the aged specimens by an average of 8.1%. There were main effects of vertebral level on all spinal cord variables and four spinal canal variables with values generally larger at C4 as compared to C6 (average increases ranged from 5.7% to 12.9% in spinal cord measures and 5.4% to 6.8% in spinal canal measures). High inter-rater reliability between two measurers was observed with a mean intraclass correlation of 0.921 and percent difference of 0.9% across all variables measured. This study clearly demonstrates that cervical spinal cord geometry changes between the ages of 3 and 12 months in Fischer 344 rats. This information can aid in the planning and interpretation of studies that use a rat model to investigate the influence of age on cervical SCI.
Holoye, P.; Libnoch, J.; Cox, J.; Kun, L.; Byhardt, R.; Almagro, U.; McCelland, S.; Chintapali, K.
Among 50 patients with small cell bronchogenic carcinoma who were placed on a protocol of combined chemotherapy and radiation therapy, seven patients developed recurrence in the spinal cord. Five cases terminated in paraplegia and death. One patient with pontine recurrence recovered with local radiation therapy. One patient, diagnosed early, responded to local radiation therapy and is ambulatory. Methods of diagnosis were myelogram, computerized axial tomography, cerebro spinal fluid, chemistry and cytologies. The poor prognosis and the difficulty of diagnosis suggest that prophylactic therapy of the entire cranio-spinal axis should be evaluated.
Antinociception induced by intravenous dipyrone (metamizol) upon dorsal horn neurons: involvement of endogenous opioids at the periaqueductal gray matter, the nucleus raphe magnus, and the spinal cord in rats.
Vazquez, Enrique; Hernandez, Norma; Escobar, William; Vanegas, Horacio
Microinjection of dipyrone (metamizol) into the periaqueductal gray matter (PAG) in rats causes antinociception. This is mediated by endogenous opioidergic circuits located in the PAG itself, in the nucleus raphe magnus and adjacent structures, and in the spinal cord. The clinical relevance of these findings, however, is unclear. Therefore, in the present study, dipyrone was administered intravenously, and the involvement of endogenous opioidergic circuits in the so-induced antinociception was investigated. In rats, responses of dorsal spinal wide-dynamic range neurons to mechanical noxious stimulation of a hindpaw were strongly inhibited by intravenous dipyrone (200 mg/kg). This effect was abolished by microinjection of naloxone (0.5 microg/0.5 microl) into the ventrolateral and lateral PAG or into the nucleus raphe magnus or by direct application of naloxone (50 microg/50 microl) onto the spinal cord surface above the recorded neuron. These results show that dipyrone, a non-opioid analgesic with widespread use in Europe and Latin America, when administered in a clinically relevant fashion causes antinociception by activating endogenous opioidergic circuits along the descending pain control system.
Abstract The objective of the study was to determine whether physical exercise combined with epidural spinal cord magnetic stimulation could improve recovery after injury of the spinal cord. Spinal cord lesioning in mice resulted in reduced locomotor function and negatively affected the muscle strength tested in vitro. Acrobatic exercise attenuated the behavioral effects of spinal cord injury. The exposure to magnetic fields facilitated further this improvement. The progress in behavioral recovery was correlated with reduced muscle degeneration and enhanced muscle contraction. The acrobatic exercise combined with stimulation with magnetic fields significantly facilitates behavioral recovery and muscle physiology in mice following spinal cord injury. PMID:18986227
Shelyakin, A M; Preobrazhenskaya, I G; Komantsev, V N; Makarovskii, A N; Bogdanov, O V
Transdermal micropolarization of the spinal cord was performed in patients suffering sequelae of spinal cord trauma and tuberculous spondylitis. Changes in clinical and electrophysiological status were monitored. These studies demonstrated that the use of local direct currents passed via skin electrodes promoted improvements in motor and autonomic functions in these patients, leading to positive changes in measures of the functional state of the spinal cord and heart activity. The possible mechanisms of the action of direct currents acting on the spinal cord are discussed, along with the potential for applying micropolarization in the treatment of spinal cord lesions.
Bolshakov, I. N.; Sergienko, V. I.; Kiselev, S. L.; Lagarkova, M. A.; Remigaylo, A. A.; Mihaylov, A. A.; Prokopenko, S. V.
In the treatment of patients with complicated spinal cord injury the Russian Health spends about one million rubles for each patient in the acute and the interim period after the injury. The number of complicated spinal cord injury is different in geographical areas Russian Federation from 30 to 50 people per 1 million that is affected by the year 5600. Applied to the present surgical and pharmacological techniques provide unsatisfactory results or minimally effective treatment. Transplantation of 100 thousand neuronal mouse predecessors (24 rats) or human neuronal predecessors (18 rats) in the anatomical gap rat spinal cord, followed by analysis of neurological deficit. The neuro-matrix implantation in the rat spinal cord containing 100 thousand neuronal precursors hESC, repeatable control neuro-matrix transplantation, non-cell mass, eliminating neurological deficit for 14 weeks after transplantation about 5-9 points on the scale of the BBB. The cultivation under conditions in vitro human induced pluripotent stem cells on collagen-chitosan matrix (hIPSC) showed that neurons differentiated from induced pluripotent stem cells grown on scaffolds as compact groups and has no neurites. Cells do not penetrate into the matrix during long-term cultivation and formed near the surface of the spherical structures resembling neurospheres. At least 90% of the cells were positive for the neuronal marker tubulin b3. Further studies should be performed to examine the compatibility of neuronal cultures and matrices.
Chen, Suliang; Phang, Isaac; Zoumprouli, Argyro; Papadopoulos, Marios C; Saadoun, Samira
The management of patients having traumatic spinal cord injury would benefit from understanding and monitoring of spinal cord metabolic states. We hypothesized that the metabolism of the injured spinal cord could be visualized using Kohonen self-organizing maps. Sixteen patients with acute, severe spinal cord injuries were studied. Starting within 72 h of the injury, and for up to a week, we monitored the injury site hourly for tissue glucose, lactate, pyruvate, glutamate, and glycerol using microdialysis as well as intraspinal pressure and spinal cord perfusion pressure. A Kohonen map, which is an unsupervised, self-organizing topology-preserving neural network, was used to analyze 3366 h of monitoring data. We first visualized the different spinal cord metabolic states. Our data show that the injured cord assumes one or more of four metabolic states. On the basis of their metabolite profiles, we termed these states near-normal, ischemic, hypermetabolic, and distal. We then visualized how patients' intraspinal pressure and spinal cord perfusion pressure affect spinal cord metabolism. This revealed that for more than 60% of the time, spinal cord metabolism is patient-specific; periods of high intraspinal pressure or low perfusion pressure are not associated with specific spinal cord metabolic patterns. Finally, we determined relationships between spinal cord metabolism and neurological status. Patients with complete deficits have shorter periods of near-normal spinal cord metabolic states (7 ± 4% vs. 58 ± 12%, p < 0.01, mean ± standard error) and more variable injury site metabolic responses (metabolism spread in 70 ± 11 vs. 40 ± 6 hexagons, p < 0.05), compared with patients who have incomplete neurological deficits. We conclude that Kohonen maps allow us to visualize the metabolic responses of the injured spinal cord and may thus aid us in treating patients with acute spinal cord injuries.
Garbuzova-Davis, Svitlana; Hernandez-Ontiveros, Diana G; Rodrigues, Maria C O; Haller, Edward; Frisina-Deyo, Aric; Mirtyl, Santhia; Sallot, Sebastian; Saporta, Samuel; Borlongan, Cesario V; Sanberg, Paul R
Vascular pathology, including blood-brain/spinal cord barrier (BBB/BSCB) alterations, has recently been recognized as a key factor possibly aggravating motor neuron damage, identifying a neurovascular disease signature for ALS. However, BBB/BSCB competence in sporadic ALS (SALS) is still undetermined. In this study, BBB/BSCB integrity in postmortem gray and white matter of medulla and spinal cord tissue from SALS patients and controls was investigated. Major findings include (1) endothelial cell damage and pericyte degeneration, (2) severe intra- and extracellular edema, (3) reduced CD31 and CD105 expressions in endothelium, (4) significant accumulation of perivascular collagen IV, and fibrin deposits (5) significantly increased microvascular density in lumbar spinal cord, (6) IgG microvascular leakage, (7) reduced tight junction and adhesion protein expressions. Microvascular barrier abnormalities determined in gray and white matter of the medulla, cervical, and lumbar spinal cord of SALS patients are novel findings. Pervasive barrier damage discovered in ALS may have implications for disease pathogenesis and progression, as well as for uncovering novel therapeutic targets.
Cook, G; Sharp, R A
Extramedullary haemopoiesis resulting in spinal cord compression is rare. This report of extramedullary myeloid metaplasia in a patient with myelofibrosis serves to illustrate the value of magnetic resonance imaging (MRI) in the diagnosis and management of good neurological recovery. Images PMID:8027402
Hawthorne, Alicia L; Popovich, Phillip G
Traumatic spinal cord injury (SCI) affects the activation, migration, and function of microglia, neutrophils and monocyte/macrophages. Because these myeloid cells can positively and negatively affect survival of neurons and glia, they are among the most commonly studied immune cells. However, the mechanisms that regulate myeloid cell activation and recruitment after SCI have not been adequately defined. In general, the dynamics and composition of myeloid cell recruitment to the injured spinal cord are consistent between mammalian species; only the onset, duration, and magnitude of the response vary. Emerging data, mostly from rat and mouse SCI models, indicate that resident and recruited myeloid cells are derived from multiple sources, including the yolk sac during development and the bone marrow and spleen in adulthood. After SCI, a complex array of chemokines and cytokines regulate myelopoiesis and intraspinal trafficking of myeloid cells. As these cells accumulate in the injured spinal cord, the collective actions of diverse cues in the lesion environment help to create an inflammatory response marked by tremendous phenotypic and functional heterogeneity. Indeed, it is difficult to attribute specific reparative or injurious functions to one or more myeloid cells because of convergence of cell function and difficulties in using specific molecular markers to distinguish between subsets of myeloid cell populations. Here we review each of these concepts and include a discussion of future challenges that will need to be overcome to develop newer and improved immune modulatory therapies for the injured brain or spinal cord.
Watson, Charles; Sengul, Gulgun; Tanaka, Ikuko; Rusznak, Zoltan; Tokuno, Hironobu
The marmoset spinal cord possesses all the characteristic features of a typical mammalian spinal cord, but with some interesting variation in the levels of origin of the limb nerves. In our study Nissl and ChAT sections of the each segment of the spinal cord in two marmosets (Ma5 and Ma8), we found that the spinal cord can be functionally and anatomically divided into six regions: the prebrachial region (C1 to C3); the brachial region (C4 to C8) - segments supplying the upper limb; the post-brachial region (T1 to L1) - containing the sympathetic outflow, and supplying the hypaxial muscles of the body wall; the crural region (L2 to L5) - segments supplying the lower limb; the postcrural region (L6) - containing the parasympathetic outflow; and the caudal region (L7 to Co4) - supplying the tail. In the rat, mouse, and rhesus monkey, the prebrachial region consists of segments C1 to C4 (with the phrenic nucleus located at the C4 segment), and the brachial region extends from C5 to T1 inclusive. The prefixing of the upper limb outflow in these two marmosets mirrors the finding in the literature that a large C4 contribution to the brachial plexus is common in humans.
Heinemann, Allen; And Others
Hope has motivational importance to individuals who have suffered a major physical loss. Theories of adjustment to a spinal cord injury take one of three approaches: (1) premorbid personality, which highlights the individual's past experiences, personal meanings, and body image; (2) typologies of injury reactions, which range from normal to…
Cariga, P; Catley, M; Mathias, C; Savic, G; Frankel, H; Ellaway, P
Objectives: The sympathetic skin response (SSR) is a technique to assess the sympathetic cholinergic pathways, and it can be used to study the central sympathetic pathways in spinal cord injury (SCI). This study investigated the capacity of the isolated spinal cord to generate an SSR, and determined the relation between SSR, levels of spinal cord lesion, and supraspinal connections. Methods: Palmar and plantar SSR to peripheral nerve electrical stimulation (median or supraorbital nerve above the lesion, and peroneal nerve below the lesion) were recorded in 29 patients with SCI at various neurological levels and in 10 healthy control subjects. Results: In complete SCI at any neurological level, SSR was absent below the lesion. Palmar SSR to median nerve stimuli was absent in complete SCI with level of lesion above T6. Plantar SSR was absent in all patients with complete SCI at the cervical and thoracic level. In incomplete SCI, the occurrence of SSR was dependent on the preservation of supraspinal connections. For all stimulated nerves, there was no difference between recording from ipsilateral and contralateral limbs. Conclusions: No evidence was found to support the hypothesis that the spinal cord isolated from the brain stem could generate an SSR. The results indicate that supraspinal connections are necessary for the SSR, together with integrity of central sympathetic pathways of the upper thoracic segments for palmar SSR, and possibly all thoracic segments for plantar SSR. PMID:11861696
Ishii, Ken; Nakamura, Masaya
Intramedullary spinal cord cavernous hemangiomas (angiomas) are occult vascular malformations characterized by rare lesions consisting of closely packed capillary-like vessels. In general, patients with this disease become symptomatic because of hemorrhage leads to progressive neurological deficits. Therefore, surgical tumor resection should be considered for symptomatic patients should be considered a surgical tumor resection.
O'Donovan, Michael J; Bonnot, Agnès; Wenner, Peter; Mentis, George Z
We have used calcium imaging to visualize the spatiotemporal organization of activity generated by in vitro spinal cord preparations of the developing chick embryo and the neonatal mouse. During each episode of spontaneous activity, we found that chick spinal neurons were activated rhythmically and synchronously throughout the transverse extent of the spinal cord. At the onset of a spontaneous episode, optical activity originated in the ventrolateral part of the cord. Back-labeling of spinal interneurons with calcium dyes suggested that this ventrolateral initiation was mediated by activation of a class of interneurons, located dorsomedial to the motor nucleus, that receive direct monosynaptic input from motoneurons. Studies of locomotor-like activity in the anterior lumbar segments of the neonatal mouse cord revealed the existence of a rostrocaudal wave in the oscillatory component of each cycle of rhythmic motoneuron activity. This finding raises the possibility that the activation of mammalian motoneurons during locomotion may share some of the same rostrocaudally organized mechanisms that evolved to control swimming in fishes.
Heinemann, Allen W.; And Others
Substance use histories were obtained from 103 persons (16 to 63 years of age) with recent spinal cord injuries (SCI). Lifetime exposure to and current use of substances with abuse potential were substantially greater in this sample compared to a like-age national sample. Exposure to and recent use of substances with abuse potential was…
Krause, James S.; Saunders, Lee; Staten, David
The objective of this article was to identify the relationship between race-ethnicity and employment after spinal cord injury (SCI), while evaluating interrelationships with gender, injury severity, and education. The authors used a cohort design using the most current status from a post-injury interview from the National SCI Statistical Center.…
Gurcay, Eda; Bal, Ajda; Eksioglu, Emel; Cakci, Aytul
The primary objective of this study was to assess the quality of life (QoL) in spinal cord injury (SCI) survivors. Secondary objectives were to determine the effects of various sociodemographic and clinical characteristics on QoL. This cross-sectional study included 54 patients with SCI. The Turkish version of the Short-Form-36 Health Survey was…
Anson, C. A.; Shepherd, C.
Data from 348 patients (mean age 37) with postacute spinal cord injury revealed that 95% reported at least 1 secondary problem, and 58% reported 3 or more. The number and severity of complications varied with time since the injury. Obesity, pain, spasticity, urinary tract infections, pressure sores, and lack of social integration were common…
monoclonal NG2-Antibody delivered via osmotic mini- pump can neutralize NG2-induced blockade of axonal conduction, in addition to improving axonal...Project is completed: (1) Proved that delivery of NG2-Ab via mini- pump improves plasticity, axonal conduction, retrograde transport of anatomical...osmotic mini- pump following lateral hemisection (HX) SCI, as described in our SOW. During year 3 we have completed most of research tasks for year 3
Saghaei, Elham; Abbaszadeh, Fatemeh; Naseri, Kobra; Ghorbanpoor, Samar; Afhami, Mina; Haeri, Ali; Rahimi, Farzaneh; Jorjani, Masoumeh
In our previous study we showed that central pain syndrome (CPS) induced by electrolytic injury caused in the unilateral spinothalamic tract (STT) is a concomitant of glial alteration at the site of injury. Here, we investigated the activity of glial cells in thalamic ventral posterolateral nuclei (VPL) and their contribution to CPS. We also examined whether post-injury administration of a pharmacological dose of estradiol can attenuate CPS and associated molecular changes. Based on the results,in the ipsilateral VPL the microglial phenotype switched o hyperactive mode and Iba1 expression was increased significantly on days 21 and 28 post-injury. The same feature was observed in contralateral VPL on day 28 (P<.05). These changes were strongly correlated with the onset of CPS (r(2)=0.670). STT injury did not induce significant astroglial response in both ipsilateral and contralateral VPL. Estradiol attenuated bilateral mechanical hypersensitivity 14 days after STT lesion (P<.05). Estradiol also suppressed microglial activation in the VPL. Taken together, these findings indicate that selective STT lesion induces bilateral microglia activation in VPL which might contribute to mechanical hypersensitivity. Furthermore, a pharmacological dose of estradiol reduces central pain possibly via suppression of glial activity in VPL region.
Sabapathy, Vikram; Tharion, George; Kumar, Sanjay
The spinal cord injury leads to enervation of normal tissue homeostasis ultimately leading to paralysis. Until now there is no proper cure for the treatment of spinal cord injury. Recently, cell therapy in animal spinal cord injury models has shown some progress of recovery. At present, clinical trials are under progress to evaluate the efficacy of cell transplantation for the treatment of spinal cord injury. Different types of cells such as pluripotent stem cells derived neural cells, mesenchymal stromal cells, neural stem cells, glial cells are being tested in various spinal cord injury models. In this review we highlight both the advances and lacuna in the field of spinal cord injury by discussing epidemiology, pathophysiology, molecular mechanism, and various cell therapy strategies employed in preclinical and clinical injury models and finally we discuss the limitations and ethical issues involved in cell therapy approach for treating spinal cord injury. PMID:26240569
Strand, Nicholas S; Hoi, Kimberly K; Phan, Tien M T; Ray, Catherine A; Berndt, Jason D; Moon, Randall T
Unlike mammals, zebrafish can regenerate their injured spinal cord and regain control of caudal tissues. It was recently shown that Wnt/β-catenin signaling is necessary for spinal cord regeneration in the larval zebrafish. However, the molecular mechanisms of regeneration may or may not be conserved between larval and adult zebrafish. To test this, we assessed the role of Wnt/β-catenin signaling after spinal cord injury in the adult zebrafish. We show that Wnt/β-catenin signaling is increased after spinal cord injury in the adult zebrafish. Moreover, overexpression of Dkk1b inhibited Wnt/β-catenin signaling in the regenerating spinal cord of adult zebrafish. Dkk1b overexpression also inhibited locomotor recovery, axon regeneration, and glial bridge formation in the injured spinal cord. Thus, our data illustrate a conserved role for Wnt/β-catenin signaling in adult and larval zebrafish spinal cord regeneration.
Wang, Zhong-liang; Du, Ting-ting; Zhang, Rui-guang
In patients with advanced cancer, cancer-induced bone pain (CIBP) is a severe and common problem that is difficult to manage and explain. As c-Jun N-terminal kinase (JNK) and chemokine (C-X-C motif) ligand 1 (CXCL1) have been shown to participate in several chronic pain processes, we investigated the role of JNK and CXCL1 in CIBP and the relationship between them. A rat bone cancer pain model was established by intramedullary injection of Walker 256 rat gland mammary carcinoma cells into the left tibia of Sprague-Dawley rats. As a result, intramedullary injection of Walker 256 carcinoma cells induced significant bone destruction and persistent pain. Both phosphorylated JNK1 (pJNK1) and pJNK2 showed time-dependent increases in the ipsilateral spinal cord from day 7 to day 18 after tumor injection. Inhibition of JNK activation by intrathecal administration of SP600125, a selective pJNK inhibitor, attenuated mechanical allodynia and heat hyperalgesia caused by tumor inoculation. Tumor cell inoculation also induced robust CXCL1 upregulation in the ipsilateral spinal cord on day 18 after tumor injection. Inhibition of CXCL1 by intrathecal administration of CXCL1 neutralizing antibody showed a stable analgesic effect. Intrathecal administration of SP600125 reduced CXCL1 increase in the spinal cord, whereas inhibition of CXCL1 in the spinal cord showed no influence on JNK activation. Taken together, these results suggested that JNK activation in spinal cord contributed to the maintenance of CIBP, which may act through modulation of CXCL1. Inhibition of the pJNK/CXCL1 pathway may provide a new choice for treatment of CIBP.
Cogiamanian, Filippo; Vergari, Maurizio; Schiaffi, Elena; Marceglia, Sara; Ardolino, Gianluca; Barbieri, Sergio; Priori, Alberto
Aiming at developing a new, noninvasive approach to spinal cord neuromodulation, we evaluated whether transcutaneous direct current (DC) stimulation induces long-lasting changes in the central pain pathways in human beings. A double-blind crossover design was used to investigate the effects of anodal direct current (2mA, 15min) applied on the skin overlying the thoracic spinal cord on the lower-limb flexion reflex in a group of 11 healthy volunteers. To investigate whether transcutaneous spinal cord DC stimulation (tsDCS) acts indirectly on the nociceptive reflex by modulating excitability in mono-oligosynaptic segmental reflex pathways, we also evaluated the H-reflex size from soleus muscle after tibial nerve stimulation. In our healthy subjects, anodal thoracic tsDCS reduced the total lower-limb flexion reflex area by 40.25% immediately after stimulation (T0) and by 46.9% 30min after stimulation offset (T30). When we analyzed the 2 lower-limb flexion reflex components (RII tactile and RIII nociceptive) separately, we found that anodal tsDCS induced a significant reduction in RIII area with a slight but not significant effect on RII area. After anodal tsDCS, the RIII area decreased by 27% at T0 and by 28% at T30. Both sham and active tsDCS left all the tested H-reflex variables unchanged. None of our subjects reported adverse effects after active stimulation. These results suggest that tsDCS holds promise as a tool that is complementary or alternative to drugs and invasive spinal cord electrical stimulation for managing pain. Thoracic transcutaneous direct current stimulation induces depression of nociceptive lower limb flexion reflex in human beings that persists after stimulation offset; this form of stimulation holds promise as a tool that is complementary or alternative to drugs and invasive spinal cord electrical stimulation for managing pain.
Hubli, Michèle; Krassioukov, Andrei V
Trauma to the spinal cord often results not only in sensorimotor but also autonomic impairments. The loss of autonomic control over the cardiovascular system can cause profound blood pressure (BP) derangements in subjects with spinal cord injury (SCI) and may therefore lead to increased cardiovascular disease (CVD) risk in this population. The use of ambulatory blood pressure monitoring (ABPM) allows insights into circadian BP profiles, which have been shown to be of good prognostic value for cardiovascular morbidity and mortality in able-bodied subjects. Past studies in SCI subjects using ABPM have shown that alterations in circadian BP patterns are dependent on the spinal lesion level. Tetraplegic subjects with sensorimotor complete lesions have a decreased daytime arterial BP, loss of the physiological nocturnal BP dip, and higher circadian BP variability, including potentially life-threatening hypertensive episodes known as autonomic dysreflexia (AD), compared with paraplegic and able-bodied subjects. The proposed underlying mechanisms of these adverse BP alterations mainly are attributed to a lost or decreased central drive to sympathetic spinal preganglionic neurons controlling the heart and blood vessels. In addition, several maladaptive anatomical changes within the spinal cord and the periphery, as well as the general decrease of physical daily activity in SCI subjects, account for adverse BP changes. ABPM enables the identification of adverse BP profiles and the associated increased risk for CVD in SCI subjects. Concurrently, it also might provide a useful clinical tool to monitor improvements of AD and lost nocturnal dip after appropriate treatments in the SCI population.
Whole body /sup 99m/T-pyrophosphate bone scans were obtained and correlated with skeletal radiographs for detection of heterotopic ossification in 135 spinal injury patients. There were 40 patients with recent injury (less than 6 months) and 95 with injury of over 6 months duration. Heterotopic new bone was detected on the bone scan in 33.7% of 95 patients with spinal cord injuries of more than 6 months duration and 30% of 40 patients with injuries of less than 6 months. The radionuclide scan was found to be useful in detection of heterotopic ossification at its early stage and in its differentiation from other complications in spinal cord injury patients.
Schomberg, Dominic T; Miranpuri, Gurwattan S; Chopra, Abhishek; Patel, Kush; Meudt, Jennifer J; Tellez, Armando; Resnick, Daniel K; Shanmuganayagam, Dhanansayan
Spinal cord injury (SCI) is a physically and psychologically devastating clinical condition. The typical treatment regimens of decompressive surgery and rehabilitation therapy still leave many patients with permanent disability. The development of new therapies and devices can be accelerated if relevant translational animal models are more effectively used in pre-clinical stages. Swine is a highly relevant model for SCI research, especially with respect to spine and spinal cord anatomy, spine vasculature, immune responses to injury, and functional assessments. Several spine injury models have recently been developed for swine and are beginning to be used to evaluate new therapies. Swine models of SCI offer tremendous advantages for efficient translation of pre-clinical discoveries and the development of new therapies and devices. Future swine models will also be enhanced by advances in gene-editing technology to further elucidate the complex pathophysiology associated with SCI and provide a means to engineer specific spinal pathologies.
Saxena, Tarun; Gilbert, Jeremy; Stelzner, Dennis; Hasenwinkel, Julie
The glial scar formed at the site of traumatic spinal cord injury (SCI) has been classically hypothesized to be a potent physical and biochemical barrier to nerve regeneration. One longstanding hypothesis is that the scar acts as a physical barrier due to its increased stiffness in comparison to uninjured spinal cord tissue. However, the information regarding the mechanical properties of the glial scar in the current literature is mostly anecdotal and not well quantified. We monitored the mechanical relaxation behavior of injured rat spinal cord tissue at the site of mid-thoracic spinal hemisection 2 weeks and 8 weeks post-injury using a microindentation test method. Elastic moduli were calculated and a modified standard linear model (mSLM) was fit to the data to estimate the relaxation time constant and viscosity. The SLM was modified to account for a spectrum of relaxation times, a phenomenon common to biological tissues, by incorporating a stretched exponential term. Injured tissue exhibited significantly lower stiffness and elastic modulus in comparison to uninjured control tissue, and the results from the model parameters indicated that the relaxation time constant and viscosity of injured tissue were significantly higher than controls. This study presents direct micromechanical measurements of injured spinal cord tissue post-injury. The results of this study show that the injured spinal tissue displays complex viscoelastic behavior, likely indicating changes in tissue permeability and diffusivity.
McColl, M A; Walker, J; Stirling, P; Wilkins, R; Corey, P
While our understanding of aging and mortality in spinal cord injury is evolving, precise estimates are still not available for expectations of life and health following a spinal cord injury. In order to derive these estimates, information about mortality and health must be combined into a single estimate. Health expectancy estimates have been widely used in the literature of the last decade to try to understand the relationship between population health and survival, both in the general population and in special populations. This study brought the benefit of this methodology to the question of long-term survival following spinal cord injury. Specifically, the study aimed to calculate life and health expectancy in a population of spinal cord injured individuals; and to estimate the effect of factors associated with survival and health. The study involved a retrospective cohort, all of whom sustained a spinal cord injury between the ages of 25 and 34 years, and between 1945 and 1990. The study predicted a median survival time of 38 years post-injury, with 43% surviving at least 40 years. These findings suggest an increase in life expectancy of about 5 years over previous research on the same cohort. Factors affecting survival were age at injury, level and completeness of lesion. Expectations of health found in the present study are similar to those found in studies of the general population. This study showed seven remaining years of poor health expected at injury, and five remaining years expected at 40 years post injury, presumably occurring at the end of life.
Schlaeger, Regina; Papinutto, Nico; Panara, Valentina; Bevan, Carolyn; Lobach, Iryna V.; Bucci, Monica; Caverzasi, Eduardo; Gelfand, Jeffrey M.; Green, Ari J.; Jordan, Kesshi M.; Stern, William A.; von Büdingen, H.-Christian; Waubant, Emmanuelle; Zhu, Alyssa H.; Goodin, Douglas S.; Cree, Bruce A. C.; Hauser, Stephen L.; Henry, Roland G.
Objective In multiple sclerosis (MS) cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SCGM atrophy. Using phase sensitive inversion recovery (PSIR) MRI, we determined the association of the SCGM and SCWM areas with MS disability and disease type. Methods 113 MS patients and 20 healthy controls were examined at 3T with a PSIR sequence acquired at the C2/C3 disc level. Two independent, clinically-masked readers measured the cord WM and GM areas. Correlations between cord areas and Expanded Disability Status Score (EDSS) were determined. Differences in areas between groups were assessed with age and sex as covariates. Results Relapsing (R) MS patients showed smaller SCGM areas than age and sex matched controls (p=0.008) without significant differences in SCWM areas. Progressive MS patients showed smaller SCGM and SCWM areas compared to RMS patients (all p≤0.004). SCGM, SCWM, and whole cord areas inversely correlated with EDSS (rho: −0.60, −0.32, −0.42, respectively; all p≤0.001). SCGM area was the strongest correlate of disability in multivariate models including brain GM and WM volumes, FLAIR lesion load, T1-lesion load, SCWM area, number of spinal cord T2 lesions, age, sex, disease duration. Brain and spinal GM independently contributed to EDSS. Interpretation SCGM atrophy is detectable in-vivo in absence of WM atrophy in RMS. It is more pronounced in progressive than RMS and contributes more to patient disability than spinal cord WM or brain GM atrophy. PMID:25087920
Dimitrijević, Mirjana; Kotur-Stevuljević, Jelena; Stojić-Vukanić, Zorica; Vujnović, Ivana; Pilipović, Ivan; Nacka-Aleksić, Mirjana; Leposavić, Gordana
The study examined (a) whether there is sex difference in spinal cord and plasma oxidative stress profiles in Dark Agouti rats immunised for experimental autoimmune encephalomyelitis (EAE), the principal experimental model of multiple sclerosis, and (b) whether there is correlation between the oxidative stress in spinal cord and neurological deficit. Regardless of rat sex, with the disease development xanthine oxidase (XO) activity and inducible nitric oxide synthase (iNOS) mRNA expression increased in spinal cord, whereas glutathione levels decreased. This was accompanied by the rise in spinal cord malondialdehyde level. On the other hand, with EAE development superoxide dismutase (SOD) activity decreased, while O2(-) concentration increased only in spinal cord of male rats. Consequently, SOD activity was lower, whereas O2(-) concentration was higher in spinal cord of male rats with clinically manifested EAE. XO activity and iNOS mRNA expression were also elevated in their spinal cord. Consistently, in the effector phase of EAE the concentration of advanced oxidation protein product (AOPP) was higher in spinal cord of male rats, which exhibit more severe neurological deficit than their female counterparts. In as much as data obtained in the experimental models could be translated to humans, the findings may be relevant for designing sex-specific antioxidant therapeutic strategies. Furthermore, the study indicated that the increased pro-oxidant-antioxidant balance in plasma may be an early indicator of EAE development. Moreover, it showed that plasma AOPP level may indicate not only actual activity of the disease, but also serve to predict severity of its course.
Gómez-Villafuertes, Rosa; Rodríguez-Jiménez, Francisco Javier; Alastrue-Agudo, Ana; Stojkovic, Miodrag; Miras-Portugal, María Teresa; Moreno-Manzano, Victoria
Spinal cord injury (SCI) is a major cause of paralysis with no current therapies. Following SCI, large amounts of ATP and other nucleotides are released by the traumatized tissue leading to the activation of purinergic receptors that, in coordination with growth factors, induce lesion remodeling and repair. We found that adult mammalian ependymal spinal cord-derived stem/progenitor cells (epSPCs) are capable of responding to ATP and other nucleotidic compounds, mainly through the activation of the ionotropic P2X4, P2X7, and the metabotropic P2Y1 and P2Y4 purinergic receptors. A comparative study between epSPCs from healthy rats versus epSPCis, obtained after SCI, shows a downregulation of P2Y1 receptor together with an upregulation of P2Y4 receptor in epSPCis. Moreover, spinal cord after severe traumatic contusion shows early and persistent increases in the expression of P2X4 and P2X7 receptors around the injury, which are completely reversed when epSPCis were ectopically transplanted. Since epSPCi transplantation significantly rescues neurological function after SCI in parallel to inhibition of the induced P2 ionotropic receptors, a potential avenue is open for therapeutic alternatives in SCI treatments based on purinergic receptors and the endogenous reparative modulation.
... the standard ASIA (American Spinal Injury Association) Impairment Scale for this diagnosis. X-rays, MRIs, or more ... entire length of the spine. The ASIA Impairment Scale has five classification levels, ranging from complete loss ...
Yu, Shukui; Yao, Shenglian; Wen, Yujun; Wang, Ying; Wang, Hao; Xu, Qunyuan
This study examined sustained co-delivery of vascular endothelial growth factor (VEGF), angiopoietin-1 and basic fibroblast growth factor (bFGF) encapsulated in angiogenic microspheres. These spheres were delivered to sites of spinal cord contusion injury in rats, and their ability to induce vessel formation, neural regeneration and improve hindlimb motor function was assessed. At 2–8 weeks after spinal cord injury, ELISA-determined levels of VEGF, angiopoietin-1, and bFGF were significantly higher in spinal cord tissues in rats that received angiogenic microspheres than in those that received empty microspheres. Sites of injury in animals that received angiogenic microspheres also contained greater numbers of isolectin B4-binding vessels and cells positive for nestin or β III-tubulin (P < 0.01), significantly more NF-positive and serotonergic fibers, and more MBP-positive mature oligodendrocytes. Animals receiving angiogenic microspheres also suffered significantly less loss of white matter volume. At 10 weeks after injury, open field tests showed that animals that received angiogenic microspheres scored significantly higher on the Basso-Beattie-Bresnahan scale than control animals (P < 0.01). Our results suggest that biodegradable, biocompatible PLGA microspheres can release angiogenic factors in a sustained fashion into sites of spinal cord injury and markedly stimulate angiogenesis and neurogenesis, accelerating recovery of neurologic function. PMID:27641997
Cloud, Beth A.; Ball, Bret G.; Chen, Bingkun; Knight, Andrew M.; Hakim, Jeffrey S.; Ortiz, Ana M.; Windebank, Anthony J.
Techniques used to produce partial spinal cord injuries in animal models have the potential for creating variability in lesions. The amount of tissue affected may influence the functional outcomes assessed in the animals. The recording of somatosensory evoked potentials (SSEPs) may be a valuable tool for assessing the extent of lesion applied in animal models of traumatic spinal cord injury (SCI). Intraoperative tibial SSEP recordings were assessed during surgically induced lateral thoracic hemisection SCI in Sprague-Dawley rats. The transmission of SSEPs, or lack thereof, was determined and compared against the integrity of the dosal funiculi on each side of the spinal cord upon histological sectioning. An association was found between the presence of an SSEP signal and presence of intact dorsal funiculus tissue. The relative risk is 4.50 (95% confidence interval: 1.83 to 11.08) for having an intact dorsal funiculus when the ipsilateral SSEP was present compared to when it was absent. Additionally, the amount of spared spinal cord tissue correlates with final functional assessments at nine weeks post injury: BBB (linear regression, R2 = 0.618, p <0.001) and treadmill test (linear regression, R2 = 0.369, p = 0.016). Therefore, we propose intraoperative SSEP monitoring as a valuable tool to assess extent of lesion and reduce variability between animals in experimental studies of SCI. PMID:22960163
Humanes-Valera, Desire; Aguilar, Juan; Foffani, Guglielmo
Sensory deafferentation produces extensive reorganization of the corresponding deafferented cortex. Little is known, however, about the role of the adjacent intact cortex in this reorganization. Here we show that a complete thoracic transection of the spinal cord immediately increases the responses of the intact forepaw cortex to forepaw stimuli (above the level of the lesion) in anesthetized rats. These increased forepaw responses were independent of the global changes in cortical state induced by the spinal cord transection described in our previous work (Aguilar et al., J Neurosci 2010), as the responses increased both when the cortex was in a silent state (down-state) or in an active state (up-state). The increased responses in the intact forepaw cortex correlated with increased responses in the deafferented hindpaw cortex, suggesting that they could represent different points of view of the same immediate state-independent functional reorganization of the primary somatosensory cortex after spinal cord injury. Collectively, the results of the present study and of our previous study suggest that both state-dependent and state-independent mechanisms can jointly contribute to cortical reorganization immediately after spinal cord injury. PMID:23922771
Thuret, Sandrine; Thallmair, Michaela; Horky, Laura L.; Gage, Fred H.
Adult MRL/MpJ mice have been shown to possess unique regeneration capabilities. They are able to heal an ear-punched hole or an injured heart with normal tissue architecture and without scar formation. Here we present functional and histological evidence for enhanced recovery following spinal cord injury (SCI) in MRL/MpJ mice. A control group (C57BL/6 mice) and MRL/MpJ mice underwent a dorsal hemisection at T9 (thoracic vertebra 9). Our data show that MRL/MpJ mice recovered motor function significantly faster and more completely. We observed enhanced regeneration of the corticospinal tract (CST). Furthermore, we observed a reduced astrocytic response and fewer micro-cavities at the injury site, which appear to create a more growth-permissive environment for the injured axons. Our data suggest that the reduced astrocytic response is in part due to a lower lesion-induced increase of cell proliferation post-SCI, and a reduced astrocytic differentiation of the proliferating cells. Interestingly, we also found an increased number of proliferating microglia, which could be involved in the MRL/MpJ spinal cord repair mechanisms. Finally, to evaluate the molecular basis of faster spinal cord repair, we examined the difference in gene expression changes in MRL/MpJ and C57BL/6 mice after SCI. Our microarray data support our histological findings and reveal a transcriptional profile associated with a more efficient spinal cord repair in MRL/MpJ mice. PMID:22348029
Kesherwani, V; Atif, F; Yousuf, S; Agrawal, S K
Damage from oxidative stress plays a critical role in spinal cord injury. Nuclear factor erythroid 2-related factor (Nrf-2) signaling pathway can be activated by cellular oxidative stress. Resveratrol, a plant-derived polyphenolic compound found in red wine, has antioxidant properties. In the present study, we have examined the neuroprotective effect of resveratrol and the role of Nrf-2 in spinal cord hypoxic injury. The spinal cord was removed from adult male Wistar rats from T2-T10 and the dorsal column was used to induce hypoxic injury in vitro with and without treatment with resveratrol (50μM). Significant changes were found in the compound action potential (CAP) of spinal cord dorsal column, and hematoxyline and eosin (H&E) staining showed that resveratrol significantly improved neuronal injury. The biochemical assays showed significant changes in lipid peroxidase (LPO), reduced glutathione (GSH), superoxide dismutase (SOD), protein carbonyl (PC), mitochondrial ATP content, and mitochondrial Ca(++). Furthermore, using immunohistochemistry and Western blot, we found that after resveratrol treatment during hypoxic injury there was a significant activation of NrF-2 and down regulation of the glial fibrillary acidic protein (GFAP) content. The results show that resveratrol treatment has neuroprotective effects on CAP, Ca(++) loading, and biochemical parameters after hypoxic injury. The neuroprotective effect is likely to be exerted by increased activation of transcription factor Nrf-2 by resveratrol along with its direct antioxidant effect to ameliorate the oxidative damage and preserve mitochondrial function.
Thuret, Sandrine; Thallmair, Michaela; Horky, Laura L; Gage, Fred H
Adult MRL/MpJ mice have been shown to possess unique regeneration capabilities. They are able to heal an ear-punched hole or an injured heart with normal tissue architecture and without scar formation. Here we present functional and histological evidence for enhanced recovery following spinal cord injury (SCI) in MRL/MpJ mice. A control group (C57BL/6 mice) and MRL/MpJ mice underwent a dorsal hemisection at T9 (thoracic vertebra 9). Our data show that MRL/MpJ mice recovered motor function significantly faster and more completely. We observed enhanced regeneration of the corticospinal tract (CST). Furthermore, we observed a reduced astrocytic response and fewer micro-cavities at the injury site, which appear to create a more growth-permissive environment for the injured axons. Our data suggest that the reduced astrocytic response is in part due to a lower lesion-induced increase of cell proliferation post-SCI, and a reduced astrocytic differentiation of the proliferating cells. Interestingly, we also found an increased number of proliferating microglia, which could be involved in the MRL/MpJ spinal cord repair mechanisms. Finally, to evaluate the molecular basis of faster spinal cord repair, we examined the difference in gene expression changes in MRL/MpJ and C57BL/6 mice after SCI. Our microarray data support our histological findings and reveal a transcriptional profile associated with a more