Blusson Spinal Cord Center

Vancouver, Canada

Blusson Spinal Cord Center

Vancouver, Canada
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Gordon T.,University of Alberta | Gordon T.,University of Toronto | Tetzlaff W.,Blusson Spinal Cord Center | Tetzlaff W.,University of British Columbia
European Journal of Neuroscience | Year: 2015

Chronic nerve injuries are notorious for their poor regenerative outcomes. Here, we addressed the question of whether the established reduced ability of injured motoneurons to regenerate their axons with time of disconnection with targets (chronic axotomy) is associated with a failure of injured motoneurons to express and sustain their expression of regeneration-associated genes. Sciatic motoneurons were prevented from regenerating by ligation of the transected nerves (chronic axotomy), and then subjected to a second nerve transection (acute axotomy) to mimic the clinical surgical procedure of refreshing the proximal nerve stump prior to delayed nerve repair. The expression of α1-tubulin, actin and GAP-43 mRNA was analysed in axotomized sciatic motoneurons by the use of in situ hybridization followed by autoradiography and silver grain quantification. The expression of these regeneration-associated genes by naive (acutely) axotomized motoneurons declined exponentially, to reach baseline levels within 6 months. These chronically injured motoneurons responded to a refreshment axotomy by elevating the expression of the genes to the same levels as in acutely (i.e. for the first time) axotomized sciatic motoneurons. However, the expression of these declined more rapidly than after acute axotomy. We conclude that a progressive decline in the expression of the regeneration-associated genes in chronically axotomized motoneurons and the even more rapid decline in their expression in response to a refreshment axotomy may explain why the regenerative capacity of chronically axotomized neurons declines with time. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.


Cragg J.J.,Blusson Spinal Cord Center | Scott A.L.,Blusson Spinal Cord Center | Ramer M.S.,Blusson Spinal Cord Center
Experimental Neurology | Year: 2010

Dorsal root injuries (DRIs), resulting in the permanent disconnection of nerve roots from the spinal cord, lead to sensory impairments, including both the loss of sensation and the development of neuropathic pain in the affected limb. DRI results in axonal sprouting of intraspinal serotonergic fibers, but the functional consequences of this response to spinal deafferentation remains unclear. Here we aimed to clarify the role of descending serotonergic projections in both mechanosensation and pain following DRI. By ablating serotonergic input to the spinal cord via 5,7-dihydroxytryptamine (5,7-DHT) prior to DRI in rats, we found that serotonergic input to the dorsal horn normally inhibits the recovery of mechanosensation but has no effect on the development or resolution of cold pain. Endogenous brain-derived neurotrophic factor (BDNF) is upregulated by activated microglia, is required for sprouting of serotonergic axons and neuropeptide tyrosine (NPY)-positive interneurons, and suppresses mechanosensory recovery following DRI. Intriguingly, we found that the density of activated microglia, the amount of BDNF protein, and density of NPY-positive processes were all significantly reduced in 5,7-DHT-treated rats, suggesting that serotonergic input to the deafferented dorsal horn is required for all of these consequences of spinal deafferentation. These results indicate that BDNF-dependent serotonergic and/or increases in NPY-positive fiber density slows, and ultimately halts, mechanosensory recovery following DRI. © 2010 Elsevier Inc. All rights reserved.


Plemel J.R.,Blusson Spinal Cord Center | Plemel J.R.,University of British Columbia | Manesh S.B.,Blusson Spinal Cord Center | Sparling J.S.,Blusson Spinal Cord Center | And 3 more authors.
GLIA | Year: 2013

Myelin loss is a hallmark of multiple sclerosis (MS) and promoting central nervous system myelin repair has become a major therapeutic target. Despite the presence of oligodendrocytes precursors cells (OPCs) in chronic lesions of MS, remyelination often fails. The mechanism underlying this failure of remyelination remains unknown, but it is hypothesized that environmental cues act to inhibit the maturation/differentiation of oligodendroglia, preventing remyelination. The rate of CNS remyelination is correlated to the speed of phagocytosis of myelin debris, which is present following demyelination and trauma. Thus, myelin debris could inhibit CNS remyelination. Here, we demonstrate that OPCs cultured on myelin were robustly inhibited in their maturation, as characterized by the decreased expression of immature and mature oligodendrocytes markers, the impaired production of myelin gene products, as well as their stalled morphological complexity relative to OPCs cultured on a control substrate. OPCs in contact with myelin stopped proliferating and decreased the expression of OPC markers to a comparable degree as cells grown on a control substrate. The expression of two transcription factors known to prevent OPC differentiation and maturation were increased in cells that were in contact with myelin: inhibitor of differentiation family (ID) members 2 and 4. Overexpression of ID2 and ID4 in OPCs was previously reported to decrease the percentage of cells expressing mature oligodendrocyte markers. However, knockdown of ID2 and/or ID4 in OPCs did not increase oligodendroglial maturation on or off of myelin, suggesting that contact with myelin regulates additional regulatory elements. © 2013 Wiley Periodicals, Inc.


Schouten R.,University of British Columbia | Albert T.,Thomas Jefferson University | Kwon B.K.,Blusson Spinal Cord Center
Journal of the American Academy of Orthopaedic Surgeons | Year: 2012

Failure to recognize spinal column or spinal cord injuries, or improper treatment of them, can have catastrophic and often irreversible neurologic consequences. Although the initial assessment is often shared with emergency care personnel, an orthopaedic surgeon's perspective can elevate the priority of spinal care to the level that is warranted. An accurate early appraisal, including complete neurologic assessment, is critical. All aspects of emergent care, including optimal immobilization precautions, resuscitation, and choice of imaging modalities, should be systematically reviewed, and practice guidelines should be adopted by each institution. Increased vigilance is required in patients with underlying ankylosing spinal conditions. The use of CT in the symptomatic patient is established, but the use of cervical MRI in the obtunded individual is contentious. By informing decisions around appropriate preliminary treatment, particularly for persons with neurologic deficits or those at high risk for developing neurologic impairment, long-term outcomes can be optimized.


Plemel J.R.,University of British Columbia | Plemel J.R.,University of Calgary | Plemel J.R.,Blusson Spinal Cord Center | Plemel J.R.,3330 Hospital Drive Nw | And 11 more authors.
Progress in Neurobiology | Year: 2014

After spinal cord injury (SCI) there is prolonged and dispersed oligodendrocyte cell death that is responsible for widespread demyelination. To regenerate this lost myelin, many investigators have transplanted myelin-producing cells as a treatment for contusive SCI. There are several documented examples of cellular transplantation improving function after injury, with the degree of myelin regeneration correlating with functional recovery. On the basis of these findings, remyelination is hypothesized to be a beneficial strategy to promote recovery after injury. As cellular transplantation is now entering clinical trials for treatment of SCI, it is important to dissect carefully whether accelerating remyelination after SCI is a valid clinical target. In this review we will discuss the consequences of demyelination and the potential benefits of remyelination as it relates to injury. Prolonged demyelination is hypothesized to enhance axonal vulnerability to degeneration, and is thereby thought to contribute to the axonal degeneration that underlies the permanent functional losses associated with SCI. Currently, strategies to promote remyelination after SCI are largely limited to cellular transplantation. This review discusses those strategies as well as new, and largely untested, modes of therapy that aim to coax endogenous cells residing adjacent to the injury site to differentiate in order to replace lost myelin. © 2014 Elsevier Ltd.


Heinemann A.W.,Northwestern University | Steeves J.D.,Blusson Spinal Cord Center | Boninger M.,University of Pittsburgh | Boninger M.,Human Engineering Research Laboratories | And 2 more authors.
Spinal Cord | Year: 2012

Study design: This manuscript summarizes recommendations from the State of the Science Conference in Spinal Cord Injury Rehabilitation 2011. Objectives: To develop an agenda for spinal cord injury (SCI) rehabilitation research in the next decade. Setting: Participants scheduled planning meetings and then gathered at the 2011 joint meeting of the American Spinal Injury Association and International Spinal Cord Society in Washington DC. Methods: Recommendations were made by an international, multidisciplinary team that met in large plenary sessions and breakout groups during the meeting.Results:Recommendations are organized by conference track, including neurological and functional recovery; technology issues; aging with spinal cord injury; and employment, psychosocial and quality of life issues. Conclusion: A number of themes emerged across the conference tracks, including the need for improved measures of process and outcome constructs, application of qualitative and quantitative research designs, and use of contemporary statistical analytic approaches. Participants emphasized the value of collaborative research that uses the latest methods, techniques and information. © 2012 International Spinal Cord Society. All rights reserved.


Charest-Morin R.,University of Québec | Dea N.,Université de Sherbrooke | Fisher C.G.,Blusson Spinal Cord Center
Current Treatment Options in Oncology | Year: 2016

Treatment of primary bone tumours (PBT) of the spine is complex, often involving numerous surgical and oncology disciplines. Surgical en bloc resection with oncologically appropriate margins is the modality of choice when treating malignant PBT. En bloc resection with wide or marginal margins appears to offer better local and systemic control of the disease. This type of surgical resection can also be considered when treating benign aggressive tumours such as aneurysmal bone cyst, giant cell tumour and osteoblastoma. Although these surgeries respect oncologic principles, significant morbidity and mortality are associated. Adverse event collection is highly variable in the literature and mostly from retrospective studies. Wound complication, neurologic deficit and significant blood loss are encountered with surgical resection of PBT of the mobile spine and especially, the sacrum. The adverse event profile of these surgeries is high even in experienced quaternary referral centres. Therefore, primary spinal tumour resection is best performed in experienced centre with adequate multidisciplinary support. Furthermore, prospective and systematic adverse event data collection should be developed to ensure accurate data. The impact of such extensive and potentially impairment producing procedures on health-related quality of life (HRQOL) is another critically valuable piece of information in the era of shared treatment decision making. At the present time, there is paucity of published data regarding HRQOL following these surgeries. Nonetheless, in theory, it seems that health-related quality of life after surgery for PBT is acceptable given the curative intent of the treatment. However, a decision-making process should be tailored to each patient and his or her expectations. Comprehensive discussions should be held preoperatively with the patient, family and other related allied health professionals if the informed consent and decision-making process is to be optimal. © 2016, Springer Science+Business Media New York.


Moore G.R.W.,University of British Columbia | Moore G.R.W.,Vancouver General Hospital | Moore G.R.W.,Blusson Spinal Cord Center | Laule C.,University of British Columbia
Journal of Neuropathology and Experimental Neurology | Year: 2012

The advent of magnetic resonance imaging (MRI) has revolutionized concepts of the pathogenesis of multiple sclerosis (MS). Magnetic resonance imaging provides the ability to delineate the evolution of the disease process over time; captured static snapshots can then be used in pathologic correlations studies. Certain patterns in the 2-or 3-dimensional MRI sphere correlate very well with similarpatterns of histopathology. A multimodality approach that makes use of numerous MRI techniques can lead to significant insights into the nature of the changes in the CNS. MRI-pathology correlation studies in MS are being performed using newer MRI techniques as they become available. Such correlations and basic histopathologic studies have shown abnormalities in MS far beyond the well-documented changes in the plaque and have brought into question the dogma that MS is an initially inflammatory nondegenerative disease. This review briefly outlines technical considerations in MRI-pathology correlativestudies and describes the past and current status of our ability to correlate focal and diffuse changes on the MRI with neuropathologic findings in MS patients. Copyright © 2012 by the American Association of Neuropathologists, Inc.


Scott A.L.M.,Blusson Spinal Cord Center | Ramer M.S.,Blusson Spinal Cord Center
Brain | Year: 2010

Schwann cells are attractive candidates for repair of the injured spinal cord. Transplanted Schwann cells are permissive to regeneration, but their ability to promote regeneration into distal spinal cord remains weak despite their production of growth-promoting neurotrophins. Schwann cell activation such as that which accompanies peripheral nerve injury results in massive upregulation of the p75NTR pan-neurotrophin-receptor. Here we test the hypothesis that this p75NTR upregulation following dorsal root injury limits availability of endogenous neurotrophin to axons and restricts regeneration of injured axons into the spinal cord. We injured dorsal roots (fourth cervical to second thoracic) in mice lacking the neurotrophin-binding domain of p75NTR and in wild-type littermates. Axonal regeneration was assessed by selective tracing of neurotrophin-responsive and non-responsive dorsal root ganglion neurons. Functional reinnervation of the spinal cord was assessed in behavioural experiments and via Fos immunohistochemistry following formalin injection into the forepaw. We also measured levels of nerve growth factor and neurotrophin-3 following nerve injury in knockout and wild-type mice, and used Trk-Fc receptor chimeras to block nerve growth factor and neurotrophin-3 signalling in dorsal root ganglion/Schwann cell co-cultures and following dorsal root injury in vivo. The roles of neuronal and glial p75 NTR were assessed in transplant experiments in vivo and in co-cultures. We found that nerve growth factor and neurotrophin-3-responsive axons regenerated into the spinal cord of p75NTR knockout mice where they made functional connections with dorsal horn neurons. Despite equivalent levels of nerve growth factor and neurotrophin-3 in wild-type and knockout mice, successful regeneration in knockouts was neurotrophin-dependent. Transplantation of p75-/- neurons into a wild-type environment, p75-/- peripheral nerve grafts into the injured p75+/+ spinal cord, and dissociated sensory neuron/Schwann cell co-cultures showed that the absence of p75NTR from glia, not from neurons, promotes regeneration. These findings indicate that Schwann cell p75NTR restricts neurotrophin availability to the extent that it prevents spontaneous sensory axon regeneration into the spinal cord. The implication is that inactivating p75NTR in Schwann (or olfactory ensheathing) cells may enable axons to grow beyond transplants, improving the outcome of spinal cord injury.


Scott A.L.M.,Blusson Spinal Cord Center | Ramer M.S.,Blusson Spinal Cord Center
Brain Research | Year: 2010

Spontaneous and/or treatment-evoked re-modeling of the CNS following spinal cord injury is a prerequisite for functional recovery. While there has been considerable interest in the role of endogenous neurotrophins in spontaneous plasticity of several populations of spinal axons, the same cannot be said for morphological changes to dendrites. Here, we examined the responses of dendrites in the mouse lateral spinal nucleus (LSN, a site of sensory integration in the dorsolateral white matter) to exogenous and endogenous neurotrophins. We performed a septuple dorsal rhizotomy, which permanently eliminates sensory input to the spinal cord, and stimulates sprouting of spinal axons. While dendrites showed no change in density following injury alone, they sprouted vigorously (a two-fold increase in density) upon addition of exogenous brain-derived neurotrophic factor (BDNF). On the other hand, endogenous nerve growth factor (NGF) severely restricted dendritic sprouting, as TrkA-Fc treatment also roughly doubled the density of dendritic processes in the LSN. Spontaneous, BDNF- and TrkA-Fc mediated sprouting was unaffected by the absence of p75NTR. Importantly, TrkA-Fc treatment markedly reduced expression of the truncated BDNF receptor TrkBT1 in both p75+/+ and p75-/- mice, which was robustly-upregulated by deafferentation in both genotypes. We propose that the upregulation of TrkBT1 by NGF results in a reduced availability of endogenous BDNF to dendrites. Accordingly, sprouting of serotonergic axons, a BDNF-dependent consequence of dorsal root injury, was significantly enhanced in TrkA-Fc-treated animals. These results suggest that NGF and BDNF signaling differentially regulates dendritic plasticity in the deafferented spinal cord. © 2010 Elsevier B.V. All rights reserved.

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