Dr. Fehlings and his team are dedicated to improving patient care for individuals living with central nervous system injuries and disease. Read more on a selection of discoveries below to learn about ongoing and past research from the lab.
Secondary Injury Mechanisms
Early spinal cord injury (SCI) research focused on the mechanisms of injury during the primary traumatic insult to the cord. However, my 1991 publication was the first to describe the secondary injury mechanisms following SCI, highlighting the role of posttraumatic ischemia on poor functional recovery. Building on this work, we have numerous publications characterizing the harsh post-SCI microvenvironment, which acts as a potent barrier to the use of regenerative techniques to repair the injured cord. Furthermore, to counteract this reparative barrier, our research team has developed targeted approaches to promote repair in this environment, such as the degradation of the glial scar to allow for cell migration and proliferation at the site of injury.
- Tator, C.H., Fehlings, M.G. (1991). Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg, 75(1), 15-26.
- Karimi-Abdolrezaee, S., Schut, D., Wang, J., Fehlings, M.G. (2012). Chondroitinase and growth factors enhance activation and oligodendrocyte differentiation of endogenous neural precursor cells after spinal cord injury. PLoS One, 7(5), e37589.
- Iwasaki, M., Wilcox, J.T., Nishimura, Y., Zweckberger, K., Suzuki, h., Wang, J., Liu, y., Karadimas, S.K., Fehlings, M.G. (2014). Synergistic effects of self-assembling peptide and neural stem/progenitor cells to promote tissue repair and forelimb functional recovery in cervical spinal cord injury. Biomaterials, 35(9), 2617-29.
Spinal Cord Injury Model Development
A major focus of our lab has been on developing more translationally relevant models of SCI, which will in turn aid in the translation of preclinical research to SCI patients. For example, the majority of SCIs occur at the cervical level in humans, however preclinical SCI experiments are typically performed at the thoracic level. To address this issue, we have examined SCI at the cervical, thoracic and lumbar levels to gain a better understanding of site-specific injury effects. This work has demonstrated unique differences in cavity size, secondary molecule expression, and temporal progression of injury. In addition to studying injury to the cervical spine, we also use a clip-compression model of SCI, which more accurately replicates real-world injury as opposed to transecting the cord to induce SCI.
- Alluin, O., Karimi-Abdolrezaee, S., Delivet-Mongrain, H., Leblond, H., Fehlings, M.G., Rossignol, S. (2011). Kinematic study of locomotor recovery after spinal cord clip compression injury. J Neurotrauma, 28(9), 1963-81.
- Forgione, N., Karadimas, S.K., Foltz, W.D., Satkunendrarajah, K., Lip, A., Fehlings,M.G. (2014). Bilateral contusion-compression model of incomplete traumatic cervical spinal cord injury. J Neurotrauma. 2014;31(21):1776-88.
- Moonen, G., Satkunendrarajah, K., Wilcox, J.T, Badner, A., Mothe, A., Foltz, W., Fehlings, M.G., Tator, C.H. (2016). A New Acute Impact-Compression Lumbar Spinal Cord Injury Model. J Neurotrauma, 33(3), 278-89.
- Wilcox, J.T., Satkunendrarajah, K., Nasirzadeh, Y., Laliberte, A.M, Lip, A., Cadotte, D.W., Foltz, W.D, Fehlings, M.G. (2017). Generating level-dependent models of cervical and thoracic spinal cord injury: Exploring the interplay of neuroanatomy, physiology, and function. Neurobiol Dis, 105, 194-212.
Riluzole Neuroprotective Effects
Given our expertise in characterizing injury mechanisms in SCI patients, our group hypothesized that the targeted use of the sodium channel blocker drug riluzole, already approved for use in patients with Amyotrophic Lateral Sclerosis, would demonstrate neuroprotective effects following SCI and cervical spondylotic myelopathy. In addition to the neuroprotective effects, administration of riluzole in preclinical models has shown enhanced functional recovery. These exciting results hold promise for improving functional recovery following SCI in human patients.
- Wu,Y., Satkunendrarajah, K., Teng, Y., Chow, D.S, Buttigieg, J., Fehlings, M.G. (2013). Delayed post-injury administration of riluzole is neuroprotective in a preclinical model of cervical spinal cord injury. J Neurotrauma, 30(6), 441-52. PubMed PMID: 23517137.
- Wu,Y., Satkunendrarajah, K., Fehlings, M.G. (2014). Riluzole improves outcome following ischemia-reperfusion injury to the spinal cord by preventing delayed paraplegia. Neuroscience, 18(265), 302-12.
- Karadimas, S.K., Laliberte, A.M., Tetreault, L., Chung, Y.S., Arnold, P., Foltz, W.D., Fehlings, M.G. (2015). Riluzole blocks perioperative ischemia-reperfusion injury and enhances postdecompression outcomes in cervical spondylotic myelopathy. Sci Transl Med, 7(316), 316ra194.
Neural Stem Cells to Repair and Regenerate the Injured Spinal Cord
Neural Stem Cells (NSCs) are an exciting and promising approach for repairing and regenerating the injured central nervous system. Previous work from our lab has shown improved functional recovery following cell transplantation, however, a number of well documented challenges remain that limit the effectiveness of cell transplantation therapy. Our team is currently developing exciting approaches to target these regenerative barriers, which include:
- The harsh post-injury microenvironment
- The densely packed chondroitin sulfate proteoglycans that form the glial scar
- Poor integration of grafted cells into the host neural network
- Differentiation of stem cells to less needed cell types
- Salewski, R.P., Mitchell, R.A., Li, L., Shen, C., Milekovskaia, M., Nagy, A., Fehlings, M.G. (2015). Transplantation of induced pluripotent stem cell-derived neural stem cells mediate functional recovery following thoracic spinal cord injury through remyelination of axons. Stem Cells Transl Med, 4(7), 743-54.
- Zweckberger, K., Ahuja, C.S., Liu, Y., Wang, J., Fehlings, M.G. (2016). Self-assembling peptides optimize the post-traumatic milieu and synergistically enhance the effects of neural stem cell therapy after cervical spinal cord injury. Acta Biomater, 42, 77-89.
- Khazaei, M., Ahuja, C.S., Fehlings, M.G. (2017). Generation of oligodendrogenic spinal neural progenitor cells from human induced pluripotent stem cells. Curr Protoc Stem Cell Biol, 42, 2D.20.1-2D.20.14
- Suzuki, H., Ahuja, C.S., Salewski, R.P., Li, L., Satkunendrarajah, K., Nagoshi, N., Shibata, S., Fehlings, M.G. (2017). Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury. PLoS One, 12(8), e0182339.
The Effect of Injury on Neural Networks
In addition to the primary traumatic injury to the spinal cord, a number of secondary complications often occur in SCI patients, contributing to reduced quality of life and shortened life expectancy. Our group was involved in a prospective, multi-center trial that demonstrated respiratory failure was the most common complication following SCI. Our work examining the effect of compressive SCI on the rostro-ventro-lateral medulla (RVLM), a nucleus key to cardiovascular control, demonstrated for the first time the disconnection of RVLM neurons after injury, and showed these effects were proportional to the severity of injury. Further, my work with a high cervical hemisection model of SCI in our basic science lab demonstrated a significant loss of motoneurons caudal to the injury. Interestingly, this loss was minimized in the lab following treatment with Riluzole, resulting in significantly improved respiratory function.
- Krassioukov, A.V., Fehlings, M.G. (1999). Effect of graded spinal cord compression on cardiovascular neurons in the rostro-ventral-lateral medulla. Neuroscience, 88(3), 959-73.
- Grossman, R.G.,….Fehlings, M.G.,….Harrop, J.S. (2012). Incidence and severity of acute complications after spinal cord injury. J Neurosurg Spine, 17(1 Suppl), 119-28.
- Satkunendrarajah, K., Nassiri, F., Karadimas, S,K., Lip, A., Yao, G., Fehlings, M.G. (2016). Riluzole promotes motor and respiratory recovery associated with enhanced neuronal survival and function following high cervical spinal hemisection. Exp Neurol, 276, 59-71.
- Satkunendrarajah, K., Karadimas, S,K., Laliberte, A.M., Montando, G., Fehlings, M.G. (2018). Cervical excitatory neurons sustain breathing after spinal cord injury. Nature, 562(7727), 419-422.
Electrophysiological Assessment of Neural Function
My lab has developed a variety of electrophysiological techniques needed to effectively assess neural circuits. Our novel method of recording from the entire corpus callosum represents a new approach for assessing axonal function in both myelinated and non-myelinated axons. We have designed a double sucrose gap apparatus for improved recording of compound action potentials, which has subsequently resulted in more robust and accurate analysis of the functional properties of myelinated and non-myelinated axonal populations. For approaching the glial cell function at a cellular level, we developed an approach to record from white matter astrocytes and oligodendrocytes with patch-clamp electrodes using horizontal slice preparations of a spinal cord. This longitudinal slice preparation facilitates a combined electrophysiological and imaging examination of spinal cord circuits after trauma and ischemia, and is beneficial for uncovering the underlying injury effects on respiratory circuits. In addition, we have extensive expertise in in vivo electrophysiology including motor and somatosensory evoked potentials (MEPs and SSEPs) that we have been using for over 25 years.
- Li, L., Velumian, A.A., Samoilova, M., Fehlings, M.G. (2016). A novel approach for studying physiology and pathophysiology of myelinated and non-myelinated axons in the CNS white matter. PLoS One, 11(11), e0165637.
- Velumian, A.A., Wan, Y., Samoilova, M., Fehlings, M.G. (2010). Modular double sucrose gap apparatus for improved recording of compound action potentials from spinal cord white matter preparations. J Neuroscie Methods, 187(1), 33-40.
- Eftekharpour, E., Karimi-Abdolrezaee, S., Sinha, K., Velumian, A.A., Fehlings, M.G. (2005). Structural and functional alterations of dysmelinated spinal cord axons . Exp Neurol, 193, 334-49.
- Nashmi, R., Velumian, A.A., Chung, I., Zhang, L., Agrawal, S.K., Fehlings, M.G. (2002). Patch-clamp recordings from white matter glia in thin longitudinal slices of spinal cord. J Neurosci Methods, 117(2), 159-66.
Early Surgical Decompression
Past preclinical work demonstrated that surgically decompressing the injured spinal cord post-injury resulted in enhanced neurological recovery. Based on these promising results, I led a multicenter, international trial examining the efficacy of surgical decompression following cervical SCI. The Surgical Timing in Acute Spinal Cord Injury Study (STASCIS) demonstrated that surgery performed within 24 hours after injury could be performed safely and resulted in improved neurological outcomes. Further work demonstrated that early surgical decompression was cost effective, and this treatment approach was recently published as part of clinical practice guidelines for the management of acute traumatic SCI.
- Fehlings, M.G., et al. (2012). Early versus delayed decompression for traumatic cervical spinal cord injury: results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). PLoS One, 7(2), e32037.
- Furlan, J.C., Craven, B.C., Massicotte, E.M., Fehlings, M.G. (2016). Early Versus Delayed Surgical Decompression of Spinal Cord after Traumatic Cervical Spinal Cord Injury: A Cost-Utility Analysis. World Neurosurg, 88, 166-74.
- Fehlings, M.G., et al. (2017). A Clinical Practice Guideline for the Management of Patients with Acute Spinal Cord Injury and Central Cord Syndrome: Recommendation on the Timing (≤24 Hours versus >24 Hours) of Decompressive Surgery. Global Spine J, 7(3S), 195S-205S.
Degenerative Cervical Myelopathy
In 2015, I was instrumental in introducing the term degenerative cervical myelopathy (DCM) to describe myelopathy caused by various degenerative changes in the cervical spine, including cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament. This was an important step, as although DCM is the leading cause of spinal cord dysfunction, the condition and treatment strategies remain poorly understood. Since this time I have had numerous publications characterizing the disease. Furthermore, I led the international effort to develop clinical practice guidelines for DCM published this year.
- Nouri, A., Tetreault, L., Singh, A., Karadimas, S.K., Fehlings, M.G. (2015). Degenerative Cervical Myelopathy: Epidemiology, Genetics and Pathogenesis. Spine (Phila Pa 1976), 40(14), 1092-100.
- Tetreault, L., Goldstein, C.L., Arnold, P., … Fehlings, M.G. (2015). Degenerative Cervical Myelopathy: A Spectrum of Related Disorders Affecting the Aging Spine. Neurosurgery, 77(Suppl 4), S51-67.
- Fehlings, M.G., et al. (2017). A Clinical Practice Guideline for the Management of Patients with Degenerative Cervical Myelopathy: Recommendations for Patients with Mild, Moderate, and Severe Disease and Nonmyelopathic Patients with Evidence of Cord Compression. Global Spine J, 7(3S), 70S-83S.
Neural Stem Cells to Treat Cerebral Palsy
Cerebral palsy (CP) is a common pediatric neurodevelopmental disorder, with one feature being impaired oligodendrocyte maturation that results in white matter injury and reduced axonal myelination. Our lab has optimized models of hemiplegic brain injury that mimic the pathophysiology of CP. Using these models, we have demonstrated the exciting potential for neural stem cells to improve functional outcomes and repair damaged brain structures.
- Ruff, C.A., Ye, H., Legasto, J.M., … Fehlings, M.G.. (2013). Effects of adult neural precursor-derived myelination on axonal function in the perinatal congenitally dysmelinated brain: optimizing time of intervention, developing accurate prediction models, and enhancing performance. J Neurosci, 33(29), 11899-915.
- Ruff, C.A., Faulkner, S.D., Rumajogee, P., … Fehlings, M.G. (2017). The extent of intrauterine growth restriction determines the severity of cerebral injury and neurobehavioural deficitis in rodents. PLoS One, 12(9), e0184653.
- Rumajogee P., Altamentova, S., Li, L.,… Fehlings, M.G. (2018). Exogenous neural precursor cell transplantation results in structural and functional recovery in a hypoxic-ischemic hemiplegic mouse model. eNeuro, [Epub ahead of print].
From Bench to Bedside – Clinical Trials
I have led a number of international multi-center clinical trials that have translated exciting findings from our preclinical studies to human patients. Following the promising results of Riluzole in models of SCI (mentioned above), the RISCIS clinical trial was undertaken to examine the efficacy of the drug for improving functional outcomes in SCI patients. Similarly, to examine the efficacy of Riluzole to improve outcomes in patients with degenerative cervical myelopathy, the CSM-Protect trial was formed. Furthermore, I led the clinical trial using the Rho-inhibitor drug Cethrin for the treatment of spinal cord injury. In those individuals given Cethrin, an improvement in motor score was observed at 12-months post-injury, indicating a likely benefit to blocking the Rho pathway following SCI
- Fehlings, M.G., et al. (2011). A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J Neurotrauma, 28(5), 787-796.
- Fehlings, M.G., Wilson, J.R., Karadimas, S.K., Arnold, P.M., Kopjar, B. (2013). Clinical evaluation of a neuroprotective drug in patients with cervical spondylotic myelopathy undergoing surgical treatment: Design and rationale for the CSM-Protect trial. Spine, 38(22 Suppl), S68-S75.
- Fehlings, M.G., Nakashima, H., Nagoshi, H., Chow, D.S., Grossman, R.G., Kopjar, B. (2016). Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): a randomized, double-blinded, placebo-controlled parallel multi-center trial. Spinal Cord, 54(1), 8-15.