Correlations between severity of clinical signs and histopathological changes in 60 dogs with spinal cord injury associated with acute thoracolumbar intervertebral disc disease

The outcome of spinal surgery in dogs with absent voluntary motor function and nociception following intervertebral disc (IVD) herniation is highly variable, which likely attests to differences in the severity of spinal cord damage. This retrospective study evaluated the extent to which neurological signs correlated with histologically detected spinal cord damage in 60 dogs that were euthanased because of thoracolumbar IVD herniation. Clinical neurological grades correlated significantly with the extent of white matter damage (P<0.001). However, loss of nociception also occurred in 6/31 (19%) dogs with relatively mild histological changes. The duration of clinical signs, Schiff-Sherrington posture, loss of reflexes and pain on spinal palpation were not significantly associated with the severity of spinal cord damage. Although clinical-pathological correlation was generally good, some clinical signs frequently thought to indicate severe cord injury did not always correlate with the degree of cord damage, suggesting functional rather than structural impairment in some cases.

Restoring tactile awareness through the rubber hand illusion in cervical spinal cord injury

BACKGROUND Bodily sensations are an important component of corporeal awareness. Spinal cord injury can leave affected body parts insentient and unmoving, leading to specific disturbances in the mental representation of one's own body and the sense of self. OBJECTIVE Here, we explored how illusions induced by multisensory stimulation influence immediate sensory signals and tactile awareness in patients with spinal cord injuries. METHODS The rubber hand illusion paradigm was applied to 2 patients with chronic and complete spinal cord injury of the sixth cervical spine, with severe somatosensory impairments in 2 of 5 fingers. RESULTS Both patients experienced a strong illusion of ownership of the rubber hand during synchronous, but not asynchronous, stroking. They also, spontaneously reported basic tactile sensations in their previously numb fingers. Tactile awareness from seeing the rubber hand was enhanced by progressively increasing the stimulation duration. CONCLUSIONS Multisensory illusions directly and specifically modulate the reemergence of sensory memories and enhance tactile sensation, despite (or as a result of) prior deafferentation. When sensory inputs are lost, and are later illusorily regained, the brain updates a coherent body image even several years after the body has become permanently unable to feel. This particular example of neural plasticity represents a significant opportunity to strengthen the sense of the self and the feelings of embodiment in patients with spinal cord injury.

Brain fiber tract plasticity in experimental spinal cord injury: diffusion tensor imaging.

Diffusion tensor imaging (DTI) and immunohistochemistry were performed in spinal cord injured rats to understand the basis for activation of multiple regions in the brain observed in functional magnetic resonance imaging (fMRI) studies. The measured fractional anisotropy (FA), a scalar measure of diffusion anisotropy, along the region encompassing corticospinal tracts (CST) indicates significant differences between control and injured groups in the 3 to 4 mm area posterior to bregma that correspond to internal capsule and cerebral peduncle. Additionally, DTI-based tractography in injured animals showed increased number of fibers that extend towards the cortex terminating in the regions that were activated in fMRI. Both the internal capsule and cerebral peduncle demonstrated an increase in GFAP-immunoreactivity compared to control animals. GAP-43 expression also indicates plasticity in the internal capsule. These studies suggest that the previously observed multiple regions of activation in spinal cord injury are, at least in part, due to the formation of new fibers.

Astrocytes from the contused spinal cord inhibit oligodendrocyte differentiation of adult oligodendrocyte precursor cells by increasing the expression of bone morphogenetic proteins.

Promotion of remyelination is an important therapeutic strategy to facilitate functional recovery after traumatic spinal cord injury (SCI). Transplantation of neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) has been used to enhance remyelination after SCI. However, the microenvironment in the injured spinal cord is inhibitory for oligodendrocyte (OL) differentiation of NSCs or OPCs. Identifying the signaling pathways that inhibit OL differentiation in the injured spinal cord could lead to new therapeutic strategies to enhance remyelination and functional recovery after SCI. In the present study, we show that reactive astrocytes from the injured rat spinal cord or their conditioned media inhibit OL differentiation of adult OPCs with concurrent promotion of astrocyte differentiation. The expression of bone morphogenetic proteins (BMP) is dramatically increased in the reactive astrocytes and their conditioned media. Importantly, blocking BMP activity by BMP receptor antagonist, noggin, reverse the effects of active astrocytes on OPC differentiation by increasing the differentiation of OL from OPCs while decreasing the generation of astrocytes. These data indicate that the upregulated bone morphogenetic proteins in the reactive astrocytes are major factors to inhibit OL differentiation of OPCs and to promote its astrocyte differentiation. These data suggest that manipulation of BMP signaling in the endogenous or grafted NSCs or OPCs may be a useful therapeutic strategy to increase their OL differentiation and remyelination and enhance functional recovery after SCI.

Neuronal and axonal degeneration in experimental spinal cord injury: in vivo proton magnetic resonance spectroscopy and histology.

Longitudinal in vivo proton magnetic resonance spectroscopy (1H-MRS) and immunohistochemistry were performed to investigate the tissue degeneration in traumatically injured rat spinal cord rostral and caudal to the lesion epicenter. On 1H-MRS significant decreases in N-acetyl aspartate (NAA) and total creatine (Cr) levels in the rostral, epicenter, and caudal segments were observed by 14 days, and levels remained depressed up to 56 days post-injury (PI). In contrast, the total choline (Cho) levels increased significantly in all three segments by 14 days PI, but recovered in the epicenter and caudal, but not the rostral region, at 56 days PI. Immunohistochemistry demonstrated neuronal cell death in the gray matter, and reactive astrocytes and axonal degeneration in the dorsal, lateral, and ventral white-matter columns. These results suggest delayed tissue degeneration in regions both rostrally and caudally from the epicenter in the injured spinal cord tissue. A rostral-caudal asymmetry in tissue recovery was seen both on MRI-observed hyperintense lesion volume and the Cho, but not NAA and Cr, levels at 56 days PI. These studies suggest that dynamic metabolic changes take place in regions away from the epicenter in injured spinal cord.

Contemporary spinal cord protection during thoracic and thoracoabdominal aortic surgery and endovascular aortic repair: a position paper of the vascular domain of the European Association for Cardio-Thoracic Surgery†.

Ischaemic spinal cord injury (SCI) remains the Achilles heel of open and endovascular descending thoracic and thoracoabdominal repair. Neurological outcomes have improved coincidentially with the introduction of neuroprotective measures. However, SCI (paraplegia and paraparesis) remains the most devastating complication. The aim of this position paper is to provide physicians with broad information regarding spinal cord blood supply, to share strategies for shortening intraprocedural spinal cord ischaemia and to increase spinal cord tolerance to transitory ischaemia through detection of ischaemia and augmentation of spinal cord blood perfusion. This study is meant to support physicians caring for patients in need of any kind of thoracic or thoracoabdominal aortic repair in decision-making algorithms in order to understand, prevent or reverse ischaemic SCI. Information has been extracted from focused publications available in the PubMed database, which are cohort studies, experimental research reports, case reports, reviews, short series and meta-analyses. Individual chapters of this position paper were assigned and after delivery harmonized by Christian D. Etz, Ernst Weigang and Martin Czerny. Consequently, further writing assignments were distributed within the group and delivered in August 2014. The final version was submitted to the EJCTS for review in September 2014.

Longitudinal extension of myelomalacia by intramedullary and subdural hemorrhage in a canine model of spinal cord injury

BACKGROUND CONTEXT In canine intervertebral disc (IVD) extrusion, a spontaneous animal model of spinal cord injury, hemorrhage is a consistent finding. In rodent models, hemorrhage might be involved in secondary tissue destruction by biochemical mechanisms. PURPOSE This study aimed to investigate a causal association between the extents of intramedullary, subdural and epidural hemorrhage and the severity of spinal cord damage following IVD extrusion in dogs. STUDY DESIGN/SETTING A retrospective study using histologic spinal cord sections from 83 dogs euthanized following IVD extrusion was carried out. METHODS The degree of hemorrhage (intramedullary, subdural, epidural), the degree of spinal cord damage in the epicenter (white and gray matter), and the longitudinal extent of myelomalacia were graded. Associations between the extent of hemorrhage and the degree of spinal cord damage were evaluated statistically. RESULTS Intramedullary and subdural hemorrhages were significantly associated with the degree of white (p<.001/ p=.004) and gray (both p<.001) matter damage, and with the longitudinal extension of myelomalacia (p<.001/p=.005). Intriguingly, accumulation of hemorrhagic cord debris inside or dorsal to a distended and ruptured central canal in segments distant to the epicenter of the lesion was observed exhibiting a wave-like pattern on longitudinal assessment. The occurrence of this debris accumulation was associated with high degrees of tissue destruction (all p<.001). CONCLUSIONS Tissue liquefaction and increased intramedullary pressure associated with hemorrhage are involved in the progression of spinal cord destruction in a canine model of spinal cord injury and ascending or descending myelomalacia. Functional and dynamic studies are needed to investigate this concept further.

Description and repeatability of a newly developed spinal cord injury scale for dogs.

The objectives of this study were to describe a new spinal cord injury scale for dogs, evaluate repeatability through determining inter-rater variability of scores, compare these scores to another established system (a modified Frankel scale), and determine if the modified Frankel scale and the newly developed scale were useful as prognostic indicators for return to ambulation. A group of client-owned dogs with spinal cord injury were examined by 2 independent observers who applied the new Texas Spinal Cord Injury Score (TSCIS) and a modified Frankel scale that has been used previously. The newly developed scale was designed to describe gait, postural reactions and nociception in each limb. Weighted kappa statistics were utilized to determine inter-rater variability for the modified Frankel scale and individual components of the TSCIS. Comparisons were made between raters for the overall TSCIS score and between scales using Spearman's rho. An additional group of dogs with surgically treated thoracolumbar disk herniation was enrolled to look at correlation of both scores with spinal cord signal characteristics on magnetic resonance imaging (MRI) and ambulatory outcome at discharge. The actual agreement between raters for the modified Frankel scale was 88%, with a weighted kappa value of 0.93. The TSCIS had weighted kappa scores for gait, proprioceptive positioning and nociception components that ranged from 0.72 to 0.94. Correlation between raters for the overall TSCIS score was Spearman's rho=0.99 (P<0.001). Comparison of the overall TSCIS score to the modified Frankel score resulted in a Spearman's rho value of 0.90 (P<0.001). The modified Frankel score was weakly correlated with the length of hyperintensity of the spinal cord: L2 vertebral body length ratio on mid-sagittal T2-weighted MRI (Spearman's rho=-0.45, P=0.042) as was the overall TSCIS score (Spearman's rho=-0.47, P=0.037). There was also a significant difference in admitting modified Frankel scores (P=0.029) and admitting overall TSCIS scores (P=0.02) between dogs that were ambulatory at discharge and those that were not. Results from this study suggest that the TSCIS is an easy to administer scale for evaluating canine spinal cord injury based on the standard neurological exam and correlates well with a previously described modified Frankel scale.

In-vivo diffusion tensor imaging of rat spinal cord with a phased array coil at 7T

Magnetic resonance imaging (MRI) is a non-invasive technique that offers excellent soft tissue contrast for characterizing soft tissue pathologies. Diffusion tensor imaging (DTI) is an MRI technique that has shown to have the sensitivity to detect subtle pathology that is not evident on conventional MRI. ^ Rats are commonly used as animal models in characterizing the spinal cord pathologies including spinal cord injury (SCI), cancer, multiple sclerosis, etc. These pathologies could affect both thoracic and cervical regions and complete characterization of these pathologies using MRI requires DTI characterization in both the thoracic and cervical regions. Prior to the application of DTI for investigating the pathologic changes in the spinal cord, it is essential to establish DTI metrics in normal animals. ^ To date, in-vivo DTI studies of rat spinal cord have used implantable coils for high signal-to-noise ratio (SNR) and spin-echo pulse sequences for reduced geometric distortions. Implantable coils have several disadvantages including: (1) the invasive nature of implantation, (2) loss of SNR due to frequency shift with time in the longitudinal studies, and (3) difficulty in imaging the cervical region. While echo planar imaging (EPI) offers much shorter acquisition times compared to spin-echo imaging, EPI is very sensitive to static magnetic field inhomogeneities and the existing shimming techniques implemented on the MRI scanner do not perform well on spinal cord because of its geometry. ^ In this work, an integrated approach has been implemented for in-vivo DTI characterization of rat spinal cord in the thoracic and cervical regions. A three element phased array coil was developed for improved SNR and extended spatial coverage. A field-map shimming technique was developed for minimizing the geometric distortions in EPI images. Using these techniques, EPI based DWI images were acquired with optimized diffusion encoding scheme from 6 normal rats and the DTI-derived metrics were quantified. ^ The phantom studies indicated higher SNR and smaller bias in the estimated DTI metrics than the previous studies in the cervical region. In-vivo results indicated no statistical difference in the DTI characteristics of either gray matter or white matter between the thoracic and cervical regions. ^

A computational model coupling mechanics and electrophysiology in spinal cord injury

Traumatic brain injury and spinal cord injury have recently been put under the spotlight as major causes of death and disability in the developed world. Despite the important ongoing experimental and modeling campaigns aimed at understanding the mechanics of tissue and cell damage typically observed in such events, the differenti- ated roles of strain, stress and their corresponding loading rates on the damage level itself remain unclear. More specif- ically, the direct relations between brain and spinal cord tis- sue or cell damage, and electrophysiological functions are still to be unraveled. Whereas mechanical modeling efforts are focusing mainly on stress distribution and mechanistic- based damage criteria, simulated function-based damage cri- teria are still missing. Here, we propose a new multiscale model of myelinated axon associating electrophysiological impairment to structural damage as a function of strain and strain rate. This multiscale approach provides a new framework for damage evaluation directly relating neuron mechanics and electrophysiological properties, thus provid- ing a link between mechanical trauma and subsequent func- tional deficits.

A computational model coupling mechanics and electrophysiology in spinal cord injury

Traumatic brain injury and spinal cord injury have recently been put under the spotlight as major causes of death and disability in the developed world. Despite the important ongoing experimental and modeling campaigns aimed at understanding the mechanics of tissue and cell damage typically observed in such events, the differentiated roles of strain, stress and their corresponding loading rates on the damage level itself remain unclear. More specifically, the direct relations between brain and spinal cord tissue or cell damage, and electrophysiological functions are still to be unraveled. Whereas mechanical modeling efforts are focusing mainly on stress distribution and mechanistic-based damage criteria, simulated function-based damage criteria are still missing. Here, we propose a new multiscale model of myelinated axon associating electrophysiological impairment to structural damage as a function of strain and strain rate. This multiscale approach provides a new framework for damage evaluation directly relating neuron mechanics and electrophysiological properties, thus providing a link between mechanical trauma and subsequent functional deficits

CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury

CM101, an antiangiogenic polysaccharide derived from group B streptococcus, was administered by i.v. injection 1 hr post-spinal-cord crush injury in an effort to prevent inflammatory angiogenesis and gliosis (scarring) in a mouse model. We postulated that gliosis would sterically prevent the reestablishment of neuronal connectivity; thus, treatment with CM101 was repeated every other day for five more infusions for the purpose of facilitating regeneration of neuronal function. Twenty-five of 26 mice treated with CM101 survived 28 days after surgery, and 24 of 26 recovered walking ability within 2–12 days. Only 6 of 14 mice in the control groups survived 24 hr after spinal cord injury, and none recovered function in paralyzed limbs. MRI analysis of injured untreated and treated animals showed that CM101 reduced the area of damage at the site of spinal cord compression, which was corroborated by histological analysis of spinal cord sections from treated and control animals. Electrophysiologic measurements on isolated central nervous system and neurons in culture showed that CM101 protected axons from Wallerian degeneration; reversed γ-aminobutyrate-mediated depolarization occurring in traumatized neurons; and improved recovery of neuronal conductivity of isolated central nervous system in culture.

Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury

Antagonists of glutamate receptors of the N-methyl-d-aspartate subclass (NMDAR) or inhibitors of nitric oxide synthase (NOS) prevent nervous system plasticity. Inflammatory and neuropathic pain rely on plasticity, presenting a clinical opportunity for the use of NMDAR antagonists and NOS inhibitors in chronic pain. Agmatine (AG), an endogenous neuromodulator present in brain and spinal cord, has both NMDAR antagonist and NOS inhibitor activities. We report here that AG, exogenously administered to rodents, decreased hyperalgesia accompanying inflammation, normalized the mechanical hypersensitivity (allodynia/hyperalgesia) produced by chemical or mechanical nerve injury, and reduced autotomy-like behavior and lesion size after excitotoxic spinal cord injury. AG produced these effects in the absence of antinociceptive effects in acute pain tests. Endogenous AG also was detected in rodent lumbosacral spinal cord in concentrations similar to those previously detected in brain. The evidence suggests a unique antiplasticity and neuroprotective role for AG in processes underlying persistent pain and neuronal injury.

The Role of Hope in Rehabilitation and Long-term Outcomes among patients with Comorbid Spinal Cord and Traumatic Brain Injuries.

Spinal cord injury (SCI) and traumatic brain injury (TBI) are two potentially devastating conditions alone; when they co-occur in an individual they can be doubly so. The role of hope in rehabilitating oneself and recovering emotionally is examined in this paper. More specifically, Snyder's Model of Hope (1991) is examined as a tool that can aid in the rehabilitative process and help treatment providers, their patients, and the families of patients keep hope alive during a time of physical and emotional upheaval. This paper further examines the roles of hope in a rehabilitation program at Craig Hospital, a private, non-profit hospital dedicated exclusively to the rehabilitation of SCIs and TBIs and designated as a TBI and SCI Model Systems Center.