Spinal Cord White Matter Research Articles

Aging of bovine spinal cord: an alteration of myelinated nerve fibers in the white matter

To gain more knowledge of age-related changes in the spinal cord of the bovine species, the structure of 15 clinically normal aged cattle (Holstein-Friesian cows 8–13 years of age) was histopathologically examined. In 12 (80%) of the 15 animals, the common histopathological features identified were alteration of a small number of myelinated nerve fibers in the white matter, with less than 4 nerve fibers affected per cross-sectional area of the spinal cord. Alteration of nerve fibers was characterized by dilation of myelin sheaths with loss of axons or macrophage infiltration, resembling features of Wallerian axonal degeneration. The occurrence of this nerve fiber alteration had a predilection for the lateral and ventral white matter funiculi. In eight cattle, so-called axonal spheroids were rarely present in the white matter. There was little evidence of glial reaction against nerve fiber alteration. Gray horn neurons were unremarkable. Lipofuscin granules were recognized in neurons, glial cells, and neuropil of the medulla oblongata examined in six cows. The changes observed in the spinal cord white matter of the present cows were similar to those described previously in aged human beings and domestic and laboratory animals, and thus were likely to have been a phenomenon which was closely related to aging. The strict clinical significance of the histopathological changes in the spinal cord white matter remains undetermined.

Open-source pipeline for multi-class segmentation of the spinal cord with deep learning

This paper presents an open-source pipeline to train neural networks to segment structures of interest from MRI data. The pipeline is tailored towards homogeneous datasets and requires relatively low amounts of manual segmentations (few dozen, or less depending on the homogeneity of the dataset). Two use-case scenarios for segmenting the spinal cord white and grey matter are presented: one in marmosets with variable numbers of lesions, and the other in the publicly available human grey matter segmentation challenge [1]. The pipeline is freely available at: https://github.com/neuropoly/multiclass-segmentation.

Resection of a Pediatric Intramedullary Spinal Cord Tumor: 2-Dimensional Operative Video

This video is a case presentation and demonstration of surgical approach to a pediatric intramedullary spinal cord tumor (IMSCT). IMSCT can be associated with significant morbidity and aggressive resection is associated with more favorable long-term outcome. A 13-yr-old male presented to clinic for evaluation of rapidly progressive scoliosis to the left. A contrasted MRI revealed expansion of the spinal cord with edema from approximately T3 to T9 and an enhancing lesion at T6-7 associated with a small cyst. On neurological exam, the patient had good strength throughout, but decreased sensation in the T7-12 dermatomes and decreased deep tendon reflexes in his lower extremities. The procedure included T5 to T8 osteoplastic laminectomies and IMSCT resection followed by spinal reconstruction. Intraoperative ultrasound was used to verify the tumor's location and somatosensory and motor evoked potentials were monitored throughout the procedure. Intraoperative consultation with neuropathology suggested the mass was likely pilocytic astrocytoma; therefore, it was aggressively debulked using microsurgical techniques including an ultrasonic aspirator. There was a plane between the tumor and spinal cord white matter allowing for a gross total resection. Postoperatively the patient had good strength throughout and sensation was intact except for continued numbness of the anterior thigh bilaterally. Immediate postoperative MRI demonstrated complete resection of the tumor without residual enhancement and the patient was ultimately discharged home on postoperative day 8. Follow-up imaging remained stable at 2 mo and the patient continued to do well neurologically. All patient identifiers were removed from the presented material, thus, patient consent was not obtained.

Western diet‐induced insulin resistance impairs recovery after experimental spinal cord injury

The cardinal signs of systemic metabolic dysfunction, including insulin resistance, hypertension and a systemic pro‐inflammatory state are risk factors for the development of cardiovascular disease, type 2 diabetes, and neurodegenerative conditions, but there is limited information regarding the impact on recovery after spinal cord injury (SCI). To address this gap, we investigated the impact of systemic insulin resistance generated by consumption of a diet high in fat and sucrose, often referred to as a Western Diet, on neuropathophysiological outcomes in a murine compression model of incomplete SCI. Ten‐week‐old female C57BL6 mice were provided a regular diet (RD) or a diet high in fat and sucrose (HFHS) for 7 weeks prior to experimental compression SCI.Mice consuming a Western Diet showed signs of systemic insulin resistance such as evaluated blood glucose. In addition, signs of insulin resistance within the substance of the spinal cord were also observed, including reductions in the abundance of insulin‐like growth factor 1 receptor (IGF‐1R). Impairments in motor recovery evaluated by BMS score and subscore were present in mice consuming HFHS at 14 and 30 days post injury (dpi). Consumption of a diet rich in fat and sucrose also impaired the mean maximal angle achieved on the inclined plane test and resulted in significant impairments in bladder release. Immunochemical analysis of the spinal cord revealed a number of differences in markers of neural injury between the two groups. First, mice consuming HFHS exhibited significant increases in astrogliosis measured by glial fibrillary acidic protein (GFAP) prior to injury, compared to mice consuming a RD. In fact, the prominent increases in GFAP observed in the intact spinal cord of mice consuming HFHS were equivalent to those observed after SCI in mice consuming a regular chow. In the subacute period, markers of microglial/monocyte activation were elevated in all mice with SCI; however, the increase was substantially greater in the spinal cords of mice consuming HFHS. The spinal cord white matter of mice consuming HFHS also showed reductions in the number of oligodendrocyte progenitor and mature myelinating cells prior to SCI and HFHS‐associated reductions in myelin producing cells persisted at 14 and 30 dpi. In addition, loss of serotonergic axons in the spinal cord after SCI was exacerbated in mice consuming HFHS. Growth associated protein 43 (GAP43), a marker of axonal growth cones was elevated after SCI in the spinal cords of mice consuming a RD or a HFHS diet; however, the magnitude of the increase in growth cones was severely impaired in mice consuming HFHS.These findings suggest that consumption of a Western Diet increases the risk of insulin resistance within the central nervous system and impairs neurobehavioral recovery after SCI. These studies highlight insulin resistance as a new mechanism that limits nervous system repair after SCI and as a potential target for intervention to improve functional outcomes.Support or Funding InformationNIH R01 NS052741 and The Minnesota State SCI and TBI Research Grant Program.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Measurement of T2* in the human spinal cord at 3T.

To measure the transverse relaxation time T2* in healthy human cervical spinal cord gray matter (GM) and white matter (WM) at 3T. Thirty healthy volunteers were recruited. Axial images were acquired using an averaged multi-echo gradient-echo (mFFE) T2*-weighted sequence with 5 echoes. We used the signal equation for an mFFE sequence with constant dephasing gradients after each echo to jointly estimate the spin density and T2* for each voxel. No global difference in T2* was observed between all GM (41.3 ± 5.6ms) and all WM (39.8 ± 5.4ms). No significant differences were observed between left (43.2 ± 6.8ms) and right (43.4 ± 5.5ms) ventral GM, left (38.3 ± 6.1ms) and right (38.6 ± 6.5ms) dorsal GM, and left (39.4 ± 5.8ms) and right (40.3 ± 5.8ms) lateral WM. However, significant regional differences were observed between ventral (43.4 ± 5.7ms) and dorsal (38.4 ± 6.0ms) GM (p<0.05), as well as between ventral (42.9 ± 6.5ms) and dorsal (37.9 ± 6.2ms) WM (p<0.05). In analyses across slices, inferior T2* was longer than superior T2* in GM (44.7ms vs. 40.1ms; p<0.01) and in WM (41.8ms vs. 35.9ms; p<0.01). Significant differences in T2* are observed between ventral and dorsal GM, ventral and dorsal WM, and superior and inferior GM and WM. There is no evidence for bilateral asymmetry in T2* in the healthy cord. These values of T2* in the spinal cord are notably lower than most reported values of T2* in the cortex.

Gray vs. White Matter Segmentation of the Conus Medullaris: Reliability and Variability in Healthy Volunteers

Magnetic resonance imaging (MRI)-derived spinal cord (SC) gray and white matter (GM/WM) volume are useful indirect measures of atrophy and neurodegeneration over time, typically obtained in the upper SC. Neuropathological evidence suggests that in certain neurological conditions, early degeneration may occur as low as the sacral SC. In this study, the feasibility of GM/WM segmentation of the conus medullaris (CM) was assessed in vivo. Twenty-three healthy volunteers (11 female, mean age 47 years) underwent high-resolution 3T MRI of the CM using a 3-dimensional fast field echo sequence. Reproducibility of the volume measurements was assessed in 5 subjects (2 female, 25-37 years) by one rater who repeated the analysis 3 times and also with 2 additional raters working independently in order to calculate the intra- and interrater coefficient of variation (COV), respectively. Furthermore, the influence of age, gender, spine and SC metrics on tissue-specific measures of the CM was investigated. Volumetric CM analyses (N = 23) for the SC, GM, and WM revealed a mean (SD) total volume of CM-TV = 1746.9 (296.7) mm3 , CM-GM-TV = 731.2 (106.0) mm3 , and CM-WM-TV = 1014.6 (211.3) mm3 , respectively. The intra-rater COV for measuring the CM-TV and CM-GM-TV was 3.38% and 7.42%, respectively; the interrater COV was 3.43% and 10.80%, respectively. Using age, gender, spine and SC metrics in regression models substantially reduced group variability for CM-TV, CM-WM-TV, and CM-GM-TV by up to 39.2%, 42.7%, and 21.2%, respectively. The results from this study demonstrate the feasibility of obtaining tissue-specific volume measurements in the CM by means of MRI with good reproducibility and provide normative data for future applications in neurological diseases affecting the lower SC.

Energy based mechano-electrophysiological model of CNS damage at the tissue scale

Injuries to the central nervous system (CNS) have become a major health challenge in our society. Such injuries can affect the electrophysiological properties, and thus functional behaviour of the nervous system. Most of the related computational studies to date have mainly been focussed on the cellular, subcellular or axonal scales. Although essential for understanding the characteristics of spinal cord injury and traumatic brain injury at the cellular level, these approaches suffer from a lack of scalability to meso- and macroscopic scenarios. To this end, this work presents a tissue level framework describing the coupled mechanical and electrophysiological behaviour of CNS tissue. The proposed mechanical large deformation constitutive model accounts for strain rate dependency, viscous effects and mechanical damage within a thermodynamically consistent framework. Coupled to it, a FitzHugh–Nagumo based model that includes axonal fibre informed anisotropic conduction describes the electrophysiological behaviour. The mechanical model is first calibrated against experimental deformation measurements of spinal cord white matter. The complete framework is then calibrated and used to study the mechano-electrophysiological coupling in spinal cord samples subjected to tension-free relaxation tests by considering electrophysiological damage as a function of mechanical energetic terms. The flexibility of the proposed model is illustrated with the case of mechano-electrophysiological coupling in spinal cord subjected to blast loading. After validation of the coupled model, the mechanical parameters are identified for white matter and an analysis of the influence of axonal dispersion on anisotropic AP conduction in an in silico rat model is presented. This work provides a novel mechano-electrophysiological framework able to model the mechanics of spinal cord and brain tissue and its translation into electrophysiological dysfunction through energetic terms at the tissue level.

Connexin 30 Deficiency Attenuates Chronic but Not Acute Phases of Experimental Autoimmune Encephalomyelitis Through Induction of Neuroprotective Microglia.

Glial connexins (Cxs) form gap junction channels through which a pan-glial network plays key roles in maintaining homeostasis of the central nervous system (CNS). In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), expression of astrocytic Cx43 is lost in acute lesions but upregulated in chronic plaques, while astrocytic Cx30 is very low in normal white matter and changes in its expression have not been convincingly shown. In Cx30 or Cx43 single knockout (KO) mice and even in Cx30/Cx43 double KO mice, acute EAE is unaltered. However, the effects of Cx30/Cx43 deficiency on chronic EAE remains to be elucidated. We aimed to clarify the roles of Cx30 in chronic neuroinflammation by studying EAE induced by myelin oligodendrocyte glycoprotein peptide 35–55 in Cx30 KO mice. We found that Cx30 deficiency improved the clinical symptoms and demyelination of chronic but not acute EAE without influencing CD3+ T cell infiltration. Furthermore, increased ramified microglia in the naïve state and induced earlier and stronger microglial activation in the acute and chronic phases of EAE was observed. These activated microglia had an anti-inflammatory phenotype, as shown by the upregulation of arginase-1 and brain-derived neurotrophic factor and the downregulation of nitric oxide synthase 2. In the naïve state, Cx30 deficiency induced modest enlargement of astrocytic processes in the spinal cord gray matter and a partial reduction of Cx43 expression in the spinal cord white matter. These astrocytes in Cx30 KO mice showed earlier and stronger activation during the acute phase of EAE, with upregulated A2 astrocyte markers and a significant decrease in Cx43 in the chronic phases. Spinal cord neurons and axons were more preserved in Cx30 KO mice than in littermates in the chronic phase of EAE. These findings suggest that Cx30 deficiency increased ramified microglia in the CNS in the naïve state and improved chronic EAE through redirecting microglia toward an anti-inflammatory phenotype, suggesting a hitherto unknown critical role of astrocytic Cx30 in regulating microglial number and functional state.

Two-dimensional magnetization-transfer - CPMG MRI reveals tract-specific signatures in fixed rat spinal cord.

Multiexponential T2 (MET2) Relaxometry and Magnetization Transfer (MT) are among the most promising MRI-derived techniques for white matter (WM) characterization. Both techniques are shown to have histologically correlated sensitivity to myelin, but these correlations are not fully understood. Furthermore, MET2 and MT report on different WM features, thus they can be considered specific to different (patho)physiological states. Two-dimensional studies potentially resolving interactions, such as those commonly used in NMR, have been rarely performed in this context. Here, we investigated how off-resonance irradiation affects different MET2 components in fixed rat spinal cord white matter at 16.4 T. These 2D MT-MET2 experiments reveal that MT affects both short and long T2 components in a tract-specific fashion. The spatially distinct signal modulations enhanced contrast between microstructurally-distinct spinal cord tracts. Two hypotheses to explain these findings were proposed: either selective elimination of a short T2 component through pre-saturation combines with intercompartmental water exchange effects occurring on the irradiation timescale; or, other macromolecular species that exist within the tissue - other than myelin - such as neurofilaments, may be involved in the apparent microstructural segregation of the spinal cord (SC) from MET2. Though further investigation is required to elucidate the underlying mechanism, this phenomenon adds a new dimension for WM characterization.

Diffusion Tensor Imaging Assessment of Regional White Matter Changes in the Cervical and Thoracic Spinal Cord in Pediatric Subjects.

There are no studies to date,describing changes in the diffusion tensor imaging (DTI) metrics of the white matter (WM) regions of the entire cervical and thoracic spinal cord (SC) remote from the lesion in pediatric spinal cord injury (SCI) subjects. The purpose of this study was to determine whether DTI at sites cephalad and caudal to a lesion provides measures of cord abnormalities in children with chronic SCI. A retrospective study included 10 typically developing subjects (TD) and 10 subjects with chronic SCI who underwent SC imaging in 2014-2017. Axial diffusion tensor images using an inner field of view DTI sequence were acquired to cover the entire cervical and thoracic SC. Regions of interest were drawn on the SC WM: right and left lateral (motor), ventral (motor), and dorsal (sensory) tracts. To detect differences in DTI metrics between TD and SCI of the cord, a one way analysis of variance with pooled t test was performed. A stepwise regression analysis was performed to assess the correlation between DTI metrics and clinical scores. In motor and sensory tracts, fractional anisotropy (FA) and axial diffusivity (AD) were significantly decreased in the proximal segments of the caudal cord. In motor tracts cephalad to the lesion, FA was significantly decreased whereas AD was significantly increased in the proximal segment; however, AD was decreased in the distal and middle segments. International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) total score was significantly correlated with FA and AD of the motor and sensory tracts cephalad to the lesion. This study demonstrates that FA and AD have the potential to be sensitive biomarkers of the full extent of cord injury and might be useful in detecting remote injuries to the SC and in guiding new treatments.

Neuroprotective Effects of 6-Shogaol and Its Metabolite, 6-Paradol, in a Mouse Model of Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease characterized by progressive neuronal loss, neuroinflammation, axonal degeneration, and demyelination. Previous studies have reported that 6-shogaol, a major constituent of ginger (Zingiber officinale rhizome), and its biological metabolite, 6-paradol, have anti-inflammatory and anti-oxidative properties in the central nervous system (CNS). In the present study, we investigated whether 6-shogaol and 6-paradol could ameliorate against experimental autoimmune encephalomyelitis (EAE), a mouse model of MS elicited by myelin oligodendrocyte glycoprotein (MOG35-55) peptide immunization with injection of pertussis toxin. Once-daily administration of 6-shogaol and 6-paradol (5 mg/kg/day, p.o.) to symptomatic EAE mice significantly alleviated clinical signs of the disease along with remyelination and reduced cell accumulation in the white matter of spinal cord. Administration of 6-shogaol and 6-paradol into EAE mice markedly reduced astrogliosis and microglial activation as key features of immune responses inside the CNS. Furthermore, administration of these two molecules significantly suppressed expression level of tumor necrosis factor-α, a major proinflammatory cytokine, in EAE spinal cord. Collectively, these results demonstrate therapeutic efficacy of 6-shogaol or 6-paradol for EAE by reducing neuroinflammatory responses, further indicating the therapeutic potential of these two active ingredients of ginger for MS.

Neurite orientation dispersion and density imaging can detect presymptomatic axonal degeneration in the spinal cord of ALS mice.

Neurite orientation dispersion and density imaging (NODDI), a MRI multi-shell diffusion technique, has offered new insights for the study of microstructural changes in neurodegenerative diseases. Mainly, the present study aimed to determine the connection between NODDI-derived parameters and changes in white matter (WM) abnormalities at early stages of amyotrophic lateral sclerosis (ALS). Spinal cords from ALS mice (G93A-SOD1 mice) were scanned in a Bruker Avance III HD 17.6T magnet. Fluorescent axonal-tagged mice (YFP, G93A-SOD1 mice) were used for quantitative histological analysis. NODDI showed a decrease in intra-cellular volume fraction (-24%) and increases in orientation dispersion index (+35%) and isotropic volume fraction (+33%). In addition, histoathological results demonstrated a reductions in axonal area (-11%) and myelin content (-29%). A histological decrease in WM intra-axonal space (-71%) and an increase in the extra-axonal compartment (+22%) were also detected. Our studies demonstrate that NODDI may be a suitable technique for detecting presymptomatic spinal cord WM microstructural degeneration in ALS.

In vivo diffusion MRI detects early spinal cord axonal pathology in a mouse model of amyotrophic lateral sclerosis.

Diffusion magnetic resonance imaging (MRI) exhibits contrast that identifies macro- and microstructural changes in neurodegenerative diseases. Previous studies have shown that MR diffusion tensor imaging (DTI) can observe changes in spinal cord white matter in animals and humans affected with symptomatic amyotrophic lateral sclerosis (ALS). The goal of this preclinical work was to investigate the sensitivity of DTI for the detection of signs of tissue damage before symptoms appear. High-field MRI data were acquired using a 9.4-T animal scanner to examine the spinal cord of an ALS mouse model at pre- and post-symptomatic stages (days 80 and 120, respectively). The MRI results were validated using yellow fluorescent protein (YFP) via optical microscopy of spinal cord tissue slices collected from the YFP,G93A-SOD1 mouse strain. DTI maps of diffusion-weighted imaging (DWI) signal intensity, mean diffusivity (MD), fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were computed for axial slices of the lumbar region of the spinal cord. Significant changes were observed in FA (6.7% decrease, p<0.01), AD (19.5% decrease, p<0.01) and RD (16.1% increase, p<0.001) at postnatal day 80 (P80). These differences were correlated with changes in axonal fluorescence intensity and membrane cellular markers. This study demonstrates the value of DTI as a potential tool to detect the underlying pathological progression associated with ALS, and may accelerate the discovery of therapeutic strategies for patients with this disease.

Ultrasound-guided spinal stereotactic system for intraspinal implants.

OBJECTIVE The overall goal of this study was to develop an image-guided spinal stereotactic setup for intraoperative intraspinal microstimulation (ISMS). System requirements were as follows: 1) ability to place implants in various segments of the spinal cord, targeting the gray matter with a < 0.5-mm error; 2) modularity; and 3) compatibility with standard surgical tools. METHODS A spine-mounted stereotactic system was developed, optimized, and tested in pigs. The system consists of a platform supporting a micromanipulator with 6 degrees of freedom. It is modular and flexible in design and can be applied to various regions of the spine. An intraoperative ultrasound imaging technique was also developed and assessed for guidance of electrode alignment prior to and after electrode insertion into the spinal cord. Performance of the ultrasound-guided stereotactic system was assessed both in pigs (1 live and 6 fresh cadaveric pigs) and on the bench using four gelatin-based surrogate spinal cords. Pig experiments were conducted to evaluate the performance of ultrasound imaging in aligning the electrode trajectory using three techniques and under two conditions. Benchtop experiments were performed to assess the performance of ultrasound-guided targeting more directly. These experiments were used to quantify the accuracy of electrode alignment as well as assess the accuracy of the implantation depth and the error in spatial targeting within the gray matter of the spinal cord. As proof of concept, an intraoperative ISMS experiment was also conducted in an additional live pig using the stereotactic system, and the resulting movements and electromyographic responses were recorded. RESULTS The stereotactic system was quick to set up (< 10 minutes) and provided sufficient stability and range of motion to reach the ISMS targets reliably in the pigs. Transverse ultrasound images with the probe angled at 25°-45° provided acceptable contrast between the gray and white matter of the spinal cord. In pigs, the largest electrode alignment error using ultrasound guidance, relative to the minor axis of the spinal cord, was ≤ 3.57° (upper bound of the 95% confidence interval). The targeting error with ultrasound guidance in bench testing for targets 4 mm deep into the surrogate spinal cords was 0.2 ± 0.02 mm (mean ± standard deviation). CONCLUSIONS The authors developed and evaluated an ultrasound-guided spinal stereotactic system for precise insertion of intraspinal implants. The system is compatible with existing spinal instrumentation. Intraoperative ultrasound imaging of the spinal cord aids in alignment of the implants before insertion and provides feedback during and after implantation. The ability of ultrasound imaging to distinguish between spinal cord gray and white matter also improves confidence in the localization of targets within the gray matter. This system would be suitable for accurate guidance of intraspinal electrodes and drug or cell injections.

BDNF haploinsufficiency exerts a transient and regionally different influence upon oligodendroglial lineage cells during postnatal development

Brain-Derived Neurotrophic Factor (BDNF) plays important roles in promoting myelination in the developing central nervous system (CNS), however the influence it exerts on oligodendrocyte development in vivo remains unclear. As BDNF knockout mice die in the perinatal period, we undertook a systematic developmental analysis of oligodendroglial lineage cells within multiple CNS regions of BDNF heterozygous (HET) mice. Our data identify that BDNF heterozygosity results in transient reductions in oligodendroglial lineage cell density and progression that are largely restricted to the optic nerve, whereas the corpus callosum, cerebral cortex, basal forebrain and spinal cord white matter tracts are unaffected. In the first two postnatal weeks, BDNF HET mice exhibit reductions in the density of oligodendroglial lineage cells, oligodendrocyte precursor cells (OPCs) and postmitotic oligodendrocytes selectively in the optic nerve, but not in the brain or spinal cord white matter tracts. However, this normalizes later in development. The overall proportion of OPCs and mature oligodendrocytes remains unchanged from P9 to P30 in all CNS regions. This study identifies that BDNF exerts transient effects on oligodendroglial lineage cells selectively in the optic nerve during postnatal development. Taken together, this provides compelling evidence that BDNF haploinsufficiency exerts modest effects upon oligodendroglial cell density and lineage progression in vivo, suggesting its major role is restricted to promoting oligodendrocyte myelination.

Compressive mechanical characterization of non-human primate spinal cord white matter

The goal of developing computational models of spinal cord injury (SCI) is to better understand the human injury condition. However, finite element models of human SCI have used rodent spinal cord tissue properties due to a lack of experimental data. Central nervous system tissues in non human primates (NHP) closely resemble that of humans and therefore, it is expected that material constitutive models obtained from NHPs will increase the fidelity and the accuracy of human SCI models. Human SCI most often results from compressive loading and spinal cord white matter properties affect FE predicted patterns of injury; therefore, the objectives of this study were to characterize the unconfined compressive response of NHP spinal cord white matter and present an experimentally derived, finite element tractable constitutive model for the tissue. Cervical spinal cords were harvested from nine male adult NHPs (Macaca mulatta). White matter biopsy samples (3 mm in diameter) were taken from both lateral columns of the spinal cord and were divided into four strain rate groups for unconfined dynamic compression and stress relaxation (post-mortem <1-hour). The NHP spinal cord white matter compressive response was sensitive to strain rate and showed substantial stress relaxation confirming the viscoelastic behavior of the material. An Ogden 1st order model best captured the non-linear behavior of NHP white matter in a quasi-linear viscoelastic material model with 4-term Prony series. This study is the first to characterize NHP spinal cord white matter at high (>10/sec) strain rates typical of traumatic injury. The finite element derived material constitutive model of this study will increase the fidelity of SCI computational models and provide important insights for transferring pre-clinical findings to clinical treatments. Statement of SignificanceSpinal cord injury (SCI) finite element (FE) models provide an important tool to bridge the gap between animal studies and human injury, assess injury prevention technologies (e.g. helmets, seatbelts), and provide insight into the mechanisms of injury. Although, FE model outcomes depend on the assumed material constitutive model, there is limited experimental data for fresh spinal cords and all was obtained from rodent, porcine or bovine tissues. Central nervous system tissues in non human primates (NHP) more closely resemble humans. This study characterizes fresh NHP spinal cord material properties at high strains rates and large deformations typical of SCI for the first time. A constitutive model was defined that can be readily implemented in finite strain FE analysis of SCI.

Future Brain and Spinal Cord Volumetric Imaging in the Clinic for Monitoring Treatment Response in MS.

Volumetric analysis of brain imaging has emerged as a standard approach used in clinical research, e.g., in the field of multiple sclerosis (MS), but its application in individual disease course monitoring is still hampered by biological and technical limitations. This review summarizes novel developments in volumetric imaging on the road towards clinical application to eventually monitor treatment response in patients with MS. In addition to the assessment of whole-brain volume changes, recent work was focused on the volumetry of specific compartments and substructures of the central nervous system (CNS) in MS. This included volumetric imaging of the deep brain structures and of the spinal cord white and gray matter. Volume changes of the latter indeed independently correlate with clinical outcome measures especially in progressive MS. Ultrahigh field MRI and quantitative MRI added to this trend by providing a better visualization of small compartments on highly resolving MR images as well as microstructural information. New developments in volumetric imaging have the potential to improve sensitivity as well as specificity in detecting and hence monitoring disease-related CNS volume changes in MS.

G-Protein-Coupled Receptor Gpr17 Regulates Oligodendrocyte Differentiation in Response to Lysolecithin-Induced Demyelination

Oligodendrocytes are the myelin-producing cells of the central nervous system (CNS). A variety of brain disorders from “classical” demyelinating diseases, such as multiple sclerosis, stroke, schizophrenia, depression, Down syndrome and autism, are shown myelination defects. Oligodendrocyte myelination is regulated by a complex interplay of intrinsic, epigenetic and extrinsic factors. Gpr17 (G protein-coupled receptor 17) is a G protein-coupled receptor, and has been identified to be a regulator for oligodendrocyte development. Here, we demonstrate that the absence of Gpr17 enhances remyelination in vivo with a toxin-induced model whereby focal demyelinated lesions are generated in spinal cord white matter of adult mice by localized injection of LPC(L-a-lysophosphatidylcholine). The increased expression of the activated form of Erk1/2 (phospho-Erk1/2) in lesion areas suggested the potential role of Erk1/2 activity on the Gpr17-dependent modulation of myelination. The absence of Gpr17 enhances remyelination is correlate with the activated Erk1/2 (phospho-Erk1/2).Being a membrane receptor, Gpr17 represents an ideal druggable target to be exploited for innovative regenerative approaches to acute and chronic CNS diseases.

Dynamic changes and molecular analysis of cell death in the spinal cord of SJL mice infected with the BeAn strain of Theiler's murine encephalomyelitis virus.

Theiler's murine encephalomyelitis (TME) is caused by the TME virus (TMEV) and represents an important animal model for multiple sclerosis (MS). Oligodendroglial apoptosis and reduced apoptotic elimination of encephalitogenic leukocytes seem to participate in autoimmune demyelination in MS. The present study quantified apoptotic cells in BeAn-TMEV-induced spinal cord white matter lesions at 14, 42, 98, and 196 days post infection (dpi) using immunostaining. Apoptotic cells were identified by transmission electron microscopy and double-immunofluorescence. The mRNA expression of apoptosis-related genes was investigated using microarray analysis. Oligodendroglial apoptosis was already detected in the predemyelinating phase at 14 dpi. Apoptotic cell numbers peaked at 42 dpi and decreased until 196 dpi partly due to reduced T cell apoptosis. In addition to genes involved in the classical pathways of apoptosis induction, microarray analysis detected the expression of genes related to alternative mechanisms of cell death such as pyroptosis, necroptosis, and endoplasmic reticulum stress. Consequently, oligodendroglial apoptosis is involved in the initiation of the TME demyelination process, whereas the development of apoptosis resistance of T cells potentially favors the maintenance of inflammation and myelin loss.

Quantitative spinal cord MRI in radiologically isolated syndrome.

ObjectivesTo assess whether quantitative spinal cord MRI (SC-MRI) measures, including atrophy, and diffusion tensor imaging (DTI) and magnetization transfer imaging metrics were different in radiologically isolated syndrome (RIS) vs healthy controls (HCs).MethodsTwenty-four participants with RIS and 14 HCs underwent cervical SC-MRI on a 3T magnet. Manually segmented regions of interest circumscribing the spinal cord cross-sectional area (SC-CSA) between C3 and C4 were used to extract SC-CSA, fractional anisotropy, mean, perpendicular, and parallel diffusivity (MD, λ⊥, and λ||) and magnetization transfer ratio (MTR). Spinal cord (SC) lesions, SC gray matter (GM), and SC white matter (WM) areas were also manually segmented. Multivariable linear regression was performed to evaluate differences in SC-MRI measures in RIS vs HCs, while controlling for age and sex.ResultsIn this cross-sectional study of participants with RIS, 71% had lesions in the cervical SC. Of quantitative SC-MRI metrics, spinal cord MTR showed a trend toward being lower in RIS vs HCs (p = 0.06), and there was already evidence of brain atrophy (p = 0.05). There were no significant differences in SC-DTI metrics, GM, WM, or CSA between RIS and HCs.ConclusionThe SC demonstrates minimal microstructural changes suggestive of demyelination and inflammation in RIS. These findings are in contrast to established MS and raise the possibility that the SC may play an important role in triggering clinical symptomatology in MS. Prospective follow-up of this cohort will provide additional insights into the role the SC plays in the complex sequence of events related to MS disease initiation and progression.