Longitudinal assessment of white matter pathology in the injured mouse spinal cord through ultra-high field (16.4T) in vivo diffusion tensor imaging

This study examined the sensitivity of ultra-high field (16.4 T) diffusion tensor imaging (DTI; 70 mu m in-plane resolution, 1 mm slice thickness) to evaluate the spatiotemporal development of severe mid-thoracic contusive spinal cord injury (SCI) in mice. In vivo imaging was performed prior to SCI, then again at 2 h, 1 day, 3 days, 7 days, and 30 days post-SCI using a Bruker 16.4 T small animal nuclear magnetic resonance spectrometer. Cross-sectional spinal cord areas were measured in axial slices and various DTI parameters, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda(parallel to)) and radial diffusivity (lambda(perpendicular to)), were calculated for the total spared white matter (WM), ventral funiculi (VF), lateral funiculi (LF) and dorsal columns (DCs) and then correlated with histopathology. Cross-sectional area measurements revealed significant atrophy (32% reduction) of the injured spinal cord at the lesion epicentre in the chronic phase of injury. Analysis of diffusion tensor parameters further showed that tissue integrity was most severely affected in the DCs, i.e. the site of immediate impact, which demonstrated a rapid and permanent decrease in FA and lambda(parallel to). In contrast, DTI parameters for the ventrolateral white matter changed more gradually with time, suggesting that these regions are undergoing more delayed degeneration in a manner that may be amenable to therapeutic intervention. Of all the DTI parameters, lambda(perpendicular to) was most closely correlated to myelin content whereas changes in FA and lambda(parallel to) appeared more indicative of axonal integrity, Wallerian degeneration and associated presence of macrophages. We conclude that longitudinal DTI at 16.4 T provides a clinically relevant, objective measure for assessing white matter pathology following contusive SCI in mice that may aid the translation of putative neuroprotective strategies into the clinic. (C) 2013 Elsevier Inc. All rights reserved

Anatomo-functional magnetic resonance imaging of the spinal cord and its application to the characterization of spinal lesions in cats

Les lésions de la moelle épinière ont un impact significatif sur la qualité de la vie car elles peuvent induire des déficits moteurs (paralysie) et sensoriels. Ces déficits évoluent dans le temps à mesure que le système nerveux central se réorganise, en impliquant des mécanismes physiologiques et neurochimiques encore mal connus. L'ampleur de ces déficits ainsi que le processus de réhabilitation dépendent fortement des voies anatomiques qui ont été altérées dans la moelle épinière. Il est donc crucial de pouvoir attester l'intégrité de la matière blanche après une lésion spinale et évaluer quantitativement l'état fonctionnel des neurones spinaux. Un grand intérêt de l'imagerie par résonance magnétique (IRM) est qu'elle permet d'imager de façon non invasive les propriétés fonctionnelles et anatomiques du système nerveux central. Le premier objectif de ce projet de thèse a été de développer l'IRM de diffusion afin d'évaluer l'intégrité des axones de la matière blanche après une lésion médullaire. Le deuxième objectif a été d'évaluer dans quelle mesure l'IRM fonctionnelle permet de mesurer l'activité des neurones de la moelle épinière. Bien que largement appliquées au cerveau, l'IRM de diffusion et l'IRM fonctionnelle de la moelle épinière sont plus problématiques. Les difficultés associées à l'IRM de la moelle épinière relèvent de sa fine géométrie (environ 1 cm de diamètre chez l'humain), de la présence de mouvements d'origine physiologique (cardiaques et respiratoires) et de la présence d'artefacts de susceptibilité magnétique induits par les inhomogénéités de champ, notamment au niveau des disques intervertébraux et des poumons. L'objectif principal de cette thèse a donc été de développer des méthodes permettant de contourner ces difficultés. Ce développement a notamment reposé sur l'optimisation des paramètres d'acquisition d'images anatomiques, d'images pondérées en diffusion et de données fonctionnelles chez le chat et chez l'humain sur un IRM à 3 Tesla. En outre, diverses stratégies ont été étudiées afin de corriger les distorsions d'images induites par les artefacts de susceptibilité magnétique, et une étude a été menée sur la sensibilité et la spécificité de l'IRM fonctionnelle de la moelle épinière. Les résultats de ces études démontrent la faisabilité d'acquérir des images pondérées en diffusion de haute qualité, et d'évaluer l'intégrité de voies spinales spécifiques après lésion complète et partielle. De plus, l'activité des neurones spinaux a pu être détectée par IRM fonctionnelle chez des chats anesthésiés. Bien qu'encourageants, ces résultats mettent en lumière la nécessité de développer davantage ces nouvelles techniques. L'existence d'un outil de neuroimagerie fiable et robuste, capable de confirmer les paramètres cliniques, permettrait d'améliorer le diagnostic et le pronostic chez les patients atteints de lésions médullaires. Un des enjeux majeurs serait de suivre et de valider l'effet de diverses stratégies thérapeutiques. De telles outils représentent un espoir immense pour nombre de personnes souffrant de traumatismes et de maladies neurodégénératives telles que les lésions de la moelle épinière, les tumeurs spinales, la sclérose en plaques et la sclérose latérale amyotrophique.Spinal cord injury has a significant impact on quality of life since it can lead to motor (paralysis) and sensory deficits. These deficits evolve in time as reorganisation of the central nervous system occurs, involving physiological and neurochemical mechanisms that are still not fully understood. Given that both the severity of the deficit and the successful rehabilitation process depend on the anatomical pathways that have been altered in the spinal cord, it may be of great interest to assess white matter integrity after a spinal lesion and to evaluate quantitatively the functional state of spinal neurons. The great potential of magnetic resonance imaging (MRI) lies in its ability to investigate both anatomical and functional properties of the central nervous system non invasively. To address the problem of spinal cord injury, this project aimed to evaluate the benefits of diffusion-weighted MRI to assess the integrity of white matter axons that remain after spinal cord injury. The second objective was to evaluate to what extent functional MRI can measure the activity of neurons in the spinal cord. Although widely applied to the brain, diffusion-weighted MRI and functional MRI of the spinal cord are not straightforward. Various issues arise from the small cross-section width of the cord, the presence of cardiac and respiratory motions, and from magnetic field inhomogeneities in the spinal region. The main purpose of the present thesis was therefore to develop methodologies to circumvent these issues. This development notably focused on the optimization of acquisition parameters to image anatomical, diffusion-weighted and functional data in cats and humans at 3T using standard coils and pulse sequences. Moreover, various strategies to correct for susceptibility-induced distortions were investigated and the sensitivity and specificity in spinal cord functional MRI was studied. As a result, acquisition of high spatial and angular diffusion-weighted images and evaluation of the integrity of specific spinal pathways following spinal cord injury was achieved. Moreover, functional activations in the spinal cord of anaesthetized cats was detected. Although encouraging, these results highlight the need for further technical and methodological development in the near-future. Being able to develop a reliable neuroimaging tool for confirming clinical parameters would improve diagnostic and prognosis. It would also enable to monitor the effect of various therapeutic strategies. This would certainly bring hope to a large number of people suffering from trauma and neurodegenerative diseases such as spinal cord injury, tumours, multiple sclerosis and amyotrophic lateral sclerosis

Diffusion Tensor Imaging of the Central Nervous System Following an Injury to the Spinal Cord and Cell Transplant

The purpose of this dissertation research was to characterize the use of magnetic resonance diffusion tensor imaging (DTI) as a diagnostic and prognostic tool in understanding the changes that occur throughout the spinal cord and brain following a spinal cord injury (SCI) and following stem cell transplant. The diffusion of water inside the nervous system is dramatically altered around the lesion site following a traumatic SCI. However, following damage to the spinal cord, little is known about the diffusion characteristics away from an injury and even less is understood about DTI\u27s sensitivity to structural changes that occur following regenerative transplant therapies. The non-invasive nature of DTI could potentially allow for diagnostic and prognostic indicators of an SCI remote from injury and could provide physicians a method for tracking and monitoring the effectiveness of injected stem cells. To evaluate the sensitivity of DTI to structural changes in the central nervous system (CNS) following a traumatic SCI, diffusion metrics in the brain and cervical spinal cord were compared for four different injury severities in a thoracic contusion model of a rat SCI. Structural changes in the cervical region of the spinal cord after transplantation of C17.2 neuronal stem cells were also examined with the use of DTI. The findings from this dissertation suggest that diffusion tensor imaging is sensitive to changes in tissue structure in regions remote from injury and for cellular environments that increased astrocytic sprouting as a result of stem cell transplant. Mean water diffusion in the distal locations of the spinal cord and in the brain decreased following SCI. Neuronal stem cells that are known to elicit astrocytic proliferation produced mean increases in water diffusion. These results further clarify the potential for DTI to provide physicians a method to non-invasively monitor how the CNS changes following SCI and detec

Correlation of Diffusion Tensor Imaging Indices with Histological Parameters in Rat Cervical Spinal Cord Gray Matter Following Distal Contusion Spinal Cord Injury

The purpose of this study was to delineate the diffusion tensor imaging (DTI) parameters across the cervical spinal cord gray matter (GM) in a distal (T8) rat contusion spinal cord injury (SCI) model. DTI data were obtained from ex vivo rat spinal cords and registered to corresponding histological slices in samples from the acute through chronic stages of SCI including uninjured control, 2 weeks post injury, 15 weeks post injury and 25 weeks post injury groups (n = 5 in all groups). After imaging, samples were dehydrated, blocked in paraffin, sliced axially and stained with eriochrome cyanine R stain and H&E counter-stain. A corresponding sample was post fixed with osmium tetroxide and stained with toluidine blue. Histology images of the eriochrome cyanine R stained and H&E counter-stained slices were captured at 4x and then segmented into white matter (WM) and GM and dorsal and ventral GM using a custom cluster analysis. Using whole cord templates, DTI images for each animal were then registered to the corresponding histology images. The WM and the GM regions of interest (ROI) histological templates were then used to map DTI indices, including fractional anisotropy (FA), longitudinal apparent diffusion coefficient (lADC) and transverse apparent diffusion coefficient (tADC) across the GM. The average values for each index were also calculated in predefined gray matter ROIs. Histology images of the above mentioned ROIs were captured at 40x resolution using the toluidine blue stained slices for the control and post injury groups (n=4). Motoneuron size in the ventral GM was calculated for each of the control and post injury groups. It was observed that the FA and lADC values in the dorsal GM ROI were significantly higher than that in the ventral GM ROI in controls, fifteen weeks post injury and twenty five weeks post injury groups (P \u3c 0.05). The overall GM FA value at twenty five weeks was significantly higher than the FA value at two weeks post injury (P \u3c 0.05) and the FA value in controls (P \u3c 0.05). Group analysis of the size of the motor neurons showed a 9% increase in the motoneuron size at two weeks (P \u3c 0.01) and 42% increase at twenty five weeks (P \u3c 0.01) post injury as compared to controls. The motor neurons also showed a significant increase in size at twenty five weeks post injury (P \u3c 0.01) as compared to the motor neuron size at two weeks post injury. These results indicate changes in gray matter structure rostral to a contusion injury that can be detected and monitored using DTI

Diffusion Tensor Tractography in Cerebral White Matter

Conventional magnetic resonance imaging (MRI) allows researchers and clinicians to observe the anatomy and injuries of the cerebral white matter (CWM) in dogs. However, dynamic images based on the diffusion tensor (DT) technique are required to assess fiber tract integrity of the CWM. Diffusion tensor tractography (DTT) produces a three-dimensional representation in which data are displayed on a colored map obtained from the anisotropy of water molecules in the CWM tracts. Fractional anisotropy (FA) is a value that measures changes in water diffusion, which can occur if the CWM tracts are displaced, disrupted, or infiltrated. The goal of this study was to determine the feasibility of DTT for in vivo examination of the normal appearance of CWM in dogs through visual and quantitative analysis of the most representative CWM tracts

Diagnostic Imaging in Intervertebral Disc Disease

Imaging is integral in the diagnosis of canine intervertebral disc disease (IVDD) and in differentiating subtypes of intervertebral disc herniation (IVDH). These include intervertebral disc extrusion (IVDE), intervertebral disc protrusion (IVDP) and more recently recognized forms such as acute non-compressive nucleus pulposus extrusion (ANNPE), hydrated nucleus pulposus extrusion (HNPE), and intradural/intramedullary intervertebral disc extrusion (IIVDE). Many imaging techniques have been described in dogs with roles for survey radiographs, myelography, computed tomography (CT), and magnetic resonance imaging (MRI). Given how common IVDH is in dogs, a thorough understanding of the indications and limitations for each imaging modality to aid in diagnosis, treatment planning and prognosis is essential to successful case management. While radiographs can provide useful information, especially for identifying intervertebral disc degeneration or calcification, there are notable limitations. Myelography addresses some of the constraints of survey radiographs but has largely been supplanted by cross-sectional imaging. Computed tomography with or without myelography and MRI is currently utilized most widely and have become the focus of most contemporary studies on this subject. Novel advanced imaging applications are being explored in dogs but are not yet routinely performed in clinical patients. The following review will provide a comprehensive overview on common imaging modalities reported to aid in the diagnosis of IVDH including IVDE, IVDP, ANNPE, HNPE, and IIVDE. The review focuses primarily on canine IVDH due to its frequency and vast literature as opposed to feline IVDH

Utility of Diffusion and Magnetization Transfer MRI in Cervical Spondylotic Myelopathy: A Pilot Study

Diffusion tensor imaging (DTI) and magnetization transfer (MT) magnetic resonance imaging (MRI) can help detect spinal cord pathology, and tract-specific analysis of their parameters, such as fractional anisotropy (FA), mean diffusivity, axial diffusivity (AD), radial diffusivity (RD) and MT ratio (MTR), can give microstructural information. We performed the tract-based acquisition of MR parameters of three major motor tracts: the lateral corticospinal (CS), rubrospinal (RuS) tract, and lateral reticulospinal (RS) tract as well as two major sensory tracts, i.e., the fasciculus cuneatus (FC) and spinal lemniscus, to detect pathologic change and find correlations with clinical items. MR parameters were extracted for each tract at three levels: the most compressed lesion level and above and below the lesion. We compared the MR parameters of eight cervical spondylotic myelopathy patients and 12 normal controls and analyzed the correlation between clinical evaluation items and MR parameters in patients. RuS and lateral RS showed worse DTI parameters at the lesion level in patients compared to the controls. Worse DTI parameters in those tracts were correlated with weaker power grasp at the lesion level. FC and lateral CS showed a correlation between higher RD and lower FA and MTR with a weaker lateral pinch below the lesion level.ope

Volume Changes After Traumatic Spinal Cord Injury in Animal Studies - A Systematic Review

There are limited data on the lesion volume changes following spinal cord injury (SCI). In this study, a meta-analysis was performed to evaluate the volume size changes of the injured spinal cord over time among animal studies in traumatic SCI. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive electronic search of English literature of PubMed and EMBASE databases from 1946 to 2015 concerning the time-dependent changes in the volume of the spinal cord following mechanical traumatic SCI. A hand-search was also performed for non-interventional, non-molecular, and non-review studies. Quality appraisal, data extraction, qualitative and quantitative analyses were performed afterward. Of 11,561 articles yielded from electronic search, 49 articles were assessed for eligibility after reviewing of titles, abstracts, and references. Ultimately, 11 articles were eligible for quantitative synthesis. The ratio of lesion volume to spinal cord total volume increased over time. Avascularity appeared in spinal cord 4 hours after injury. During the first week, the spinal subarachnoid space decreased. The hemorrhagic lesion size peaked in 1 week and decreased thereafter. Significant loss of gray and white matter occurred from day 3 with a slower progression of white matter damage. Changes of lesion extent over time is critical in pathophysiologic processes after SCI. Early avascularity, rapid loss of gray matter, slow progression of white matter damage, and late cavitation are the pathophysiologic key points of SCI, which could be helpful in choosing the proper intervention on a timely basis