Neurite orientation dispersion and density imaging of the healthy cervical spinal cord in vivo

Here we present the application of neurite orientation dispersion and density imaging (NODDI) to the healthy spinal cord in vivo. NODDI provides maps such as the intra-neurite tissue volume fraction (vin), the orientation dispersion index (ODI) and the isotropic volume fraction (viso), and here we investigate their potential for spinal cord imaging. We scanned five healthy volunteers, four of whom twice, on a 3 T MRI system with a ZOOM-EPI sequence. In accordance to the published NODDI protocol, multiple b-shells were acquired at cervical level and both NODDI and diffusion tensor imaging (DTI) metrics were obtained and analysed to: i) characterise differences in grey and white matter (GM/WM); ii) assess the scan–rescan reproducibility of NODDI; iii) investigate the relationship between NODDI and DTI; and iv) compare the quality of fit of NODDI and DTI. Our results demonstrated that: i) anatomical features can be identified in NODDI maps, such as clear contrast between GM and WM in ODI; ii) the variabilities of vin and ODI are comparable to that of DTI and are driven by biological differences between subjects for ODI, have similar contribution from measurement errors and biological variation for vin, whereas viso shows higher variability, driven by measurement errors; iii) NODDI identifies potential sources contributing to DTI indices, as in the brain; and iv) NODDI outperforms DTI in terms of quality of fit. In conclusion, this work shows that NODDI is a useful model for in vivo diffusion MRI of the spinal cord, providing metrics closely related to tissue microstructure, in line with findings in the brain

Microstructural imaging of the human spinal cord with advanced diffusion MRI

The aim of this PhD thesis is to advance the state-of-the-art of spinal cord magnetic resonance imaging (MRI) in multiple sclerosis (MS), a demyelinating, inflammatory and neurodegenerative disease of the central nervous system. Neurite orientation dispersion and density imaging (NODDI) is a recent diffusion-weighted (DW) MRI technique that provides indices of density and orientation dispersion of neuronal processes. These could be new useful biomarkers for the spinal cord, since they could better characterise overall, widespread MS pathology than conventional metrics. In this thesis, we test innovative clinically feasible acquisitions as well as signal analysis methods to study the potential of NODDI for the spinal cord. We also design and run computer simulations that corroborate our in vivo findings. Furthermore, we compare NODDI metrics to quantitative histological features, with the aim of validating their specificity. The thesis is divided in two parts. In the first part, in vivo experiments are described. Specific objectives are: i) to demonstrate the feasibility of performing NODDI in the spinal cord and in clinical settings; ii) to study the possibility of extracting with new approaches such as NODDI more specific microstructural information from standard DW acquisitions; iii) to assess how features typical of spinal cord microstructure, such as presence of large axons, influence NODDI metrics. In the second part of the thesis, ex vivo experiments are discussed. Their objective is the validation of the specificity of NODDI metrics via comparison to quantitative histology in post mortem spinal cord tissue. The experiments required the implementation of high-field DW scans as well as histological procedures and complex analysis pipelines. The results of this thesis contribute to current scientific knowledge. They prove that NODDI offers new opportunities to study how neurodegenerative diseases such as MS alter neural tissue complexity. We showed for the first time that NODDI can be performed in the spinal cord in vivo and in clinical scans. We also demonstrated that NODDI analysis of standard DW data is challenging, and quantified how the presence of large axons in the spinal cord influences NODDI metrics. Lastly, our ex vivo data highlight that unlike routine DW MRI methods, NODDI can detect reliably pathological variations of neurite orientation dispersion. NODDI is also sensitive to the density of axons and dendrites, but can not fully resolve axonal loss and demyelination in MS. We believe that the technique is a key element of a more general multi-modal MRI approach, which is necessary to obtain a complete description of complex diseases such as MS

Quantitative MRI and EMG study of the brachial plexus

This thesis describes the development and applications of quantitative MRI and combined EMG and MRI study of Brachial Plexus. The protocols developed in this thesis have been used on normal healthy subjects, aiming at characterizing the tissues based on their MR and EMG parameters. The Brachial Plexus is the upper portion of the peripheral nervous system and controls the movements of shoulder and arms. Neurological disorders in the brachial plexus can result from cervical spondylotic neuropathy due to compression of nerve roots exiting from vertebra or compression of the spinal cord due to bulging discs. MRI provides the opportunity to obtain precise information on the location of these disorders and to provide quantitative biomarkers. EMG in the form of the distribution of F-latency (DFL) is a recently introduced nerve conduction parameter that can detect functional symptoms with such disorders. To study the brachial plexus the diffusion weighted MRI with body signal suppression (DWIBS) technique was used to highlight the nerves from surrounding tissues. This technique was then used to investigate the diffusivity of water molecules in the peripheral nerve axon. The diffusion time dependency of the diffusion coefficient was used to study the presence of restricted diffusion in the brachial plexus. A clear reduction of the apparent diffusion coefficient was observed with long diffusion times and confirmed the restricted diffusion in nerves and cord. The T2 relaxation was used to investigate the properties of intercellular and intracellular space in peripheral nerves. Diffusion weighting dependency of T2 and echo time dependency of apparent diffusion coefficient (ADC) was observed in initial studies. The magnetisation transfer (MT) and z-spectra were used to study macromolecular characteristics and exchange mechanisms. Asymmetry in z-spectra both for nerves and spinal cord was observed, this relates to possible detection of the nuclear overhauser effect (NOE) in the brachial plexus. Quantitative MRI studies showed that these parameters can be used as important biomarkers for neurological studies in the brachial plexus. The DFL, representing the motor nerve fibres conduction characteristics, was measured for normal healthy nerves and combined with MR parameters. Correlation between DFL and MR parameters was observed for the first time

Magnetic resonance imaging of muscle structure and function

Ziel dieser Arbeit ist die Implementierung und kombinierte Anwendung verschiedener MRT Techniken zur Untersuchung der Struktur und Funktion der humanen Skelettmuskulatur. Insbesondere steht deren Applikation an der Rückenmuskulatur im Vordergrund, um auf Basis dieser Untersuchungen einen Beitrag zur Ursachenforschung des unspezifischen - meist chronifizierten - Rückenschmerzes zu leisten. Vor diesem Hintergrund wurden in der vorliegenden Dissertation dezidierte MR-Pulssequenzen und Bildrekonstruktionsverfahren entwickelt, welche unter Verwendung der diffusionsgewichteten MR-Bildgebung (diffusion-weighted imaging, DWI) die 3D-Rekonstruktion der Muskelfaserarchitektur sowie die Quantifizierung der muskulären Vaskularität ermöglichen. Die Erfassung der Faserarchitektur basiert auf der Diffusionstensorbildgebung (diffusion tensor imaging, DTI) - einer Weiterentwicklung der DWI - und wurde am Tiermodell anhand sequentiell durchgeführter in vivo und post mortem Messungen validiert. Anschließend wurde diese Methode in einer Pilotstudie genutzt, um degenerative Veränderungen bei Patienten nach Wirbelsäulenoperation zu erfassen. Im zweiten Schritt dieser Arbeit, wurde ein Messprotokoll zur funktionellen MR-Untersuchung implementiert, welches Messungen vor, während und nach willkürlicher Muskelkontraktion beinhaltet. Dieses Protokoll sieht weiterhin die Applikation einer neuartigen perfusionsensitiven DWI-Sequenz sowie optimierten Sequenzen zur quantitativen T2-gewichteten MR-Bildgebung und ortaufgelösten 31P-MR-Spektroskopie vor, wobei die beiden letztgenannten Techniken es erlauben, komplexe funktionelle Vorgänge, wie beispielsweise die des Energiemetabolismus, unter Einfluss einer Belastungssituation zu untersuchen. Diese funktionellen MR-Messprinzipien werden in der Regel unter dem Begriff muscle functional MRI (mfMRI) subsumiert und ermöglichen die multi-parametrische Erfassung unterschiedlicher funktioneller und struktureller Eigenschaften der Muskelphysiologie. Dies wird in der vorliegenden Arbeit anhand einer gerontologischen Studie demonstriert, wobei die hierbei gewonnenen Ergebnisse Einblick in zahlreiche altersassoziierte Aspekte der Rückenphysiologie geben. Zusammenfassend werden in dieser Dissertation verschiedene Ansätze der MR-Bildgebung und MR-Spektroskopie vorgestellt, die einerseits für grundlagenwissenschaftliche Fragestellungen zum unspezifischen Rückenschmerz, andererseits aber auch in der klinischen Routine zur Untersuchung degenerativer Veränderungen der Skelettmuskulatur herangezogen werden können.The aim of this work is the implementation and combined application of different MRI-based methods, which facilitate the comprehensive assessment of the skeletal muscle structure and function. Especially, the application of these MRI techniques to human back muscles has been put into focus, which may provide deeper insights into the origin of non-specific - and in most cases chronic - back pain. To this end, dedicated MRI sequences and quantitative image reconstruction approaches were developed in this work, which are based on diffusion-weighted imaging (DWI) and enable the 3D reconstruction of the muscle fiber architecture as well as the assessment of a surrogate measure of the vascular capacity. The MRI-based reconstruction of the fiber architecture relies on diffusion tensor imaging (DTI) - an extension of DWI - and was validated by successive in vivo and post mortem measurements. Afterwards, this method was employed in a pre-clinical pilot study in order to assess surgeryrelated degenerative changes of the back muscles in patients after spinal surgery. In the second step of this work, functional measurements of the human skeletal muscles, which means quantitative measurements prior to, during and after muscular loading, were performed by using a novel perfusion-sensitive DWI sequence as well as optimized sequence protocols of quantitative T2-weighted MRI and spatially resolved 31P-MR spectroscopy. The latter two methods allow the quantification of complex physiological processes, such as of the high-energy metabolism, during the exercise of skeletal muscles, and are often subsumed under the term muscle functional MRI (mfMRI). Combined application of these mfMRI techniques provides multi-parametric evaluation of several structural and functional determinants and, thus, allows comprehensive characterization of the muscle physiology. In order to demonstrate the capabilities of the proposed multi-parametric mfMRI approach, a gerontological study is performed in this work, while the obtained results indicate several age-related aspects of the human back muscle physiology. Overall, this thesis introduces MR imaging and MR spectroscopy techniques, which may, on the one hand, contribute to research of low back pain and, on the other hand, serve as basis of clinical investigations in order to investigate degenerative processes of skeletal muscles

Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI

The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'