MR Susceptibility Mapping: Improved Quantification and Applications in Developmental Brain Imaging

The white matter fibers of the human brain are primarily composed of myelinated axons, which connect different brain regions, transmit neural signals, and form efficient communication pathways that shape the neural systems responsible for higher-order functioning. The fatty myelin sheath protects and insulates the axons and acts as an electrical insulator that facilitates the electrical flow through the axons, and is crucial in the transmission of nerve impulses. Human cognition, sensation and motor functions all rely on the efficient transmission of neural signals, where compromised myelin integrity may lead to severe neurological and physical disorders. Myelin abnormality can be a hallmark of numerous neurological disorders such as cerebral palsy, multiple sclerosis, and autism. Abnormal myelination can be a result of direct damages to the myelin sheath, or indirect causes such as neuro-inflammation which affects the oligodendrocytes that generate the myelin sheath, or even genetic disorders.To approach the pathology and potential therapeutic effects for these neurological disorders, studies have been directed towards the remyelination or repair of the myelin in the central nervous system (CNS). Previously, myelin in the CNS can only be reliably quantified by in vitro methods such as myelin staining and measuring myelin basic protein. Magnetic Resonance Imaging (MRI), with its excellent soft tissue contrast and non-invasive nature, has revolutionized the ways to investigate white matter properties. Several methods in effort to assess the white matter have been developed, such as diffusion tensor imaging (DTI), which has been used to quantify the water diffusion in white matter and thus the connectivity of the brain. However, DTI-derived measurements, while sensitive to white matter microstructural changes, are difficult to interpret due to multiple factors that can alter water diffusion, including axonal membrane, neural tubules, crossing fibers, and myelin. It is possible that either axonal or myelin alternations could impact the conductivity of the fibers and further affect the diffusion measures. Therefore, DTI does not have the specificity to single out the origins of the connectivity change behind neurodegenerative diseases or brain development. Prior studies using quantitative susceptibility mapping (QSM) have shown its unique sensitivity to myelin. However, due to the cylindrical structure of myelin sheaths wrapping around axons, the magnetic susceptibility measured by QSM of the white matter has been found to be dependent on the angular orientations of white matter fibers. Susceptibility Tensor Imaging (STI) has been developed to address this orientation-dependence of susceptibility values in white matter, which requires images acquired from at least 6 non-colinear orientations to solve the susceptibility tensor, and is not practical in clinical settings. Therefore, the goal of this dissertation work is to develop a clinically practical MR susceptibility mapping method to quantitatively assess the magnetic susceptibility anisotropy (MSA) of white matter, which will greatly help us understand the role of myelination in the treatment of neurological diseases and in normal brain development. The work presented here includes the development of the methodology and two in vivo studies to prove its efficacy: (1) The magnetic susceptibility anisotropy in white matter was observed and measured by relating the apparent tissue susceptibility as a function of the white matter angle with respect to the applied magnetic field. A clinically practical solution to estimate the MSA of white matter fibers with QSM images acquired from a single orientation is proposed using prior information obtained through DTI, namely DTI-guided QSM. (2) The DTI-guided QSM methodology was used to investigate the potential mechanism behind the motor function improvement of cerebral palsy (CP) patients who underwent autologous stem cell therapy. Results showed that this motor function improvement was correlated with the connectivity increase in the motor network, and was further traced down to a focal increase of the magnetic susceptibility at the periventricular corticospinal tract (CST), which may indicate an increase in the local myelin content after treatment. (3) This methodology was then applied to profile the myelin maturation pattern of the white matter fiber bundles in pediatric subjects. Results revealed a spatio-temporal myelination pattern of the corpus callosal fibers, which follows a posterior to anterior myelination trajectory with the peak developmental rate spurts at around 2-3 years of age. This result is consistent with previous studies using histological methods and relaxometry-based methods, with better specificity to myelin, and improved consistency across subjects. In conclusion, the proposed DTI-guided QSM has shown its ability to accurately quantify the magnetic susceptibility anisotropy of major fiber tracts with high spatial accuracy and minimal angle dependence, and has addressed its potential in delineating the underlying neural mechanism in neurodevelopmental disorders such as CP, as well as in profiling the myelination pattern during normal brain development. It is anticipated that this quantitative approach may find broader applications to help characterize white matter properties in both healthy and diseased brains across the life span.