Multiple sclerosis (MS) is common, affecting about 0.1% of the US population. It is a chronic inflammatory disease of the central nervous system (CNS) with primary destruction of myelin sheaths. It has been known for decades that axonal loss also occurs in MS. In principle, the functional deficit induced by inflammation and demyelination may be reversible. In contrast, the damage to axons and neurons is likely to be irreversible once the threshold of compensation is exceeded. Thus, it has been widely speculated that axonal loss is the pathologic correlate of irreversible neurological impairment in MS. On the other hand, axonal loss is not always evident in lesions from patients who are severely affected. The complexity and heterogeneity of the underlying mechanisms of MS require new para-clinical markers for more accurate diagnosis. The growing number of agents that can slow the disease process requires more precise therapeutic management of the disease. The advent of magnetic resonance imaging (MRI) has revolutionized the diagnosis of MS. It has been used extensively as a sensitive, objective, and quantifiable measure of pathology and therapeutic responses in MS. However, the complex MS pathology has proven too illusive to be accurately reflected by the existing imaging modalities, including conventional MRI.

Diffusion, the microscopic random translational motion of molecules, in biological tissues such as human CNS tissues, can be measured using MRI. The water diffusion in a glass of water is isotropic, identical in all directions. However, water diffusion in CNS tissue is directionally dependent, reflecting the underlying tissue structure. For example, in white matter axons water diffusion is faster along the fiber tracts than across it due to the axonal membrane and myelin sheaths restricting water movements. Our lab has proposed and demonstrated that axonal injury leads to decreased water diffusion coefficient along axonal fiber tracts (axial diffusivity). On the other hand, demyelination causes increased water diffusion coefficient across axonal fiber tracts (radial diffusivity). The axial and radial diffusivity can be derived using diffusion tensor imaging (DTI), a widely used technique to reflect CNS injury. Previously, our group demonstrated that axonal injury is the primary substrate correlating with neurological disability of the EAE mice. However, such success has not been fully realized in human MS despite some encouraging results from our own group in optic neuritis patients.

The primary limitation of DTI is that it assumes that the imaged tissue can be described as a single tensor. It takes the imaged tissue as a whole and averages the effect of different tissue components. Although this approach has proven to be useful to detect white matter injuries, it fails to correctly quantify the complex MS pathologies. In the onset of optic neuritis, if there is only inflammation in the optic nerve without axonal damage, water diffusion in the infiltrating cell is highly restricted due to the hindrance to water movement of the cell membrane. Using DTI, the estimated axial diffusivity would be significantly underestimated due to the averaging effect leading to a false prediction of the presence of axonal injury. To resolve this shortcoming of DTI, we have developed a novel diffusion MRI method, diffusion basis spectrum imaging (DBSI), to correctly estimate the diffusion property of water in each pathological components of the MS lesion. By the use of 99 directions of diffusion weighting gradients with varied diffusion weighting factor, the water molecule was extensively sampled to reflect the tissue structure of both infiltrating cells and axonal fibers. The diffusion data acquired will then undergo a multiple-tensor analysis to correctly determine the diffusion property of each component with the size of each component quantified. Thus, DBSI will correctly reveal the extent of cell infiltration and axonal integrity of the optic nerve suffering initial attack of optic neuritis. The capability of DBSI to correctly depict the various underlying tissue pathologies underlying the neurological deficit would be invaluable in stratification of MS patient treatments and the evaluation of therapeutic efficacy.