This doctoral dissertation presents a series of studies that were conducted to investigate the relationship between morphological, as well as functional, changes and clinical disability in multiple sclerosis (MS) using magnetic resonance imaging (MRI) and functional MRI (fMRI). / The extent of macroscopic brain tissue damage, as seen on T2-weighted MRI scans, is poorly correlated with measures of functional impairment in MS. We hypothesized that this might be due to the failure to take lesion location into account. By combining sophisticated lesion segmentation tools with the statistical and stereotaxic techniques of functional neuroimaging, we have shown a relationship between lesion location and the extent and type of physical and cognitive disability. / Brain atrophy is another manifestation of MS. We conducted the first large-scale study of focal cortical atrophy in MS that uses cortical thickness measurements across the entire cortex. We present evidence that cortical atrophy occurs relatively early in the course of the disease, despite the lack of severe disability in MS patients, as assessed by the Expanded Disability Status Scale (EDSS), and follows a pattern of focal thinning that is more pronounced in areas that are heavily inter-connected with other brain regions, such as anterior cingulate cortex and association areas, suggesting that interruption of white matter tracts by MS plaques might play a causative role in cortical atrophy. / Finally, we conducted an fMRI study of working memory in controls, cognitively unimpaired and impaired MS patients that revealed significant differences in the regions that were activated between the groups. Most interestingly, while both cognitively unimpaired MS patients and control subjects significantly activated the left dorsolateral prefrontal cortex and the left thalamus, cognitively impaired MS patients failed to significantly activate these areas. Levels of deactivation within the medial prefrontal/anterior cingulate cortices and posterior cingulate cortex were inferior in MS patients than in controls. This study suggests that with an increased white matter lesion volume there is an increased damage to a number of afferents and efferents to and from the thalamus (cortico-basal ganglia-thalamo-cortical loops and other thalamo-cortical projections) that ultimately causes the observed cognitive deficits. These cognitive deficits seem also to be dependent on a reduced capacity of MS patients to show task-related deactivations.

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