Functional Magnetic Resonance Imaging in Pediatric-onset Multiple Sclerosis: Relation to Structural Damage and Cognition

Pediatric Multiple Sclerosis (MS) is increasingly being recognized, with special concern being placed on how the demyelinating disease process affects normal brain development and the acquisition of cognitive abilities required for vocational success in adulthood. While pediatric MS patients are at risk for cognitive impairment early in their disease, many youth with pediatric MS appear to function at the same level as their age-matched peers despite the accrual of disease-related structural brain damage. This thesis aims to investigate whether functional magnetic resonance imaging (fMRI) can help understand mechanisms for cognitive preservation as well as the discrepancy between performance and accrual of structural disease insult, using both resting-state and a task-based processing speed paradigm. It was observed overall that pediatric MS patients demonstrate higher resting-state functional connectivity, particularly of the default-mode network, compared to healthy controls. Furthermore, higher functional connectivity of the precuneus within the default-mode network was associated with reduced white matter structural integrity as measured using diffusion tensor imaging (DTI). There is, however, a breakdown specifically of thalamo-cortical networks with increasing lesion accrual and reductions in thalamic volume. It was also observed that lower cognitive performance was associated with greater functional connectivity of the frontal medial cortex with the anterior cingulate and precuneus during resting-state, suggesting less neural efficiency in patients who demonstrate some cognitive challenges though are not yet impaired. During the performance of an actual processing speed fMRI task, faster performance was associated with activation of a greater number of brain regions suggesting that a compensatory mechanism is present during actual task performance. Overall, this thesis demonstrates that pediatric MS is associated with brain activation abnormalities during resting-state that relates to the extent of neuronal injury. This work also sheds light on the factors which may be accounting for preservation of cognitive abilities, namely greater overall group activation during resting-state and greater activation associating with faster performance during a task that probes processing speed.Ph.D