Understanding Network Level Changes in Multiple Sclerosis: Relationships with Cognitive Dysfunction

Abstract

Cognitive impairment is a debilitating symptom of multiple sclerosis (MS). The pathological mechanisms are poorly understood, making it difficult to monitor decline clinically and develop interventions. Advanced MRI measures are increasingly used to identify the brain structural and functional substrates of cognitive dysfunction. This thesis aimed to build upon this work by investigating network changes in people with MS and assessing links with cognitive impairment. A systematic review established that functional network changes are commonly associated with cognitive impairment across studies and MS phenotypes, but there was no consistent pattern of connectivity increases or decreases, likely due to the large heterogeneity of methods and population studied in the literature to date. This review highlighted the need for more model-led studies which probe the mechanisms of functional connectivity changes. The second study of the thesis combined resting state functional MRI with diffusion MRI and cerebral blood flow to test the nodal stress hypothesis, which predicts that the high metabolic demands of network hub regions make them susceptible to degeneration. We found altered anatomical connectivity and cerebral blood flow measures around the networks with abnormal functional connectivity in cognitively impaired relative to non-impaired patients, thus providing preliminary support for the nodal stress hypothesis. The third study of the thesis tested the energy failure hypothesis, which is based on observations of sodium accumulation in demyelinated axons, resulting from inadequate energy to pump sodium out of the cell. By combining resting state functional MRI with sodium MRI we were able to show evidence of sodium accumulation in functional network regions, which correlated with cognitive test performance, providing further support for altered metabolic function of brain networks supporting cognitive function. The final study of the thesis explored whether damage to structural connectivity in MS is dominated by one or more patterns of pathology that resemble those seen using typical functional network assessments, to understand if damaged anatomical connections could be a driver of functional connectivity abnormalities. No evidence of a network structure within white matter was found, but results highlight the need to understand the relationship between anatomical and functional connectivity better. Together, these studies confirm the importance of network changes as a correlate of cognitive impairment in MS and highlight the need for more model-led research into the mechanisms of network changes. A better understanding of what causes connectivity changes has the potential to provide an MRI marker of cognitive decline for clinical translation.

Date of Award	31 Dec 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Geoff Parker (Supervisor), Laura Parkes (Supervisor) & Nils Muhlert (Supervisor)