Abstract Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that can impair both motor and cognitive ability. Upwards of 70% of MS patients experience cognitive impairment with processing speed and memory ability as the most prominent neuropsychological deficits observed. Processing speed, defined as the amount of time needed to process elementary cognitive operations may be especially important for cognitive functions that are widely distributed across brain regions. Current models of working memory posit that it is a widely distributed system involving persistent neural activity in various brain regions during memory delays. For instance, the completion of a working memory task requires persistent neural activity in sensory, executive, motor, and associative cortical areas, and functional connectivity between these areas. MS is known to degrade the white matter microstructure that mediates neural-vascular communication and functioning, also known as neural-vascular coupling. I hypothesize that poor neural-vascular coupling impedes the ability of neurons to fire persistently and maintain memory traces in brain regions needed for working memory tasks. Timely coordination between brain areas is also critical for executing working memory tasks. Therefore, any impediment to the persistent neural activity required within a region could affect connectivity between working memory-related brain regions. Thus, I hypothesize that, due to altered neural-vascular coupling within working memory regions, functional connectivity between working memory-related regions is adversely affected. In Aim 1, I will test the hypothesis that abnormal neural-vascular coupling in working memory regions is related to slower processing speed in MS. In Aim 2, I will test the hypothesis that abnormal neural-vascular coupling in working memory regions leads to altered functional connectivity between working memory-related brain regions. To assess the Aim 1 hypotheses, I will use advanced dual-echo functional magnetic resonance imaging to obtain measures of blood-oxygen-level-dependent (BOLD) signal, cerebral blood flow, maximum blood-oxygen capacity (the factor M), and cerebral metabolic rate of oxygen in MS and healthy controls during a Sternberg-type Working Memory Task (SWMT). To assess the Aim 2 hypotheses, I will use resting-state and task-based functional connectivity analyses along with structural diffusion imaging analyses to investigate the functional and structural connectivity between working memory-related regions associated with the SWMT. Achieving these grant aims will yield new knowledge about MS-related neurophysiologic alterations, MS- related connectivity changes, and how these changes may be associated with interactions between processing speed and working memory impairments in MS.