The Cognitive, Neurophysiologic, and Connectivity Effects of Multiple Sclerosis on Information Processing Speed and Memory

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that can negatively impact both motor and cognitive ability. About 70% of MS patients experience cognitive impairment with reduced information processing speed (IPS) and memory decrements as the most prevalent. IPS, defined as the amount of time needed to process elementary cognitive operations, might be especially critical for cognitive functions that require the coordination of widely distributed 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. In my dissertation, I first hypothesize that reduced IPS in MS disrupts the timely coorination needed between the brain regions associated with working memory function and that this reduced IPS underlies memory declines in MS patients. Furthermore, MS-related neuroinflammation might lead to a strain on oxygen resource availability that can cause neurologic and neurocognitive deficits. Therefore, my second hypothesis is that MS-related metabolic resource constraints impede the ability of neurons to fire persistently and are associated with MS-related reductions in IPS performance. Additionally, timely coordination of interregional connectivity is critical for IPS and memory function. Therefore, dysfunction to the persistent neural activity within a region could affect interregional connectivity. Therefore, my third hypothesis is that, due to altered metabolic resource availability, connectivity between brain regions involved in cognitive function is adversely affected. To test these hypotheses, MS and healthy control (HC) participants underwent extensive neuropsychological evaluation and then advanced dual-echo functional magnetic resonance imaging (fMRI) 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 (CMRO2) while they performed an IPS task. Participants also underwent resting-state fMRI and structural diffusion imaging to investigate functional and structural connectivity. Neuropsychological evaluation results showed that MS-related variability in IPS explained variability in verbal episodic and working memory ability in MS patients even after controlling for motor, visual, disease and demographic variables, and after using a composite variable to attenuate task-specific variability. Neurophysiologic results showed that levels of metabolism in the dorsolateral prefrontal cortex (dlPFC), and area known to be associated with IPS, significantly predicted IPS ability in MS patients. Connectivity analysis results showed that MS-related changes in prefrontal metabolism that significantly explained IPS ability were explained by MS-related changes in resting-state connectivity from the cerebellum. Furthermore, disrupted functional and structural connectivity between the cerebellum and parahippocampal gyri was associated with verbal learning and episodic memory impairment. These results suggest that MS-related metabolic disruptions in an executive area, the dlPFC, are associated with reduced IPS and connectivity changes in MS, and that this disruption has negative effects on episodic and working memory.