Investigating the link between regional oxygen metabolism and cognitive speed in multiple sclerosis: Implications for fatigue

Background: Most multiple sclerosis (MS) patients experience fatigue and cognitive decline but the underlying mechanisms remain unknown. Previous work has shown whole brain resting cerebral metabolic rate of oxygen (CMRO₂) is associated with the extent of these symptoms. However, it is not known if the association between global CMRO₂ and MS-related cognitive speed and fatigue can be localized to specific brain regions. Based upon previous research suggesting prefrontal involvement in MS-related changes in cognitive speed and fatigue, we hypothesized that oxygen metabolic changes within prefrontal cortex (PFC) might form the pathophysiologic basis of cognitive performance and fatigue in MS patients. Objective: Investigate whether PFC ΔCMRO₂ is associated with cognitive speed and fatigue in MS. Methods: MS and healthy control (HC) participants were scanned using a dual-­echo fMRI sequence and underwent a hypercapnia calibration experiment that permitted estimation of ΔCMRO₂ while performing a scanner version of symbol-digit modalities task, a measure of information processing speed and utilized in the clinic as a reliable sentinel biomarker for global cognitive impairment in MS. Participants then completed the Modified Fatigue Impact Scale (MFIS) to measure fatigue. Results: MS patients exhibited significant reductions in cognitive performance relative to HCs (p < 0.04). Prefrontal ΔCMRO₂ explained significant variability (ΔR² = 0.11) in cognitive speed, over and above disease and demographic variables, for the MS group only. Prefrontal ΔCMRO₂ was not associated with fatigue across groups. ΔCMRO₂ in visual and motor areas were not associated with cognitive performance or fatigue for either group. Conclusion: Prefrontal oxygen metabolism may be a sensitive measure of MS-related cognitive decline.