The current field of multiple sclerosis (MS) research is an active and highly interesting one: structural abnormalities such as inflammatory lesions and brain atrophy are studied with a wide array of advanced neuroimaging techniques (1). These techniques are subsequently used to try to explain the large clinical heterogeneity in patients. Clinically important in MS is cognitive dysfunction, which is present in 40–70% of all patients (2, 3). Cognitive impairment in MS receives much attention, as there is currently no proven effective treatment, but symptoms may nevertheless start in early stages of disease already (4). Cognitive decline is known to exert deleterious effects on psychosocial functioning (2, 5, 6). Traditional structural imaging measures like lesion volumes are notoriously poorly related with cognitive function (7), so a move toward more sensitive, comprehensive measures is required, such as those that measure brain function in addition to brain structure.

Historically, most early imaging studies have used the paced auditory serial addition test (PASAT) to study cognition in MS, a task that measures information processing speed (8–10). These observed a combination of hyperactivation of frontal regions in response to the task and a recruitment of additional areas, not normally attributed to the task in controls. The functional changes were mostly positively related to the amount of structural damage in the brain, and were stronger in patients who scored normally on the PASAT, indicating that it might be a beneficial process. Later studies investigated