Network Collapse and Cognitive Impairment in Multiple Sclerosis

FUNCTIONAL REORGANIZATION IN MS: AN OUTDATED CONCEPT? 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 other cognitive domains and also showed such an apparently beneficial increased local activation, for example, during a memory task in the hippocampus (11) and during the N-back working memory task in the dorsolateral prefrontal cortex (DLPFC) (12). Importantly, these studies also showed decreased activation in cognitively impaired patients. The body of literature of that point in time led to our previous hypothesis of functional reorganization in MS (13). This hypothesis asserted that a “compensatory” change is seen in the brains of MS patients in the form of an increase in brain function, i.e., both increased activation and increased connectivity. Functional connectivity is conceptually quite different from task-based activation and reflects the amount of communication between brain regions, i.e., coherent patterns of firing typically measured with correlation measures. Early connectivity studies investigated the so-called “default mode network” (DMN), which is only coherently active during a resting state. Two such studies found DMN changes that were interpreted in the same way as the task-based activation studies: increased DMN connectivity in clinically isolated syndrome (CIS) patients (14) and decreased DMN connectivity in progressive MS, which was related to cognitive impairment (15). We proposed that increasing structural damage, in combination with an optimum curve of “functional reorganization,” results in a delayed, non-linear, development of cognitive dysfunction. However, the previous model was mostly based on task-based activation studies, while the connectivity field was still in its infancy. As the concept of functional reorganization was gaining support, the field was primed for finding cognitively relevant connectivity changes. Interestingly, recent studies have mostly related increased functional connectivity to cognitive dysfunction, raising doubts on the previous concept of functional reorganization in MS. In this paper, we will review this recent functional connectivity literature and reiterate the case around functional connectivity changes in MS and their potential effects on cognition. Which reported connectivity changes can be justifiably said to be “compensatory”or“beneficial”? Which are likely “maladaptive”? Can any such predicate be arrived at all, based on the neuroscientific studies available? Is it perhaps time to revise our previous model of functional reorganization?