The network collapse in multiple sclerosis: An overview of novel concepts to address disease dynamics

Abstract

Multiple sclerosis is a neuroinflammatory and neurodegenerative disorder of the central nervous system that can be considered a network disorder. In MS, lesional pathology continuously disconnects structural pathways in the brain, forming a disconnection syndrome. Complex functional network changes then occur that are poorly understood but closely follow clinical status. Studying these structural and functional network changes has been and remains crucial to further decipher complex symptoms like cognitive impairment and physical disability. Recent insights especially implicate the importance of monitoring network hubs in MS, like the thalamus and default-mode network which seem especially hit hard. Such network insights in MS have led to the hypothesis that as the network continues to become disconnected and dysfunctional, exceeding a certain threshold of network efficiency loss leads to a "network collapse". After this collapse, crucial network hubs become rigid and overloaded, and at the same time a faster neurodegeneration and accelerated clinical (and cognitive) progression can be seen. As network neuroscience has evolved, the MS field can now move towards a clearer classification of the network collapse itself and specific milestone events leading up to it. Such an updated network-focused conceptual framework of MS could directly impact clinical decision making as well as the design of network-tailored rehabilitation strategies. This review therefore provides an overview of recent network concepts that have enhanced our understanding of clinical progression in MS, especially focusing on cognition, as well as new concepts that will likely move the field forward in the near future.

Keywords: Cognition; Connectivity; Efficiency; Hub; Multiple sclerosis; Network.

Fig. 1

State changes as a function of network organization The “ball-and-cup” heuristic might help with thinking about how the functional network dynamically changes its organization. (A) The normal state, transitioning between all brain states continuously. All possible network conformations are represented by the surface, with the current organization of the network represented by the position of the ball (i.e. the functional network at a particular time-point). The ball can move over the surface (reflecting network dynamics), but this is governed by the nature of the surface. For example, the ball is more likely to remain in the cup, so the bottom of a cup represents frequently occurring network conformations (i.e. states). Still, after passing a critical threshold (i.e. moving over the hill), the ball moves into a new state. Different factors could affect how the ball moves within the landscape. (B) State resilience. The depth of a cup or the height of the hill affects how easily it can move between states. (C) State stability. The slope of the cup’s edges affects the movement within a state.

Fig. 2

The network collapse as a cause for clinical progression and especially cognitive impairment in MS In early stages of MS, even subtle structural damage can induce extensive functional changes, usually in the form of hyperconnectivity. As structural damage becomes more severe and spreads, structural disconnection becomes apparent. Increased functional connectivity centers around hub regions, overloading these crucial network structures, leading to inefficient and rigid networks. The combination of exceeding certain thresholds of structural disconnection and hub overload is then thought to induce a “network collapse”, after which clinical progression accelerates.