Structural disconnection is responsible for increased functional connectivity in multiple sclerosis

Abstract

Increased synchrony within neuroanatomical networks is often observed in neurophysiologic studies of human brain disease. Most often, this phenomenon is ascribed to a compensatory process in the face of injury, though evidence supporting such accounts is limited. Given the known dependence of resting-state functional connectivity (rsFC) on underlying structural connectivity (SC), we examine an alternative hypothesis: that topographical changes in SC, specifically particular patterns of disconnection, contribute to increased network rsFC. We obtain measures of rsFC using fMRI and SC using probabilistic tractography in 50 healthy and 28 multiple sclerosis subjects. Using a computational model of neuronal dynamics, we simulate BOLD using healthy subject SC to couple regions. We find that altering the model by introducing structural disconnection patterns observed in those multiple sclerosis subjects with high network rsFC generates simulations with high rsFC as well, suggesting that disconnection itself plays a role in producing high network functional connectivity. We then examine SC data in individuals. In multiple sclerosis subjects with high network rsFC, we find a preferential disconnection between the relevant network and wider system. We examine the significance of such network isolation by introducing random disconnection into the model. As observed empirically, simulated network rsFC increases with removal of connections bridging a community with the remainder of the brain. We thus show that structural disconnection known to occur in multiple sclerosis contributes to network rsFC changes in multiple sclerosis and further that community isolation is responsible for elevated network functional connectivity.

Functional Connectivity in Multiple Sclerosis: Recent Findings and Future Directions

“…In our view, it is overly simplistic to interpret the change of FC between a pair of brain regions in isolation. For example, in the case of the breakdown of modularity we observe both a decrease in FC of nodes that belong to the same module and an increase in FC of nodes that belong to different modules ( 133 , 134 ). Therefore, we strongly advocate a network-based approach when trying to interpret FC or when testing hypotheses related to changes of connectivity.…”

“…This finding from a computational model corroborates the observation of decreasing small-worldness as a function of increasing lesion load in MS ( 57 ). More recently, Patel et al used simulations to demonstrate that damage to structural connectivity can give rise to increased FC which they then compared to empirical FC within MS patients ( 133 ).…”

Default Mode Network Connectivity Predicts Emotion Recognition and Social Integration After Traumatic Brain Injury

“…While a relationship between increased connectivity and reduced behavioral performance may at first seem counterintuitive, we highlight that such “hyperconnectivity” —particularly within the DMN—has been reported in several previous studies of moderate-severe TBI (60–65) as well as other neurologic disorders (66), although its functional significance has remained unclear. For example, it has been proposed that increased connectivity arises as an indirect response to structural disruption (61, 67), reflecting neural communication through alternative (and less efficient) pathways due to degraded direct connections [(68, 69); see (70), for review]. In this light, increased within-DMN connectivity may reflect a neural (but not necessarily behavioral) compensation for reduced structural integrity, arising from injury or from natural variation in white matter (14, 71, 72).…”

Concurrent anatomical, physiological and network changes in cognitively impaired multiple sclerosis patients

“…Studies which have combined the rs-fMRI and dMRI methods have found a relationship between anatomical and functional abnormalities (e.g. Hawellek et al ., 2011; Louapre et al ., 2014; Patel et al ., 2018; Tewarie et al ., 2018). Recently, computational studies support an impact of anatomical connectivity damage on FC.…”

“…These simulations demonstrated that as white matter pathology initially increased FC increased, but as it continued, FC started to decrease. This finding was interpreted as increased local FC following damage to long-range white matter fibres, followed by a global network collapse with subsequent reductions in FC as the network fails (Patel et al ., 2018; Tewarie et al ., 2018). Such findings are consistent with the prediction that axonal metabolic stress affects functional networks.…”