Dynamic functional connectivity as a neural correlate of fatigue in multiple sclerosis

Tijhuis, Floris B.; Broeders, Tommy A.A.; Santos, F. A. N.; Schoonheim, Menno M.; Killestein, Joep; Leurs, Cyra E.; Geest, Quinten van; Steenwijk, Martijn D.; Geurts, Jeroen J. G.; Hulst, Hanneke E.; Douw, Linda

doi:10.1016/j.nicl.2020.102556

Cited by 29 publications

(36 citation statements)

References 47 publications

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“…As non-hub regions are more widely dispersed across the network, 46 this might explain our lack of network-specific effects, although this hypothesis needs validation in future work. Finally, in theory, more extensive reconfiguration dynamics could require sustained effort and burden on the network, which might play an important role in the development of fatigue in multiple sclerosis, 49 but no relationship between cohesion and fatigue was observed in this study.…”

Section: Discussioncontrasting

confidence: 55%

A more unstable resting-state functional network in cognitively declining multiple sclerosis

Broeders

Douw

Eijlers

et al. 2022

Brain Communications

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Cognitive impairment is common in people with multiple sclerosis and strongly affects their daily functioning. Reports have linked disturbed cognitive functioning in multiple sclerosis to changes in the organization of the functional network. In the healthy brain, communication between brain regions and which network a region belongs to is continuously and dynamically adapted to enable adequate cognitive function. However, this dynamic network adaptation has not been investigated in multiple sclerosis, and longitudinal network data remains particularly rare. Therefore, the aim of this study was to longitudinally identify patterns of dynamic network reconfigurations that are related to the worsening of cognitive decline in multiple sclerosis. Resting-state functional MRI and cognitive scores (expanded Brief Repeatable Battery of Neuropsychological tests) were acquired in 230 patients with multiple sclerosis and 59 matched healthy controls, at baseline (mean disease duration 15 years) and at 5 year follow-up. A sliding-window approach was used for functional MRI analyses where brain regions were dynamically assigned to one of seven literature-based subnetworks. Dynamic reconfigurations of subnetworks was characterised using measures of promiscuity (number of subnetworks switched to), flexibility (number of switches), cohesion (mutual switches) and disjointedness (independent switches). Cross-sectional differences between cognitive groups and longitudinal changes were assessed, as well as relations with structural damage and performance on specific cognitive domains. At baseline, 23% of patients were cognitively impaired (≥ 2/7 domains Z< -2) and 18% were mildly impaired (≥ 2/7 domains Z< -1.5). Longitudinally, 28% of patients declined over time (0.25 yearly change on ≥ 2/7 domains based on reliable change index). Cognitively impaired patients displayed more dynamic network reconfigurations across the whole brain compared to cognitively preserved patients and controls, i.e., showing higher promiscuity (p=0.047), flexibility (p=0.008) and cohesion (p=0.008). Over time, cognitively declining patients showed a further increase in cohesion (p=0.004), which was not seen in stable patients (p=0.544). More cohesion was related to more severe structural damage (average r=0.166, p=0.015) and worse verbal memory (r=-0.156, p=0.022), information processing speed (r=-0.202, p=0.003) and working memory (r=-0.163, p=0.017). Cognitively impaired multiple sclerosis patients exhibited a more unstable network reconfiguration compared to preserved patients, i.e. brain regions switched between subnetworks more often, which was related to structural damage. This shift to more unstable network reconfigurations was also demonstrated longitudinally in patients that demonstrated cognitive decline only. These results indicate the potential relevance of a progressive destabilization of network topology for understanding cognitive decline in multiple sclerosis.

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Section: Discussioncontrasting

confidence: 55%

A more unstable resting-state functional network in cognitively declining multiple sclerosis

Broeders

Douw

Eijlers

et al. 2022

Brain Communications

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“…Fatigue and motor impairment are common features of MS. Several studies have reported inverse relationships between DMN-BG FC alterations and fatigue in MS. With a seed-based sFC approach, a negative relationship between fatigue severity and FC of BG with typical DMN structures was found [4,30]. More recently, it was similarly reported with a dynamic approach that lower FC between the BG and DMN was associated with greater fatigue in patients with MS [5]. Here, we likewise observe the involvement of the BG, but instead implicate its connections to the FPN in MS-related fatigue.…”

Section: Discussionsupporting

confidence: 82%

“…Recent studies highlight subcortical brain regions as key players in the functional changes seen in MS: altered functional connectivity (FC) of the thalamus [1][2][3] and basal ganglia (BG) [4,5] has been consistently linked to cognitive function and fatigue. In contrast, other studies have implicated both increased [6,7] and opposingly, decreased default mode network (DMN) connectivity [8] in the relationship between functional alterations and cognitive impairment in MS.…”

Section: Introductionmentioning

confidence: 99%

Functional connectivity dynamics reflect disability and multi-domain clinical impairment in patients with relapsing-remitting multiple sclerosis

Romanello

Krohn

Schwanenflug

et al. 2022

Preprint

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BackgroundFunctional neuroimaging studies have revealed complex and heterogeneous patterns of aberrant functional connectivity (FC) in multiple sclerosis (MS), yet it remains unclear how time-resolved FC relates to variance in clinical disease severity.ObjectivesTo characterize brain activity in MS patients with time-resolved FC analysis and explore the relationship between disease severity, multi-domain impairments, and altered network dynamics.MethodsResting-state functional MRI data were acquired from 101 MS patients and 101 age- and sex-matched healthy controls (HC). Dynamic FC analysis identified five connectivity states that were compared between HC and patients with high vs. low disability.ResultsPatients with higher disease severity exhibited a more widespread spatiotemporal pattern of altered FC and spent more time in a high-connectivity, low-occurrence state compared to patients with lower disease severity and HC. Depressive symptom severity was positively related to functional dynamics on global and network scales in patients, while fatigue and motor impairment were inversely related to frontoparietal network connectivity with the basal ganglia.ConclusionsTime-resolved FC analysis uncovered alterations in network dynamics and clinical correlations that remained undetected with a static account of brain activity. Such time-varying approaches are thus crucial for disentangling the relationship between brain dynamics, disease severity, and symptoms in MS.

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“…10 The dynamics of rs-FC have also been investigated in patients at the earlier stages of MS, emphasizing the complex functional changes occurring in this disorder and their relationship to the cognitive status. 11–16 Moreover, the ability of dynamic rs-FC in better capturing cognitive decline has been showed in neurodegenerative disorders. 17…”

Section: Introductionmentioning

confidence: 99%

Altered anterior default mode network dynamics in progressive multiple sclerosis

et al. 2021

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Background: Modifications in brain function remain relatively unexplored in progressive multiple sclerosis (PMS), despite their potential to provide new insights into the pathophysiology of the disease at this stage. Objectives: To characterize the dynamics of functional networks at rest in patients with PMS, and the relation with clinical disability. Methods: Thirty-two patients with PMS underwent clinical and cognitive assessment. The dynamic properties of functional networks, retrieved from transient brain activity, were obtained from patients and 25 healthy controls (HCs). Sixteen HCs and 19 patients underwent a 1-year follow-up (FU) clinical and imaging assessment. Differences in the dynamic metrics between groups, their longitudinal changes, and the correlation with clinical disability were explored. Results: PMS patients, compared to HCs, showed a reduced dynamic functional activation of the anterior default mode network (aDMN) and a decrease in its opposite-signed co-activation with the executive control network (ECN), at baseline and FU. Processing speed and visuo-spatial memory negatively correlated to aDMN dynamic activity. The anti-couplings between aDMN and auditory/sensory-motor network, temporal-pole/amygdala, or salience networks were differently associated with separate cognitive domains. Conclusion: Patients with PMS presented an altered aDMN functional recruitment and anti-correlation with ECN. The aDMN dynamic functional activity and interaction with other networks explained cognitive disability.

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Dynamic functional connectivity as a neural correlate of fatigue in multiple sclerosis

Cited by 29 publications

References 47 publications

A more unstable resting-state functional network in cognitively declining multiple sclerosis

A more unstable resting-state functional network in cognitively declining multiple sclerosis

Functional connectivity dynamics reflect disability and multi-domain clinical impairment in patients with relapsing-remitting multiple sclerosis

Altered anterior default mode network dynamics in progressive multiple sclerosis

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