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

Romanello, Amy; Krohn, Stephan; Schwanenflug, Nina von; Chien, Claudia; Bellmann‐Strobl, Judith; Ruprecht, Klemens; Paul, Friedemann; Finke, Carsten

doi:10.1016/j.nicl.2022.103203

Cited by 13 publications

(27 citation statements)

References 41 publications

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“…The observed changes in resting state network controllability in this work are consistent with previous studies reporting alterations in brain state dynamics in MS; for example, altered dwell time of specific brain states and frequency of transitions between states during resting state conditions. 8,36 The present work, however, extends previous studies by elucidating potential mechanisms in which the MS pathology disturbed the dynamics of brain states. The controllability measures used in this study described the effect of a network or region on driving state transition from different aspects.…”

Section: Discussionsupporting

confidence: 71%

Thalamic network controllability changes and cognitive impairment in multiple sclerosis

Yang,

Woollams,

Lipp

et al. 2023

Preprint

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Multiple sclerosis is a neuroinflammatory and neurodegenerative disease commonly associated with cognitive impairment. Understanding brain mechanisms of cognitive impairment in multiple sclerosis is crucial for early diagnosis and developing effective interventions to improve the quality of life in patients. Recent studies indicate that individuals with multiple sclerosis who develop cognitive impairment display changes in network activity in the brain, such as altered transitions between network states (network activity patterns). Particularly, regions within the subcortical network, like the thalamus, show abnormalities early in multiple sclerosis, possibly driving the subsequent changes in the rest of the brain. In this study, we investigated whether there are brain regions specifically involved in driving network changes throughout the brain in multiple sclerosis, and assessed how this relates to cognitive impairment in patients. To this end, we constructed functional brain networks based on resting-state functional MRI data from 102 multiple sclerosis patients and 27 healthy controls. Then we applied network controllability analysis using the most commonly used controllability measures to quantify the effect that brain networks or regions have on driving network changes and state transitions in multiple sclerosis. Furthermore, we compared network controllability changes between patients with different cognitive status. Finally, we tested the reproducibility of our main results using a separate dataset of 95 multiple sclerosis patients and 45 healthy controls. We found significant global, cortical, and subcortical controllability changes in multiple sclerosis, as indicated by increased average controllability while decreased modal controllability and decreased activation energy in patients compared to controls. These changes predominately concentrated in the subcortical network, particularly the thalamus, and were further confirmed in the replication dataset. The controllability changes suggest a compensatory strategy in the brain network of patients, towards preserving fundamental transitions between easy-to-reach network states while relinquishing energetically costly transitions between difficult-to-reach network states. Moreover, while both cognitively impaired and cognitively preserved patients showed controllability changes compared to healthy controls, the thalamus in cognitively impaired patients exhibited a significantly greater increase in average controllability than cognitively preserved patients. This emphasizes the crucial role of the thalamus in the emergence of cognitive impairment in multiple sclerosis. Overall, this study highlights the effect that the subcortical network and the thalamus has on driving network changes across the brain in multiple sclerosis and especially in those cognitively impaired patients, suggesting a possible brain mechanism underpinning cognitive impairment in individuals with multiple sclerosis.

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Section: Discussionsupporting

confidence: 71%

Thalamic network controllability changes and cognitive impairment in multiple sclerosis

Yang,

Woollams,

Lipp

et al. 2023

Preprint

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“…10/17 studies did not find any associations (Table 1) [98, 99, 102, 118, 132–134, 138, 140, 141] and 7/17 reported significant associations (Tables 1 and 2) between structural measures and depression severity [29, 47, 96, 97, 100, 135, 137]. Of note, seven of these 17 studies investigated WML measures [29, 96, 98, 99, 101, 102, 141], but only three observed associations between depression and lesion load [29, 96, 137]. Kopchak and Odintsova observed that combined lesions in frontal lobe and corpus callosum were related to depressive scores [137].…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, Jaeger et al observed associations between altered functional connectivity in regions of the sensory motor cortex (precentral, postcentral gyri) and the superior ventral striatum and high BDI scores [134]. Lastly, Romanello et al related depression severity to functional connectivity of the ventral attention network with the dorsal attention network and DMN [141].…”

Section: Resultsmentioning

confidence: 99%

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Brain connectivity changes underlying depression and fatigue in relapsing-remitting multiple sclerosis: a systematic review

Kampaite

Gustafsson

York

et al. 2022

Preprint

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Fatigue and depression are common, debilitating, and intertwined symptoms in people with relapsing-remitting multiple sclerosis (pwRRMS). To elucidate the relationship between depression/fatigue and brain connectivity in pwRRMS we conducted a systematic review. Searched databases were PubMed, Web-of-Science and Scopus. Inclusion criteria were: participants with RRMS; published between 2001-2021; fatigue and depression assessments validated for MS; brain structural, functional (fMRI) or diffusion MRI (dMRI). 16 dMRI (13 fatigue, 4 depression) and 18 fMRI (16 fatigue, 4 depression) studies were included. ~50% of studies reported no correlation between MRI measures and fatigue/depression. Positive findings showed that abnormal cortico-limbic structural and functional connectivity was associated with depression, and fatigue was linked to connectivity measures in cortico-thalamic-basal-ganglial networks. Additionally, both depression and fatigue were related to altered cingulum structural connectivity, and functional connectivity involving thalamus, cerebellum, frontal lobe, and pre-/postcentral gyri. These findings suggest neuropathological effects in these regions may underlie fatigue and depression in pwRRMS, but the overall results were inconclusive. Further studies using optimised imaging protocols and validated depression and fatigue measures are required to clarify the substrate underlying these symptoms in pwRRMS.

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“…31 To unravel the interrelations of depression in the context of MS-associated outcomes, functional MRI analyses might be more suited to identify depression with functional connectivity, temporal dynamics and neurotransmitter networks potentially paving the way for targeted drug treatment. 28,39,40 As a clinical consequence of our work, depressive symptoms should be assessed in routine clinical care in early MS. Patients during relapse seem to be particularly vulnerable.…”

Section: Discussionmentioning

confidence: 99%

Factors associated with depressive mood at the onset of multiple sclerosis - an analysis of 781 patients of the German NationMS cohort

Salmen,

Hoepner,

Fleischer

et al. 2023

Ther Adv Neurol Disord

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Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce. Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort. Design: Cross-sectional analysis within a multicenter observational study. Methods: Baseline data of n = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms. Results: Mean age was 34.3 years (95% confidence interval: 33.6–35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n = 398 (51.0%), n = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient ( c) = 1.48, p = 0.016], more severe fatigue ( c = 0.26, p < 0.0001), lower 25-OH-VD ( c = −0.03, p = 0.034) and smoking ( c = 0.35, p = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not. Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies.

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

Cited by 13 publications

References 41 publications

Thalamic network controllability changes and cognitive impairment in multiple sclerosis

Thalamic network controllability changes and cognitive impairment in multiple sclerosis

Brain connectivity changes underlying depression and fatigue in relapsing-remitting multiple sclerosis: a systematic review

Factors associated with depressive mood at the onset of multiple sclerosis - an analysis of 781 patients of the German NationMS cohort

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