Fatigue in multiple sclerosis: Does the functional or structural damage prevail?

Fatigue in multiple sclerosis (MS) is a highly invalidating symptom, lacking efficacious drugs. This topical review aims at assessing the signs in the literature of functional versus structural damage prevalence at the origin of MS fatigue by focusing on papers that assessed the two counterparts in the same patients, paying attention that the fatigue levels do not correlate with clinical severity. We summarize and discuss evidence of increased levels of fatigue occurring together with the alterations of functional connectivity at multiple levels, in the absence of any relationship with lesion load and local atrophy of the involved structures. Specifically, neuronal communication mainly altered in the corticomuscular synchronizations, between hemispheric homologs and in the resting-state networks involved in emotion (cingulate cortex) and effort-reward balance (striatum and inferior parietal lobule). Finally, given the functional prevalence in neuronal network alterations at the origin of fatigue in MS, we highlight the relevance of developing treatments aiming at compensating the neuronal electric communication dysfunctions.

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Disability in multiple sclerosis is related to thalamic connectivity and cortical network atrophy

Multiple Sclerosis Journal ◽

10.1177/13524585211008743 ◽

2021 ◽

pp. 135245852110087

Author(s):

Menno M Schoonheim ◽

Daniela Pinter ◽

Stefanos E Prouskas ◽

Tommy AA Broeders ◽

Lukas Pirpamer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Resting State ◽

Cortical Network ◽

Resting State Networks ◽

Multivariate Regression Model ◽

Sensorimotor Network ◽

Disability Status ◽

Severity Of Disability ◽

Major Predictor ◽

Thalamic Function

Background: Thalamic atrophy is proposed to be a major predictor of disability progression in multiple sclerosis (MS), while thalamic function remains understudied. Objectives: To study how thalamic functional connectivity (FC) is related to disability and thalamic or cortical network atrophy in two large MS cohorts. Methods: Structural and resting-state functional magnetic resonance imaging (fMRI) was obtained in 673 subjects from Amsterdam (MS: N = 332, healthy controls (HC): N = 96) and Graz (MS: N = 180, HC: N = 65) with comparable protocols, including disability measurements in MS (Expanded Disability Status Scale, EDSS). Atrophy was measured for the thalamus and seven well-recognized resting-state networks. Static and dynamic thalamic FC with these networks was correlated with disability. Significant correlates were included in a backward multivariate regression model. Results: Disability was most strongly related (adjusted R2 = 0.57, p < 0.001) to higher age, a progressive phenotype, thalamic atrophy and increased static thalamic FC with the sensorimotor network (SMN). Static thalamus–SMN FC was significantly higher in patients with high disability (EDSS ⩾ 4) and related to network atrophy but not thalamic atrophy or lesion volumes. Conclusion: The severity of disability in MS was related to increased static thalamic FC with the SMN. Thalamic FC changes were only related to cortical network atrophy, but not to thalamic atrophy.

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Assessing brain connectivity at rest is clinically relevant in early multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458511435930 ◽

2012 ◽

Vol 18 (9) ◽

pp. 1251-1258 ◽

Cited By ~ 92

Author(s):

Anthony Faivre ◽

Audrey Rico ◽

Wafaa Zaaraoui ◽

Lydie Crespy ◽

Françoise Reuter ◽

...

Keyword(s):

Multiple Sclerosis ◽

Independent Component Analysis ◽

Functional Mri ◽

Resting State ◽

Surrogate Marker ◽

Component Analysis ◽

Independent Component ◽

Resting State Networks ◽

Frontoparietal Network ◽

Multiple Sclerosis Patients

Objective: The present study aims to determine the clinical counterpart of brain resting-state networks reorganization recently evidenced in early multiple sclerosis. Methods: Thirteen patients with early relapsing–remitting multiple sclerosis and 14 matched healthy controls were included in a resting state functional MRI study performed at 3 T. Data were analyzed using group spatial Independent Component Analysis using concatenation approach (FSL 4.1.3) and double regression analyses (SPM5) to extract local and global levels of connectivity inside various resting state networks (RSNs). Differences in global levels of connectivity of each network between patients and controls were assessed using Mann–Whitney U-test. In patients, relationship between clinical data (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite Score – MSFC) and global RSN connectivity were assessed using Spearman rank correlation. Results: Independent component analysis provided eight consistent neuronal networks involved in motor, sensory and cognitive processes. For seven RSNs, the global level of connectivity was significantly increased in patients compared with controls. No significant decrease in RSN connectivity was found in early multiple sclerosis patients. MSFC values were negatively correlated with increased RSN connectivity within the dorsal frontoparietal network ( r = −0.811, p = 0.001), the right ventral frontoparietal network ( r = − 0.587, p = 0.045) and the prefronto-insular network ( r = −0.615, p = 0.033). Conclusions: This study demonstrates that resting state networks reorganization is strongly associated with disability in early multiple sclerosis. These findings suggest that resting state functional MRI may represent a promising surrogate marker of disease burden.

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Functional Connectivity Lateralisation Shift of Resting State Networks is Linked to Visuospatial Memory and White Matter Microstructure in Relapsing–Remitting Multiple Sclerosis

Brain Topography ◽

10.1007/s10548-021-00881-x ◽

2021 ◽

Author(s):

Dániel Veréb ◽

Márton Attila Kovács ◽

Krisztián Kocsis ◽

Eszter Tóth ◽

Bence Bozsik ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Functional Connectivity ◽

Default Mode Network ◽

Resting State ◽

Angular Gyrus ◽

Resting State Networks ◽

Functional Laterality ◽

Dorsal Attention Network ◽

Relapsing Remitting

AbstractLaterality patterns of resting state networks (RSN) change in various neuropsychiatric conditions. Multiple sclerosis (MS) causes neuro-cognitive symptoms involving dysfunctional large-scale brain networks. Yet, whether healthy laterality patterns of RSNs are maintained in MS and whether altered laterality patterns explain disease symptoms has not been explicitly investigated. We analysed functional MRI and diffusion tensor imaging data from 24 relapsing–remitting MS patients and 25 healthy participants. We performed group-level independent component analysis and used dual regression to estimate individual versions of well-established RSNs. Voxelwise laterality indices were calculated for each RSN. Group differences were assessed via a general linear model-based approach. The relationship between functional laterality and white matter microstructural asymmetry was assessed using Tract-Based Spatial Statistics. Spearman’s correlation was calculated between laterality indices and Brief International Cognitive Assessment for Multiple Sclerosis scores. Functional laterality of the dorsal attention network showed a significant leftward shift in the MS group in the posterior intraparietal sulcus (p < 0.033). Default-mode network laterality showed a significant leftward shift in the MS group in the angular gyrus (p < 0.005). Diminished dorsal attention network laterality was associated with increased fractional anisotropy asymmetry in the superior longitudinal fasciculus (p < 0.02). In the default-mode network, leftward laterality of the angular gyrus was associated with higher BVMT-R scores (R = − 0.52, p < 0.023). Our results confirm previous descriptions of RSN dysfunction in relapsing–remitting MS and show that altered functional connectivity lateralisation patterns of RSNs might contibute to cognitive performance and structural remodellation even in patients with mild clinical symptoms.

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The cerebellum and its network: Disrupted static and dynamic functional connectivity patterns and cognitive impairment in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458521999274 ◽

2021 ◽

pp. 135245852199927

Author(s):

Menno M Schoonheim ◽

Linda Douw ◽

Tommy AA Broeders ◽

Anand JC Eijlers ◽

Kim A Meijer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Functional Connectivity ◽

Resting State ◽

Structural Damage ◽

Grey Matter ◽

Grey Matter Volume ◽

Default Mode ◽

Cerebellar Damage ◽

The Impact

Background: The impact of cerebellar damage and (dys)function on cognition remains understudied in multiple sclerosis. Objective: To assess the cognitive relevance of cerebellar structural damage and functional connectivity (FC) in relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). Methods: This study included 149 patients with early RRMS, 81 late RRMS, 48 SPMS and 82 controls. Cerebellar cortical imaging included fractional anisotropy, grey matter volume and resting-state functional magnetic resonance imaging (MRI). Cerebellar FC was assessed with literature-based resting-state networks, using static connectivity (that is, conventional correlations), and dynamic connectivity (that is, fluctuations in FC strength). Measures were compared between groups and related to disability and cognition. Results: Cognitive impairment (CI) and cerebellar damage were worst in SPMS. Only SPMS showed cerebellar connectivity changes, compared to early RRMS and controls. Lower static FC was seen in fronto-parietal and default-mode networks. Higher dynamic FC was seen in dorsal and ventral attention, default-mode and deep grey matter networks. Cerebellar atrophy and higher dynamic FC together explained 32% of disability and 24% of cognitive variance. Higher dynamic FC was related to working and verbal memory and to information processing speed. Conclusion: Cerebellar damage and cerebellar connectivity changes were most prominent in SPMS and related to worse CI.

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Resting-state functional connectivity of anterior and posterior cerebellar lobes is altered in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520922770 ◽

2020 ◽

pp. 135245852092277

Author(s):

Gabriele Pasqua ◽

Silvia Tommasin ◽

Komal Bharti ◽

Serena Ruggieri ◽

Nikolaos Petsas ◽

...

Keyword(s):

Multiple Sclerosis ◽

Functional Connectivity ◽

Resting State ◽

Structural Damage ◽

Cognitive Disability ◽

Resting State Functional Connectivity ◽

Cognitive Domains ◽

Composite Scale ◽

Disability Status ◽

Magnetic Resonance Imaging Mri

Background: Damage to the cerebellar sensorimotor and cognitive domains may underlie physical and cognitive disability. Objective: To investigate resting-state functional connectivity (FC) of sensorimotor and cognitive cerebellum, and clinical correlates in multiple sclerosis (MS). Methods: A total of 119 patients with MS and 42 healthy subjects underwent multimodal 3T-magnetic resonance imaging (MRI). Patients were evaluated using the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite Scale. After parcellation of sensorimotor (lobules I–V + VIII) and cognitive cerebellum (lobules VI, VII, IX, X), we calculated cerebellar resting-state FC using a seed-based approach. Results: In patients with MS, the sensorimotor cerebellum showed increased FC mainly with cerebellar, thalamic, and cortical (frontal, parietal, temporal) areas and decreased FC with insular areas; the cognitive cerebellum showed increased FC mainly with thalamic and cortical (temporal-occipital) areas, and decreased FC with frontal-insular areas. Both sensorimotor and cognitive cerebellar FC negatively correlated with disability, and positively with cognitive scores. Cerebellar structural damage only partially influenced results. Conclusion: The two neocerebellar circuits showed altered FC with subcortical and cortical areas. The association between increased sensorimotor and cognitive cerebellar FC and low levels of physical and cognitive disability suggests that altered FC might modulate the effects of cerebellar structural damage on clinical condition.

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