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Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis.

ABSTRACT: Correlations in spontaneous brain activity provide powerful access to large-scale organizational principles of the CNS. However, making inferences about cognitive processes requires a detailed understanding of the link between these couplings and the structural integrity of the CNS. We studied the impact of multiple sclerosis, which leads to the severe disintegration of the central white matter, on functional connectivity patterns in spontaneous cortical activity. Using a data driven approach based on the strength of a salient pattern of cognitive pathology, we identified distinct networks that exhibit increases in functional connectivity despite the presence of strong and diffuse reductions of the central white-matter integrity. The default mode network emerged as a core target of these connectivity modulations, showing enhanced functional coupling in bilateral inferior parietal cortex, posterior cingulate, and medial prefrontal cortex. These findings imply a complex and diverging relation of anatomical and functional connectivity in early multiple sclerosis and, thus, add an important observation for understanding how cognitive abilities and CNS integrity may be reflected in the intrinsic covariance of functional signals.

SUBMITTER: Hawellek DJ

PROVIDER: S-EPMC3223469 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis.

Hawellek David J DJ Hipp Joerg F JF Lewis Christopher M CM Corbetta Maurizio M Engel Andreas K AK

Proceedings of the National Academy of Sciences of the United States of America 20111107 47

Correlations in spontaneous brain activity provide powerful access to large-scale organizational principles of the CNS. However, making inferences about cognitive processes requires a detailed understanding of the link between these couplings and the structural integrity of the CNS. We studied the impact of multiple sclerosis, which leads to the severe disintegration of the central white matter, on functional connectivity patterns in spontaneous cortical activity. Using a data driven approach ba ...[more]

PMID: 22065778

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Project description:Background:Cognitive impairment is frequent and disabling in multiple sclerosis (MS). Changes in information processing speed constitute the most important cognitive deficit in MS. However, given the clinical and topographical variability of the disease, cognitive impairment may vary greatly and appear in other forms in addition to slower information processing speed. Our aim was to determine the frequency of cognitive impairment, the principal cognitive domains, and components involved in MS and to identify factors associated with presence of cognitive impairment in these patients in a large series of patients. Methods:Cross-sectional study of 311 patients with MS [236 with relapsing-remitting MS (RRMS), 52 with secondary progressive MS (SPMS), and 23 with primary progressive MS (PPMS)]. Patients' cognitive function was assessed with a comprehensive neuropsychological assessment protocol. Patients displaying deficits in 2 or more cognitive domains were considered to have cognitive impairment associated with MS. We conducted a principal component analysis to detect different cognitive patterns by identifying clusters of tests highly correlated to one another. Results:Cognitive impairment was detected in 41.5% of the sample, and it was more frequent in patients with SPMS and PPMS (P?=?0.002). Expanded Disability Status Scale scores and education were independent predictors of cognitive impairment. Principal component analysis identified seven clusters: attention and basic executive function (including information processing speed), planning and high-level executive function, verbal memory and language, executive and visuospatial performance time, fatigue-depression, visuospatial function, and basic attention and verbal/visual working memory. Mean scoring of components 2 (high-order executive functioning) and 3 (verbal memory-language) was higher in patients with RRMS than in those with PPMS (component 2) and SPMS (component 3). Conclusion:MS is linked to multiple cognitive profiles and disturbances in different domains. This suggests that cognitive alterations in MS are heterogeneous and affect other domains in addition to information processing speed.

Project description:Background & aimMultiple sclerosis (MS) is an autoimmune disease of the central nervous system associated with deficits in cognitive and motor functioning. While structural brain changes such as demyelination are an early hallmark of the disease, a characteristic profile of functional brain alterations in early MS is lacking. Functional neuroimaging studies at various disease stages have revealed complex and heterogeneous patterns of aberrant functional connectivity (FC) in MS, with previous studies largely being limited to a static account of FC. Thus, it remains unclear how time-resolved FC relates to variance in clinical disability status in early MS. We here aimed to characterize brain network organization in early MS patients with time-resolved FC analysis and to explore the relationship between disability status, multi-domain clinical outcomes and altered network dynamics.MethodsResting-state functional MRI (rs-fMRI) data were acquired from 101 MS patients and 101 age- and sex-matched healthy controls (HC). Based on the Expanded Disability Status Score (EDSS), patients were split into two sub-groups: patients without clinical disability (EDSS ≤ 1, n = 36) and patients with mild to moderate levels of disability (EDSS ≥ 2, n = 39). Five dynamic FC states were extracted from whole-brain rs-fMRI data. Group differences in static and dynamic FC strength, across-state overall connectivity, dwell time, transition frequency, modularity, and global connectivity were assessed. Patients' impairment was quantified as custom clinical outcome z-scores (higher: worse) for the domains depressive symptoms, fatigue, motor, vision, cognition, total brain atrophy, and lesion load. Correlation analyses between functional measures and clinical outcomes were performed with Spearman partial correlation analyses controlling for age.ResultsPatients with mild to moderate levels of disability exhibited a more widespread spatiotemporal pattern of altered FC and spent more time in a high-connectivity, low-occurrence state compared to patients without disability and HCs. Worse symptoms in all clinical outcome domains were positively associated with EDSS scores. Furthermore, depressive symptom severity was positively related to functional dynamics as measured by state-specific global connectivity and default mode network connectivity with attention networks, while fatigue and motor impairment were related to reduced frontoparietal network connectivity with the basal ganglia.ConclusionsDespite comparably low impairment levels in early MS, we identified distinct connectivity alterations between patients with mild to moderate disability and those without disability, and these changes were sensitive to clinical outcomes in multiple domains. Furthermore, time-resolved analysis uncovered alterations in network dynamics and clinical correlations that remained undetected with conventional static analyses, showing that accounting for temporal dynamics helps disentangle the relationship between functional alterations, disability status, and symptoms in early MS.

Dataset Information

Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis.

Publications

Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis.

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