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

BACKGROUND: More than 80% of multiple sclerosis (MS) patients experience symptoms of fatigue. MS-related fatigue is only partly explained by structural (lesions and atrophy) and functional (brain activation and conventional static functional connectivity) brain properties. OBJECTIVES: To investigate the relationship of dynamic functional connectivity (dFC) with fatigue in MS patients and to compare dFC with commonly used clinical and MRI parameters. METHODS: In 35 relapsing-remitting MS patients (age: 42.83 years, female/male: 20/15, disease duration: 11 years) and 19 healthy controls (HCs) (age: 41.38 years, female/male: 11/8), fatigue was measured using the CIS-20r questionnaire at baseline and at 6-month follow-up. All subjects underwent structural and resting-state functional MRI at baseline. Global static functional connectivity (sFC) and dynamic functional connectivity (dFC) were calculated. dFC was assessed using a sliding-window approach by calculating the summed difference (diff) and coefficient of variation (cv) across windows. Moreover, regional connectivity between regions previously associated with fatigue in MS was estimated (i.e. basal ganglia and regions of the Default Mode Network (DMN): medial prefrontal, posterior cingulate and precuneal cortices). Hierarchical regression analyses were performed with forward selection to identify the most important correlates of fatigue at baseline. Results were not corrected for multiple testing due to the exploratory nature of the study. RESULTS: Patients were more fatigued than HCs at baseline (p = 0.001) and follow-up (p = 0.002) and fatigue in patients was stable over time (p = 0.213). Patients had significantly higher baseline global dFC than HCs, but no difference in basal ganglia-DMN dFC. In the regression model for baseline fatigue in patients, basal ganglia-DMN dFC-cv (standardized ß = -0.353) explained 12.5% additional variance on top of EDSS (p = 0.032). Post-hoc analysis revealed higher basal ganglia-DMN dFC-cv in non-fatigued patients compared to healthy controls (p = 0.013), whereas fatigued patients and healthy controls showed similar basal ganglia-DMN dFC. CONCLUSIONS: Less dynamic connectivity between the basal ganglia and the cortex is associated with greater fatigue in MS patients, independent of disability status. Within patients, lower dynamics of these connections could relate to lower efficiency and increased fatigue. Increased dynamics in non-fatigued patients compared to healthy controls might represent a network organization that protects against fatigue or signal early network dysfunction.

Fronto-limbic disconnection in patients with multiple sclerosis and depression.

BACKGROUND: The biological mechanism of depression in multiple sclerosis (MS) is not well understood. Based on work in major depressive disorder, fronto-limbic disconnection might be important. OBJECTIVE: To investigate structural and functional fronto-limbic changes in depressed MS (DMS) and non-depressed MS (nDMS) patients. METHODS: In this retrospective study, 22 moderate-to-severe DMS patients (disease duration 8.2 ± 7.7 years), 21 nDMS patients (disease duration 15.3 ± 8.3 years), and 12 healthy controls underwent neuropsychological testing and magnetic resonance imaging (MRI; 1.5 T). Brain volumes (white matter (WM), gray matter, amygdala, hippocampus, thalamus), lesion load, fractional anisotropy (FA) of fronto-limbic tracts, and resting-state functional connectivity (FC) between limbic and frontal areas were measured and compared between groups. Regression analysis was performed to relate MRI measures to the severity of depression. RESULTS: Compared to nDMS patients, DMS patients (shorter disease duration) had lower WM volume ( p < 0.01), decreased FA of the uncinate fasciculus ( p < 0.05), and lower FC between the amygdala and frontal regions ( p < 0.05). Disease duration, FA of the uncinate fasciculus, and FC of the amygdala could explain 48% of variance in the severity of depression. No differences in cognition were found. CONCLUSION: DMS patients showed more pronounced (MS) damage, that is, structural and functional changes in temporo-frontal regions, compared to nDMS patients, suggestive of fronto-limbic disconnection.

Predicting cognitive decline in multiple sclerosis: a 5-year follow-up study.

Cognitive decline is common in multiple sclerosis and strongly affects overall quality of life. Despite the identification of cross-sectional MRI correlates of cognitive impairment, predictors of future cognitive decline remain unclear. The objective of this study was to identify which MRI measures of structural damage, demographic and/or clinical measures at baseline best predict cognitive decline, during a 5-year follow-up period. A total of 234 patients with clinically definite multiple sclerosis and 60 healthy control subjects were examined twice, with a 5-year interval (mean = 4.9 years, standard deviation = 0.9). An extensive neuropsychological evaluation was performed at both time points and the reliable change index was computed to evaluate cognitive decline. Both whole-brain and regional MRI (3 T) measures were assessed at baseline, including white matter lesion volume, diffusion-based white matter integrity, cortical and deep grey matter volume. Logistic regression analyses were performed to determine which baseline measures best predicted cognitive decline in the entire sample as well as in early relapsing-remitting (symptom duration <10 years), late relapsing-remitting (symptom duration ≥10 years) and progressive phenotypes. At baseline, patients with multiple sclerosis had a mean disease duration of 14.8 (standard deviation = 8.4) years and 96/234 patients (41%) were classified as cognitively impaired. A total of 66/234 patients (28%) demonstrated cognitive decline during follow-up, with higher frequencies in progressive compared to relapsing-remitting patients: 18/33 secondary progressive patients (55%), 10/19 primary progressive patients (53%) and 38/182 relapsing-remitting patients (21%). A prediction model that included only whole-brain MRI measures (Nagelkerke R2 = 0.22, P < 0.001) showed cortical grey matter volume as the only significant MRI predictor of cognitive decline, while a prediction model that assessed regional MRI measures (Nagelkerke R2 = 0.35, P < 0.001) indicated integrity loss of the anterior thalamic radiation, lesions in the superior longitudinal fasciculus and temporal atrophy as significant MRI predictors for cognitive decline. Disease stage specific regressions showed that cognitive decline in early relapsing-remitting multiple sclerosis was predicted by white matter integrity damage, while cognitive decline in late relapsing-remitting and progressive multiple sclerosis was predicted by cortical atrophy. These results indicate that patients with more severe structural damage at baseline, and especially cortical atrophy, are more prone to suffer from cognitive decline. New studies now need to further elucidate the underlying mechanisms leading to cortical atrophy, evaluate the value of including cortical atrophy as a possible outcome marker in clinical trials as well as study its potential use in individual patient management.

The importance of hippocampal dynamic connectivity in explaining memory function in multiple sclerosis.

Introduction: Brain dynamics (i.e., variable strength of communication between areas), even at the scale of seconds, are thought to underlie complex human behavior, such as learning and memory. In multiple sclerosis (MS), memory problems occur often and have so far only been related to "stationary" brain measures (e.g., atrophy, lesions, activation and stationary (s) functional connectivity (FC) over an entire functional scanning session). However, dynamics in FC (dFC) between the hippocampus and the (neo)cortex may be another important neurobiological substrate of memory impairment in MS that has not yet been explored. Therefore, we investigated hippocampal dFC during a functional (f) magnetic resonance imaging (MRI) episodic memory task and its relationship with verbal and visuospatial memory performance outside the MR scanner. Methods: Thirty-eight MS patients and 29 healthy controls underwent neuropsychological tests to assess memory function. Imaging (1.5T) was obtained during performance of a memory task. We assessed hippocampal volume, functional activation, and sFC (i.e., FC of the hippocampus with the rest of the brain averaged over the entire scan, using an atlas-based approach). Dynamic FC of the hippocampus was calculated using a sliding window approach. Results: No group differences were found in hippocampal activation, sFC, and dFC. However, stepwise forward regression analyses in patients revealed that lower dFC of the left hippocampus (standardized ß = -0.30; p = .021) could explain an additional 7% of variance (53% in total) in verbal memory, in addition to female sex and larger left hippocampal volume. For visuospatial memory, lower dFC of the right hippocampus (standardized ß = -0.38; p = .013) could explain an additional 13% of variance (24% in total) in addition to higher sFC of the right hippocampus. Conclusion: Low hippocampal dFC is an important indicator for maintained memory performance in MS, in addition to other hippocampal imaging measures. Hence, brain dynamics may offer new insights into the neurobiological mechanisms underlying memory (dys)function.

Determinants of Cognitive Impairment in Patients with Multiple Sclerosis with and without Atrophy.

Purpose To investigate the discrepancy between patients with multiple sclerosis (MS) without atrophy who have already developed cognitive impairment and patients with MS with atrophy who have preserved cognitive function. Materials and Methods This retrospective imaging study, with imaging acquired between 2008 and 2012, included 332 patients with MS (106 men and 226 women; mean age, 48.1 years; range, 23.0-72.5 years) and 96 healthy control participants. Cognitive impairment was defined as cognitive performance of z less than -1.5 compared with that in control participants in greater than or equal to two cognitive domains. Atrophy was defined as cortical and deep gray matter volumes of z less than -1.5 compared with that in control participants. White matter lesions were assessed with T2-imaging, tract fractional anisotropy (ie, integrity) with diffusion MRI, and regional centrality (ie, importance within network) with functional MRI. Within each atrophy group, patients with cognitive impairment and preserved cognitive function were compared and regression analyses were performed to predict cognitive impairment. Results A total of 132 of 328 patients with MS had no atrophy; of these, 42 of 132 (32%) had cognitive impairment. Cognitive impairment in patients without atrophy was predicted by level of education (Wald test, 11.63; P < .01) and posterior cingulate centrality (Wald test, 6.82; P < .01). A total of 65 of 328 patients with MS had atrophy; of these, 49 of 65 (75%) had cognitive impairment. Cognitive impairment in patients with atrophy was predicted by white matter tract fractional anisotropy (Wald test, 4.89; P = .03) and posterior cingulate centrality (Wald test, 7.19; P < .01). Conclusion Cognitive impairment was related to white matter damage, but only in patients with MS with atrophy. In patients without atrophy, a lower level of education was most important for cognitive impairment. Posterior cingulate cortex showed functional abnormalities in all MS groups with cognitive impairment, regardless of atrophy.

Connectomic profile and clinical phenotype in newly diagnosed glioma patients.

Gliomas are primary brain tumors, originating from the glial cells in the brain. In contrast to the more traditional view of glioma as a localized disease, it is becoming clear that global brain functioning is impacted, even with respect to functional communication between brain regions remote from the tumor itself. However, a thorough investigation of glioma-related functional connectomic profiles is lacking. Therefore, we constructed functional brain networks using functional MR scans of 71 glioma patients and 19 matched healthy controls using the automated anatomical labelling (AAL) atlas and interregional Pearson correlation coefficients. The frequency distributions across connectivity values were calculated to depict overall connectomic profiles and quantitative features of these distributions (full-width half maximum (FWHM), peak position, peak height) were calculated. Next, we investigated the spatial distribution of the connectomic profile. We defined hub locations based on the literature and determined connectivity (1) between hubs, (2) between hubs and non-hubs, and (3) between non-hubs. Results show that patients had broader and flatter connectivity distributions compared to controls. Spatially, glioma patients particularly showed increased connectivity between non-hubs and hubs. Furthermore, connectivity distributions and hub-non-hub connectivity differed within the patient group according to tumor grade, while relating to Karnofsky performance status and progression-free survival. In conclusion, newly diagnosed glioma patients have globally altered functional connectomic profiles, which mainly affect hub connectivity and relate to clinical phenotypes. These findings underscore the promise of using connectomics as a future biomarker in this patient population.

The role of sleep on cognition and functional connectivity in patients with multiple sclerosis.

Sleep disturbances are common in multiple sclerosis (MS), but its impact on cognition and functional connectivity (FC) of the hippocampus and thalamus is unknown. Therefore, we investigated the relationship between sleep disturbances, cognitive functioning and resting-state (RS) FC of the hippocampus and thalamus in MS. 71 MS patients and 40 healthy controls underwent neuropsychological testing and filled out self-report questionnaires (anxiety, depression, fatigue, and subjective cognitive problems). Sleep disturbances were assed with the five-item version of the Athens Insomnia Scale. Hippocampal and thalamic volume and RS FC of these regions were determined. Twenty-three patients were categorized as sleep disturbed and 48 as normal sleeping. No differences were found between disturbed and normal sleeping patients concerning cognition and structural MRI. Sleep disturbed patients reported more subjective cognitive problems, and displayed decreased FC between the thalamus and middle and superior frontal gyrus, inferior frontal operculum, anterior cingulate cortex, inferior parietal gyrus, precuneus, and angular gyrus compared to normal sleeping patients. We conclude that sleep disturbances in MS are not (directly) related to objective cognitive functioning, but rather to subjective cognitive problems. In addition, sleep disturbances in MS seem to coincide with a specific pattern of decreased thalamic FC.

Memory impairment in multiple sclerosis: Relevance of hippocampal activation and hippocampal connectivity.

BACKGROUND: Memory impairment is frequent in multiple sclerosis (MS), but it is unclear what functional brain changes underlie this cognitive deterioration. OBJECTIVE: To investigate functional hippocampal activation and connectivity, in relation to memory performance in MS. METHODS: Structural and functional magnetic resonance imaging data were acquired for 57 MS patients and 28 healthy controls (HCs), yielding hippocampal measures of volume, lesions, functional activation during a memory task and functional connectivity at rest. Memory function was based on two subtests of a larger neuropsychological test battery and related to hippocampal neuroimaging measures, using linear regression. RESULTS: Hippocampal volume was lower in MS patients, as compared to HCs. In MS, hippocampal activation during the task was increased in cognitively preserved, but decreased in cognitively impaired, patients. Increased hippocampal connectivity was detected in MS patients, as compared to HCs, between the left hippocampus and the right posterior cingulate. Memory impairment in MS was explained (adjusted R(2) = 0.27) by male gender, decreased hippocampal activation and increased hippocampal connectivity (p = 0.001). CONCLUSIONS: Decreased activation of the hippocampus, increased connectivity and male gender were associated with worse memory performance in MS. These results indicate that increased activation and increased connectivity do not always coincide, and relate differently to cognitive dysfunction in MS.