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Background: Cognitive phenotyping may be useful for predicting rehabilitation response in multiple sclerosis., Objective: To evaluate the association between cognitive phenotype(s) and response to restorative cognitive rehabilitation (RRCR)., Methods: In a post hoc retrospective analysis of the RRCR study including 51 multiple sclerosis patients, we evaluated both impairment within specific cognitive domains as well as overall global impairment severity to investigate their relationship to improvement following rehabilitation., Results: Greater improvement in executive function was predicted by impairment within this domain as well as by having fewer impaired cognitive domains overall. Similar results were observed for visuospatial memory., Conclusions: Patients most likely to benefit from restorative cognitive rehabilitation may exhibit impairment within the domain of interest yet lower cognitive burden overall., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.Z. and T.F. have nothing to disclose. M.G.D. received grant support from Novartis, Bristol Myers Squibb, Mapi Pharma, Merck Serono, Keystone Heart Ltd., Protembis GmbH, and V-Wave Ltd. and consulting fees from Bristol Myers Squibb, Merck Serono, and Keystone Heart Ltd. R.Z. has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Sanofi, 415 Capital, Filterlex, and Mapi Pharma for speaking and as consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, EMD Serono, Octave, Mapi Pharma, CorEvitas, Protembis, and V-WAVE Medical. H.E.H. is an editor of the Multiple Sclerosis Journal controversies sections and receives research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay, and Merck BV. M.C. received honoraria for research or speaking and funds for travel from Roche, Sanofi Genzyme, Merck Serono, Biogen Idec, Teva, and Novartis Pharma. R.H.B.B. received research support from Biogen, Bristol Meyers Squibb, Novartis, National Institute of Health, and National Multiple Sclerosis Society; consultant fees from Bristol Meyers Squibb, Novartis, Roche, Sanofi; speaking fees from Bristol Meyers Squibb, EMD Serono; and royalties for Psychological Assessment Resources.

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P.T.W. has no conflict of interest regarding this publication. M.F.L.R. has no conflict of interest regarding this publication. H.E.H. is an editor of the Multiple Sclerosis Journal controversies sections, who received research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay, and Merck BV.

Background: Suboptimal performance during neuropsychological testing frequently occurs in multiple sclerosis (MS), leading to unreliable cognitive outcomes. Neurophysiological alterations correlate with MS-related cognitive impairment, but studies have not yet considered performance validity., Objectives: To investigate neurophysiological markers of cognitive impairment in MS, while explicitly addressing performance validity., Methods: Magnetoencephalography recordings, neuropsychological assessments, and performance validity testing were obtained from 90 MS outpatients with cognitive complaints. Spectral and resting-state functional connectivity (rsFC) properties were compared between cognitively impaired (CI), cognitively preserved (CP), and suboptimally performing (SUB) patients using regression models and permutation testing., Results: CI had higher power in low-frequency bands and lower power in high bands compared to CP, indicating neuronal slowing. CI also showed lower beta power compared to SUB. Overall power spectra visually differed between CI and CP, and SUB showed overlap with both groups. CI had lower rsFC than CP and SUB patients. CP and SUB patients showed no differences., Conclusion: Neuronal slowing and altered rsFC can be considered cognitive markers in MS. Patients who performed suboptimally showed resemblance with patients with and without cognitive impairments, and although their overall neurophysiological profile was more similar to patients without impairments, it suggests heterogeneity regarding their pathophysiology.

Background: Cognitive training elicits mild-to-moderate improvements in cognitive functioning in people with multiple sclerosis (PwMS), although response heterogeneity limits overall effectiveness., Objective: To identify patient characteristics associated with response and non-response to cognitive training., Methods: Eighty-two PwMS were randomized into a 7-week attention training ( n  = 58, age = 48.4 ± 10.2 years) or a waiting-list control group ( n  = 24, age = 48.5 ± 9.4 years). Structural and functional magnetic resonance imaging (MRI) was obtained at baseline and post-intervention. Twenty-one healthy controls (HCs, age = 50.27 ± 10.15 years) were included at baseline. Responders were defined with a reliable change index of 1.64 on at least 2/6 cognitive domains. General linear models and logistic regression were applied., Results: Responders ( n  = 36) and non-responders ( n  = 22) did not differ on demographics, clinical variables and baseline cognition and structural MRI. However, non-responders exhibited a higher baseline functional connectivity (FC) between the default-mode network (DMN) and the ventral attention network (VAN), compared with responders ( p  = 0.018) and HCs ( p  = 0.001). Conversely, responders exhibited no significant baseline differences in FC compared with HCs. Response to cognitive training was predicted by lower DMN-VAN FC ( p  = 0.004) and DMN-frontoparietal FC ( p  = 0.029) (Nagelkerke R 2  = 0.25)., Conclusion: An intact pre-intervention FC is associated with cognitive training responsivity in pwMS, suggesting a window of opportunity for successful cognitive interventions.

Background: Synaptic and neuronal loss contribute to network dysfunction and disability in multiple sclerosis (MS). However, it is unknown whether excitatory or inhibitory synapses and neurons are more vulnerable and how their losses impact network functioning., Objective: To quantify excitatory and inhibitory synapses and neurons and to investigate how synaptic loss affects network functioning through computational modeling., Methods: Using immunofluorescent staining and confocal microscopy, densities of glutamatergic and GABAergic synapses and neurons were compared between post-mortem MS and non-neurological control cases. Then, a corticothalamic biophysical model was employed to study how MS-induced excitatory and inhibitory synaptic loss affect network functioning., Results: In layer VI of normal-appearing MS cortex, excitatory and inhibitory synaptic densities were significantly lower than controls (reductions up to 14.9%), but demyelinated cortex showed larger losses of inhibitory synapses (29%). In our computational model, reducing inhibitory synapses impacted the network most, leading to a disinhibitory increase in neuronal activity and connectivity., Conclusion: In MS, excitatory and inhibitory synaptic losses were observed, predominantly for inhibitory synapses in demyelinated cortex. Inhibitory synaptic loss affected network functioning most, leading to increased neuronal activity and connectivity. As network disinhibition relates to cognitive impairment, inhibitory synaptic loss seems particularly relevant in MS.

Background: Cortical lesions are highly inconspicuous on magnetic resonance imaging (MRI). Double inversion recovery (DIR) has a higher sensitivity than conventional clinical sequences (i.e. T1, T2, FLAIR) but is difficult to acquire, leading to overseen cortical lesions in clinical care and clinical trials., Objective: To evaluate the usability of artificially generated DIR (aDIR) images for cortical lesion detection compared to conventionally acquired DIR (cDIR)., Methods: The dataset consisted of 3D-T1 and 2D-proton density (PD) T2 images of 73 patients (49RR, 20SP, 4PP) at 1.5 T. Using a 4:1 train:test-ratio, a fully convolutional neural network was trained to predict 3D-aDIR from 3D-T1 and 2D-PD/T2 images. Randomized blind scoring of the test set was used to determine detection reliability, precision and recall., Results: A total of 626 vs 696 cortical lesions were detected on 15 aDIR vs cDIR images (intraclass correlation coefficient (ICC) = 0.92). Compared to cDIR, precision and recall were 0.84 ± 0.06 and 0.76 ± 0.09, respectively. The frontal and temporal lobes showed the largest differences in discernibility., Conclusion: Cortical lesions can be detected with good reliability on artificial DIR. The technique has potential to broaden the availability of DIR in clinical care and provides the opportunity of ex post facto implementation of cortical lesions imaging in existing clinical trial data.

Background: Brain functional connectivity (FC) in multiple sclerosis (MS) is abnormal compared to healthy controls (HCs). More longitudinal studies in MS are needed to evaluate whether FC stability is clinically relevant., Objective: To compare functional magnetic resonance imaging (fMRI)-based FC between MS and HC, and to determine the relationship between longitudinal FC changes and structural brain damage, cognitive performance and physical disability., Methods: T1-weighted MPRAGE and resting-state fMRI (1.5T) were acquired from 70 relapsing-remitting MS patients and 94 matched HC at baseline (mean months since diagnosis 14.0 ± 11) and from 60 MS patients after 5 years. Independent component analysis and network modelling were used to measure longitudinal FC stability and cross-sectional comparisons with HC. Linear mixed models, adjusted for age and sex, were used to calculate correlations., Results: At baseline, patients with MS showed FC abnormalities both within networks and in single connections compared to HC. Longitudinal analyses revealed functional stability and no significant relationships with clinical disability, cognitive performance, lesion or brain volume., Conclusion: FC abnormalities occur already at the first decade of MS, yet we found no relevant clinical correlations for these network deviations. Future large-scale longitudinal fMRI studies across a range of MS subtypes and outcomes are required.

Background/objective: Endurance exercise can improve memory function in persons with multiple sclerosis (pwMS), but the effects on hippocampal functioning are currently unknown. We investigated the effects of a running intervention on memory and hippocampal functional connectivity in pwMS., Methods/results: Memory and resting-state functional magnetic resonance imaging (fMRI) data were collected in a running intervention ( n  = 15) and waitlist group ( n  = 14). Visuospatial memory improvement was correlated to increased connectivity between the hippocampus and the default-mode network (DMN) in the intervention group only., Conclusion: As a result of endurance exercise, improvements in visuospatial memory may be mediated by a stronger functional embedding of the hippocampus in the DMN.

Background: In multiple sclerosis (MS), abnormalities of brain network dynamics and their relevance for cognitive impairment have never been investigated., Objectives: The aim of this study was to assess the dynamic resting state (RS) functional connectivity (FC) on 62 relapsing-remitting MS patients and 65 sex-matched healthy controls enrolled at 7 European sites., Methods: MS patients underwent clinical and cognitive evaluation. Between-group network FC differences were evaluated using a dynamic approach (based on sliding-window correlation analysis) and grouping correlation matrices into recurrent FC states., Results: Dynamic FC analysis revealed, in healthy controls and MS patients, three recurrent FC states: two characterized by strong intra- and inter-network connectivity and one characterized by weak inter-network connectivity (State 3). A total of 23 MS patients were cognitively impaired (CI). Compared to cognitively preserved (CP), CI-MS patients had reduced RS-FC between subcortical and default-mode networks in the low-connectivity State 3 and lower dwell time (i.e. time spent in a given state) in the high-connectivity State 2. CI-MS patients also exhibited a lower number and a less frequent switching between meta-states, as well as a smaller distance traveled through connectivity states., Conclusion: Time-varying RS-FC was markedly less dynamic in CI- versus CP-MS patients, suggesting that slow inter-network connectivity contributes to cognitive dysfunction in MS.

Background: Cognitive problems are difficult to identify in patients with multiple sclerosis (MS)., Objective: To investigate the clinical applicability of the patient-reported MS Neuropsychological Screening Questionnaire (MSNQ-P)., Methods: Cut-off scores were determined to differentiate between cognitively impaired ( n  = 90), mildly cognitively impaired ( n  = 115), and cognitively preserved ( n  = 147) MS patients using receiver operating characteristic analyses., Results: We could not define specific and sensitive cut-off scores. Higher scores (≥27) did indicate cognitive impairment. Among patients with a higher education, lower scores (<12) indicated intact cognition., Conclusion: Certain scores can indicate intact or impaired cognitive function. Still, MSNQ-P scores should be interpreted with caution.

Background: The thalamus, affected early in multiple sclerosis (MS), is a heterogeneous composition of functionally distinct nuclei and is associated with fatigue, cognition, and other outcomes. However, most previous functional imaging studies considered the thalamus only as a whole., Objective: To investigate MS-related abnormalities in nuclei-specific thalamic functional connectivity (FC) and their associations with fatigue and cognitive outcomes., Methods: Resting-state functional magnetic resonance imaging (fMRI) was analyzed in 64 MS patients and 26 healthy controls (HC). Whole-brain FC maps for four thalamic subregions seeds were computed for each subject. FC maps were compared between groups, and group by FC interaction effects were assessed for fatigue and cognitive measures., Results: MS patients had decreased FC between the left medial thalamic nuclei and left angular gyrus and reduced FC between the left posterior thalamic nuclei and left supramarginal gyrus, as well as decreased right medial thalamic nuclei connectivity with bilateral caudate/thalamus and left cerebellar areas ( p  < 0.05 corrected). MS patients had increased FC between the left anterior thalamic nuclei and anterior cingulate cortex bilaterally. There were significant relationships between connectivity alterations and fatigue and cognitive measures between groups ( p  < 0.05 corrected)., Conclusion: FC alteration is nuclei-specific and is differentially associated with fatigue and cognition.

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.

Background: The fronto-striatal network has been implicated in both fatigue, a common multiple sclerosis (MS) symptom, and goal attainment, which has been shown to reduce fatigue in healthy individuals., Objectives: To investigate whether stimulation of the fronto-striatal network through goal attainment (potential monetary gain) leads to fatigue reduction in MS and healthy control (HC) participants., Methods: In all, 14 healthy and 19 MS participants performed a gambling task during functional magnetic resonance imaging (fMRI). Participants were presented with an opportunity to receive monetary reward during the outcome condition of the task but not during the no outcome condition. Self-reported fatigue measures were obtained after each condition and outside of the scanner. Structural alterations were also examined., Results: A significant decrease in fatigue was observed after the outcome condition compared to the no outcome condition in both groups. Significantly greater activation was observed in the ventral striatum in association with the outcome condition compared to the no outcome condition in both groups. Ventromedial prefrontal cortex showed significantly greater activation during the no outcome condition compared to the outcome condition with greater difference between conditions in the HC group., Conclusion: This is the first functional neuroimaging study showing that stimulation of the fronto-striatal network through goal attainment leads to decreased on-task fatigue in MS and healthy participants.

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., (© The Author(s), 2015.)

Previous studies showed that advanced neuroimaging measures (functional MRI, diffusion tensor imaging) could distinguish multiple sclerosis (MS) patients with and without cognitive impairment. Are these measures indeed better indicators for cognitive impairment or subjective cognitive complaints than conventional MRI? Fifty MS patients and 29 controls were investigated. Regression analysis, including socio-demographic data, disease characteristics, psychological measures, and (advanced) neuroimaging, showed that worse cognitive performance was associated with male sex, lower education, and lower gray matter volume. Subjective cognitive complaints were associated with fatigue and less hippocampal atrophy. Advanced MRI measures did not add to the predictive power of our model., (© The Author(s) 2013.)

Background: Multiple sclerosis (MS) is characterised by inflammatory lesions of the central nervous system. Interferon beta-1b (IFNB-1b) has been shown to improve clinical and magnetic resonance imaging (MRI) measures for patients with MS., Objective: To evaluate whether IFNB-1b in patients presenting with clinically isolated syndromes (CIS) prevented persisting T1 hypointensities on MRI (persistent black holes (PBHs))., Methods: In the placebo-controlled phase, patients (n = 468) were initially randomised to IFNB-1b (n = 292) or placebo (n = 176) for two years or clinically definite MS (CDMS). In the open-label phase (n = 418), both groups were offered IFNB-1b for up to five years. Lesions were classified as PBHs if T1 hypointensity persisted throughout the last available scan (minimum time one year)., Results: A total of 435 patients were evaluable for analysis. The number of PBHs/patient was lower in the early rather than the delayed treatment arm during both phases (.42 vs .71, p = .0102 and .70 vs 1.17, p = .0121). Exploratory analyses identified baseline characteristics that affected rate of conversion., Conclusions: Although the rate of lesions that converted to PBH showed no significant differences between groups, the numbers of PBHs per patient out of new lesions was significantly lower in IFNB-1b patients compared to patients on placebo., Trial Registration Number: NCT00544037.

Background: Gray-matter (GM) atrophy is strongly predictive of cognitive impairment in multiple sclerosis (MS) patients. The thalamus is the region where the atrophy/cognition correlation is most robust. However, few studies have assessed diffusion tensor imaging (DTI) metrics within the thalamus., Objective: This study was designed to determine if thalamus white matter DTI predicts cognitive impairment after accounting for the effects of volume loss., Methods: We enrolled 75 MS patients and 18 healthy controls undergoing 3T brain magnetic resonance imaging (MRI). Thalamus volumes were calculated on 3D T1 images. Voxelwise analyses of DTI metrics were performed within the thalamic white matter tracts. Neuropsychological (NP) testing, acquired using consensus standard methods, contributed measures of memory, cognitive processing speed and executive function., Results: All cognitive tests were significantly predicted (R (2) =0.31, p<0.001) by thalamus volume after accounting for influence of demographics. Mean diffusivity was retained in regression models predicting all cognitive tests, adding from 7-13% of additional explained variance (p<0.02) after accounting for thalamus volume., Conclusions: We confirm the significant role of thalamus atrophy in MS-associated cognitive disorder, and further report that subtle thalamus pathology as detected by DTI adds incremental explained variance in predicting cognitive impairment.

Background: Gender effects are strong in multiple sclerosis (MS), with male patients showing a worse clinical outcome than female patients. Functional reorganization of neural activity may contribute to limit disability, and possible gender differences in this process may have important clinical implications., Objectives: The aim of this study was to explore gender-related changes in functional connectivity and network efficiency in MS patients. Additionally, we explored the association of functional changes with cognitive function., Methods: Sixty subjects were included in the study, matched for age, education level and intelligence quotient (IQ). Male and female patients were matched for disability, disease duration and white matter lesion load. Two cognitive domains often impaired in MS, i.e. visuospatial memory and information processing speed, were evaluated in all subjects. Functional connectivity between brain regions and network efficiency was explored using resting-state functional magnetic resonance imaging and graph analysis. Differences in cognitive and functional characteristics between groups, and correlations with cognitive performance, were examined., Results: Male patients showed worse performance on cognitive tests than female and male controls, while female patients were cognitively normal. Decreases in functional connectivity and network efficiency, observed in male patients, correlated with reduced visuospatial memory (r = -0.6 and r = -0.5, respectively). In the control group, no cognitive differences were found between genders, despite differences in functional connectivity between healthy men and women., Conclusions: Functional connectivity differences were found in male patients only and were related to impaired visuospatial memory. These results underline the importance of gender in MS and require further investigation in larger and longitudinal studies.