Deficits In Multiple Sclerosis Research Articles

The nature of memory impairment in multiple sclerosis: understanding different patterns over the course of the disease.

Memory deficit is one of the most common and severe cognitive impairments in patients with multiple sclerosis and can greatly affect their quality of life. However, there is currently no agreement as to the nature of memory deficit in multiple sclerosis. This cross-sectional study, carried out at the Dr. Josep Trueta and Santa Caterina hospitals in Girona (Spain), was designed to determine the semiology of verbal memory deficit in the different stages of the disease. To this end, a modification of Rey's verbal auditory test was created by introducing two recognition trials between the five learning trials, thus monitoring what happens in terms of acquisition versus the retrieval of information during the learning phase. Linear regression models were used to evaluate verbal episodic memory performance between-groups adjusting results by age, sex, educational level, and the presence of anxiety and/or depressive symptoms. 133 patients with multiple sclerosis, clinically isolated syndrome, and radiologically isolated syndrome and 55 healthy controls aged 18-65 years were assessed. It was observed that the memory processes of multiple sclerosis patients worsen with the progression of the disease. In this respect, patients in pre-diagnostic phases (radiologically isolated syndrome and clinically isolated syndrome) show no differences in verbal episodic memory compared to the healthy controls. Patients in the inflammatory stage (relapsing-remitting multiple sclerosis) show a previously learned information retrieval deficit, while patients in progressive stages (secondary progressive multiple sclerosis and primary progressive multiple sclerosis) do not even correctly acquire information. These results provide significant information to assist in understanding the nature of memory deficits in multiple sclerosis over the course of the disease. These results are discussed in terms of possible cognitive rehabilitation strategies depending on the evolutive stage and are related to neuropathological mechanisms involved in the progression of the disease.

Beyond the simplicity of theory of mind deficit in multiple sclerosis: from kinetic perception to socio-emotional abstraction and mentalizing.

Theory of Mind (ToM) processing in Multiple Sclerosis (MS) is still poorly understood due to the difficulty of most tasks in qualifying the mentalizing deficit net of cognitive load. In this study, we administered the New False Belief Animation Task (NFBAT) to 50 MS and 33 healthy controls (HC) to investigate spontaneous mentalizing in ToM and goal-directed interactions. The global cognitive level was assessed by the Montreal Cognitive Assessment (MoCA). NFBAT appropriateness and intentionality scores were computed to investigate the ToM accuracy and intentionality attribution difficulties. NFBAT answers were qualitatively analyzed and categorized into kinetically and socially coherent/not coherent responses to test a low-level perceptual deficit. The main result showed dysfunctional mentalizing reasoning in MS compared to HC in the NFBAT Intentionality score in ToM conditions (p=0.028, d=0.501), while the two groups were equally proficient in mentalization accuracy. The Intentionality underperformance in MS was related to social low-level perceptual processing (β =0.06, p<0.001) and visuospatial functions (β =0.05, p =0.002). A predictive role of memory and executive functions on NFBAT Intentionality scores was not observed. These results strengthen the hypothesis that ToM in MS is likely related to low-level social processing.

Patterns of attention deficit in relapsing and progressive phenotypes of multiple sclerosis

Behavioral aspects and underlying pathology of attention deficit in multiple sclerosis (MS) remain unknown. This study aimed to clarify impairment of attention and its relationship with MS-related fatigue. Thirty-four relapse-remitting MS (RRMS), 35 secondary-progressive MS (SPMS) and 45 healthy controls (HC) were included. Results of psychophysics tasks (attention network test (ANT) and Posner spatial cueing test) and fatigue assessments (visual analogue scale and modified fatigue impact scale (MFIS)) were compared between groups. In ANT, attentional network effects were not different between MS phenotypes and HC. In Posner task, RRMS or SPMS patients did not benefit from valid cues unlike HC. RRMS and SPMS patients had less gain in exogenous trials with 62.5 ms cue-target interval time (CTIT) and endogenous trials with 250 ms CTIT, respectively. Total MFIS was the predictor of gain in 250 ms endogenous blocks and cognitive MFIS predicted orienting attentional effect. Executive attentional effect in RRMS patients with shorter disease duration and orienting attentional effect in longer diagnosed SPMS were correlated with MFIS scores. The pattern of attention deficit in MS differs between phenotypes. Exogenous attention is impaired in RRMS patients while SPMS patients have deficit in endogenous attention. Fatigue trait predicts impairment of endogenous and orienting attention in MS.

Cognitive deficits in multiple sclerosis: Auditory and visual attention and inhibitory control

Background A growing body of evidence has been paid to the cognitive impairment in patients with multiple sclerosis (MS). However, studies concerning cognitive functions in MS have also yielded conflicting results. This study investigates the attention and inhibitory control functions in patients with MS and their relationship with other clinical features, such as depression and fatigue in these patients. Methods Participants included 80 patients with MS and 60 healthy controls. The attention and inhibitory control, fatigue, and psychiatric screening in all subjects were studied, respectively with the Integrated Visual and Auditory Continuous Performance Test (IVA-CPT), Fatigue Severity Scale (FSS), and the Hospital Anxiety and Depression Scale (HADS). Results Patients with MS performed the IVA-CPT task more poorly than the healthy control group (p < 0.001). However, multiple regression analysis did not show any significant relationship between disease duration, FSS, and HADS on attention and inhibitory control. Conclusion Inhibitory control and attention are significantly impaired in patients with MS. Finding the basics of cognitive deficits in MS have potentially important clinical implications for developing better cognitive rehabilitation strategies.

Multivoxel 1H-mr spectroscopy as a potential diagnostic tool in the complex diagnosis of multiple sclerosis type conversion: a case report

The onset of progressive deficit in multiple sclerosis (MS) was often determined retrospectively with difficulties in diagnostic. This is a case report with subtle MS progression. Clinical and structural MRI anamnesis was complemented with multivoxel 1HMRS examination. The patient complained of the walking distance reducing, gradually increasing spasticity in the distal parts of lower extremities, unsteadiness when walking, clumsy movements. Choline and myoinositol levels were predominantly increased in the area of the cingulate gyrus versus other gray matter regions and the same picture was observed in adjacent white matter. Multivoxel 1H-MRS represents a diagnostic tool that can be very useful in complex diagnostic of MS progression. Measuring chemical-pathological changes diffusely in brain tissues may detect distinctive for progression metabolic patterns.

Ex-Gaussian analysis of simple response time as a measure of information processing speed and the relationship with brain morphometry in multiple sclerosis

BackgroundThe polyfactorial nature of the widely used symbol digit modalities test (SDMT) introduces significant measurement challenges in characterizing information processing speed (IPS) deficits in multiple sclerosis (MS). Measures with high psychometric IPS-specificity and less contamination from other cognitive domains are necessary to fully understand IPS changes. ObjectiveInvestigate how three mathematical modeling ex-Gaussian parameter estimates (mu, sigma, tau) derived from a simple response time (RT) task (1) differentiate MS from healthy control participants and (2) correspond to structural brain changes, to evaluate a novel IPS measurement approach. MethodsPersons with and without MS completed a two-minute behavioral simple RT task, structural MRI and the MS functional composite. RT distributions were deconvolved into ex-Gaussian parameter estimates using mathematical modeling. Group differences and brain-behavior relationships were statistically evaluated. ResultsPersons with MS experienced a general pattern of slowing as evidenced by a shift in the Gaussian (mu) component of the distribution. This correlated with whole brain volume and white matter specifically. Additionally, persons with MS had larger values of tau (elongated positively skewed tail) that may reflect attentional lapses. ConclusionThe ex-Gaussian approach is sensitive to disease-related IPS changes and provides nuanced information about IPS slowing in MS.

The relationship between processing speed and verbal and non-verbal new learning and memory in progressive multiple sclerosis

Objective: Processing speed (PS) deficits are the most common cognitive deficits in multiple sclerosis (MS), followed by learning and memory deficits, and are often an early cognitive problem. It has been argued that impaired PS is a primary consequence of MS, which in turn decreases learning. The current analysis examined the association between PS and learning in a large cohort of individuals with progressive MS. Methods: Baseline data from a randomized clinical trial on rehabilitation taking place at 11 centers across North America and Europe were analyzed. Participants included 275 individuals with clinically definite progressive MS (primary, secondary) consented into the trial. Results: Symbol Digit Modalities Test (SDMT) significantly correlated with California Verbal Learning Test-II (CVLT-II) (r = 0.21, p = 0.0003) and Brief Visuospatial Memory Test–Revised (BVMT-R) (r = 0.516, p < 0.0001). Receiver operating characteristic (ROC) analysis of the SDMT z score to distinguish between impaired and non-impaired CVLT-II performance demonstrated an area under the curve (AUC) of 0.61 (95% confidence interval (CI): 0.55–0.68) and a threshold of −1.62. ROC analysis between SDMT and BVMT-R resulted in an AUC of 0.77 (95% CI: 0.71–0.83) and threshold of −1.75 for the SDMT z score to predict impaired BVMT-R. Conclusion: Results indicate little ability beyond chance to predict CVLT-II from SDMT (61%), albeit statistically significant. In contrast, there was a 77% chance that the model could distinguish between impaired and non-impaired BVMT-R. Several potential explanations are discussed.

Matrine inhibits the Wnt3a/β-catenin/TCF7L2 signaling pathway in experimental autoimmune encephalomyelitis

Oligodendrocyte (OL) death and remyelination failure lead to progressive neurological deficits in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophora flavescens, has the capacity to effectively inhibit central nervous system (CNS) inflammation and to promote neuroregeneration. In the present study we explored its regulatory mechanism on the Wnt/β-catenin/TCF7L2 pathway, a negative modulator for myelination, in MOG35‐–55 peptide-induced EAE. Our results clearly indicate that MAT treatment reduced the activation of Wnt3a and β-catenin in the CNS of EAE mice, accompanied by the activation of GSK3β and decreased expression of cyclin D1 and Axin2, two target genes of the Wnt3a/β-catenin pathway. In addition, MAT increased OL maturation and myelination, as evidenced by the decreased number of NG2+Olig2+ cells and the increased numbers of MBP+ and CC1+Olig2+ cells. Taken together, these findings indicate that MAT treatment promoted the maturation of OLs and myelin repair, which is closely related to the modulation of the Wnt/β-catenin/TCF7L2 signaling pathway.

Identifying prospective memory deficits in multiple sclerosis: Preliminary evaluation of the criterion and ecological validity of a single item version of the memory for intentions test (MIST)

Objectives: Difficulties with prospective memory (PM) are not routinely assessed in persons with multiple sclerosis (MS) even though they can impact daily functioning. This study aimed to examine the preliminary criterion and ecological validity of a highly abbreviated Memory for Intentions Test (MIST) intended to serve as an initial screening of PM in persons with MS. Methods: Participants (n = 112) were classified as impaired if they performed 1.5 standard deviations below the normative mean on the MIST. Individual MIST trials with adequate difficulty and discriminability were examined using receiver operating characteristic analyses, with their classification accuracies, sensitivities, and specificities compared to each other. Regressions were run to evaluate their ecological validity, with appointment attendance and employment as the outcomes. Results: Two trials had a classification accuracy of ≥80%: Trial 3 (79% sensitivity, 84% specificity) and Trial 4 (57% sensitivity, 91% specificity). These two trials had comparable specificity (p=.127), with Trial 3 having slightly higher sensitivity (p=.083). Only Trial 4 was significantly associated with appointment attendance (b = 1.63, p=.047) and unemployment (aOR = 11.20, p=.027). Discussion:Trial 4 of the MIST, a verbal task with a time-based cue that requires participants to complete a pre-specified response after a 15-minute delay, has the potential to be a screener for PM.

Emotional processing intervention (EMOPRINT): A blinded randomized control trial to treat facial affect recognition deficits in multiple sclerosis

ObjectiveFacial affect recognition deficits have been noted in persons with MS, however there is no treatment for these impairments. We investigated the efficacy of the Emotional Processing Intervention (EMOPRINT), a 12-session behavioral intervention teaching facial affect recognition skills and mimicry to improve facial affect recognition abilities in persons with MS. MethodsThis double blind, placebo-controlled, randomized clinical trial with two time points (pre-treatment; post-treatment) included 36 participants with clinically definite MS, 21 in the treatment group and 15 in the placebo control group. Participants completed a pre-test and post-test neuropsychological assessment, which consisted of tasks of facial affect recognition (primary outcome measure) and questionnaires to assess quality of life and emotional functioning (secondary outcome measures). We hypothesized that improvements in facial affect recognition skills would be observed following treatment. We also examined changes to quality of life and social functioning. Changes in outcome measures were analyzed using a mixed-method analysis of variance. ResultsThe treatment group showed significantly improved facial affect recognition skills relative to the placebo group post-treatment, F(1,34)=5.91, p=.022, partial ꞃ2=0.146. No significant change was noted on secondary outcomes. The majority of the participants in the intervention group reported that the intervention was helpful and that they used the skills learned in their daily interactions. ConclusionEMOPRINT is effective for improving facial affect recognition skills in MS.

Resting-state functional brain connectivity for human mentalizing: biobehavioral mechanisms of theory of mind in multiple sclerosis.

Although neural hubs of mentalizing are acknowledged, the brain mechanisms underlying mentalizing deficit, characterizing different neurological conditions, are still a matter of debate. To investigate the neural underpinning of theory of mind (ToM) deficit in multiple sclerosis (MS), a region of interest (ROI)-based resting-state fMRI study was proposed. In total, 37 MS patients (23 females, mean age = 54.08 ± 11.37 years, median Expanded Disability Status Scale = 6.00) underwent an MRI and a neuro-psychosocial examination and were compared with 20 sex-age-education matched healthy subjects. A neuroanatomical ToM model was constructed deriving 11 bilateral ROIs and then between and within-functional connectivity (FCs) were assessed to test for group differences. Correlation with psychosocial scores was also investigated. Lower ToM performance was registered for MS both in cognitive and affective ToM, significantly associated with processing speed. A disconnection between limbic–paralimbic network and prefrontal execution loops was observed. A trend of aberrant intrinsic connectivity in MS within the anterior cingulate cortex (ACC) was also reported. Finally, a correlation between cognitive ToM and intrinsic FC was detected in ACC and dorsal striatum, belonging to the limbic–paralimbic network, likely explaining the behavioral deficit in MS. The results suggest that aberrant intrinsic and extrinsic connectivity constitutes a crucial neural mechanism underlying ToM deficit in MS.

Anti-CD20 therapy corrects a CD8 regulatory T cell deficit in multiple sclerosis

Objective: To determine the effect of long-term anti-CD20 B-cell-depleting treatment on regulatory T cell immune subsets that are subnormal in untreated MS patients. Methods: 30 clinically stable MS patients, before and over 38 months of ocrelizumab treatment, were compared to 13 healthy controls, 29 therapy-naïve MS, 9 interferon-β-treated MS, 3 rituximab-treated MS, and 3 rituximab-treated patients with other autoimmune inflammatory diseases. CD8, CD28, CD4, and FOXP3 expression in peripheral blood mononuclear cells was quantitated with flow cytometry. Results: CD8+ CD28− regulatory cells rose from one-third of healthy control levels before ocrelizumab treatment (2.68% vs 7.98%), normalized by 12 months (13.5%), and rose to 2.4-fold above healthy controls after 18 months of ocrelizumab therapy (19.0%). CD4+ FOXP3+ regulatory cells were lower in MS than in healthy controls (7.98%) and showed slight long-term decreases with ocrelizumab. CD8+ CD28− and CD4+ FOXP3+ regulatory T cell percentages in IFN-β-treated MS patients were between those of untreated MS and healthy controls. Interpretation: Long-term treatment with ocrelizumab markedly enriches CD8+ CD28− regulatory T cells and corrects the low levels seen in MS before treatment, while slightly decreasing CD4+ FOXP3+ regulatory T cells. Homeostatic enrichment of regulatory CD8 T cells provides a mechanism, in addition to B cell depletion, for the benefits of anti-CD20 treatment in MS.

Cognitive Processes Underlying Verbal Fluency in Multiple Sclerosis.

Background: Verbal fluency (VF) has been associated with several cognitive functions, but the cognitive processes underlying verbal fluency deficits in Multiple Sclerosis (MS) are controversial. Further knowledge about VF could be useful in clinical practice, because these tasks are brief, applicable, and reliable in MS patients. In this study, we aimed to evaluate the cognitive processes related to VF and to develop machine-learning algorithms to predict those patients with cognitive deficits using only VF-derived scores.Methods: Two hundred participants with MS were enrolled and examined using a comprehensive neuropsychological battery, including semantic and phonemic fluencies. Automatic linear modeling was used to identify the neuropsychological test predictors of VF scores. Furthermore, machine-learning algorithms (support vector machines, random forest) were developed to predict those patients with cognitive deficits using only VF-derived scores.Results: Neuropsychological tests associated with attention-executive functioning, memory, and language were the main predictors of the different fluency scores. However, the importance of memory was greater in semantic fluency and clustering scores, and executive functioning in phonemic fluency and switching. Machine learning algorithms predicted general cognitive impairment and executive dysfunction, with F1-scores over 67–71%.Conclusions: VF was influenced by many other cognitive processes, mainly including attention-executive functioning, episodic memory, and language. Semantic fluency and clustering were more explained by memory function, while phonemic fluency and switching were more related to executive functioning. Our study supports that the multiple cognitive components underlying VF tasks in MS could serve for screening purposes and the detection of executive dysfunction.

Prospective Memory Deficits in Multiple Sclerosis: Voxel-based Morphometry and Double Inversion Recovery Analysis.

Objective Prospective memory (PM) is an important social cognitive function in everyday life. PM is one of the most affected cognitive domains in multiple sclerosis (MS) patients. Gray matter (GM) atrophy and plaques have been attracting attention for various cognitive impairments in MS patients. This study aimed to clarify the atrophic GM regions associated with PM deficits and investigate the relationship between the atrophic GM regions and GM plaques. Methods Twenty-one MS patients and 10 healthy controls (HCs) underwent neuropsychological tests and MRI. PM was assessed using subtests of the Rivermead Behavioural Memory Test. A lesion symptom analysis was performed using voxel-based morphometry (VBM). We then evaluated GM plaques in the corresponding areas using double inversion recovery (DIR). Results MS patients showed lower PM scores than HCs (p=0.0064). The GM volume of MS patients tended to be lower than those of HCs. VBM analyses revealed correlations of the PM score with the orbital part of the left inferior frontal gyrus, the left hippocampus, and the right parahippocampus. There was no GM plaque in the orbital part of the left inferior frontal gyrus and the right parahippocampus. Only one patient (4.8%) had GM plaque in the left hippocampus. Conclusion The left inferior frontal gyrus, the left hippocampus, and the right parahippocampus were associated with PM in MS, whereas these atrophic GM regions were not associated with GM plaque. Regardless of the location of plaques on DIR, both PM deficit and GM atrophy should be detected using neuropsychological tests and VBM in MS patients.

Structural constraints of functional connectivity drive cognitive impairment in the early stages of multiple sclerosis

Background: The relationship between structural and functional deficits in multiple sclerosis (MS) is unclear. Objective: This study explored structure-function relationships during the 5 years following a clinically isolated syndrome and their role in cognitive performance. Methods: Thirty-two patients were enrolled after their first neurological episode suggestive of MS and followed for 5 years, along with 10 matched healthy controls. We assessed structural (using diffusion tensor imaging) and functional (using resting-state functional magnetic resonance imaging (fMRI)) brain network metrics, clinical and cognitive scores at each follow-up visit. Structural–functional coupling, calculated as the correlation coefficient between strengths of structural and functional networks, was used to assess structure–function relationships. Results: Structural clustering coefficient was significantly increased after 5 years, whereas characteristic path length decreased. Structural connections decreased after 1 year and increased after 5 years. Functional connections and related path lengths were decreased after 5 years. Structural–functional coupling had increased significantly after 5 years. This structural–functional coupling was associated with cognitive and clinical evolution, with stronger coupling associated with a decline in both domains. Conclusion: Our findings provide novel biological evidence that MS leads to a more constrained anatomical-dependant functional connectivity. The collapse of this network seems to lead to both cognitive worsening and clinical disability.

Visual-Attentional Load Unveils Slowed Processing Speed in Multiple Sclerosis Patients: A Pilot Study with a Tablet-Based Videogame.

Slowing in information processing speed (IPS) is the key cognitive deficit in multiple sclerosis (MS). Testing IPS in different cognitive load conditions by using computerized tools might reveal initial IPS slowness underestimated by classic paper-and-pencil tests. To investigate the extent to which IPS can be affected by increased task demands, we developed three tasks based on the manipulation of the visual-attentional load, delivered with a home-made, tablet-based videogame. Fifty-one patients with MS (pwMS), classified as having no cognitive impairment in classic paper-and-pencil tests, and 20 healthy controls (HC) underwent the videogame tasks; reaction times (RTs) and accuracy were recorded. A significant reduced performance of pwMS as compared with HC was found on the videogame tasks, with pwMS being on average slower and less accurate than HC. Furthermore, pwMS showed a significantly more pronounced decrement in accuracy as a function of the visual-attentional load, suggesting a higher susceptibility to increased task demands. Significant correlations among the Symbol Digit Modalities Test (SDMT) and the videogame mean RTs and accuracy were found, providing evidence for the concurrent validity of the videogame as a valid tool to test IPS in pwMS. The high potential that might derive from the adoption of computerized assessment tools in clinical practice should be taken into consideration and investigated further.

Peculiarities of an assessment of a cognitive efficacy in multiple sclerosis

A key cognitive deficit in multiple sclerosis (MS) is a poor efficacy of the information processing, with working memory impairments and a decreased speed of the information processing as components of formation of this poor efficacy. Despite of a sufficient number of single cognitive tests and test batteries, there are still essential knowledge gaps and methodological limitations connected with understanding and measurements of the cognitive deficit in MS. To study real reasons of changes of the cognitive efficacy in MS, a neurocognitive testing with the original computerized Set for Assessment of Cognitive Capacity and Switchability (сSACCAS), an assessment of levels anxiety/depression, and an assessment of level of fatigue were performed for 25 patients with MS (including 17 female patients) (with a mean age of 34.14 ± 2.13 years old) and 25 practically healthy persons (including 15 females) (with a mean age of 31.80 ± 2.60 years old). To determine neurophysiological correlates of the cognitive functioning, an examination of cognitive evoked potentials (CEP) was performed. An investigation of the distribution density of results of the MS patients’ testing defined 3 groups among them. These groups had differences on the time of performing of test tasks, the “real mistake ratio”, switchability, parameters of N2- and P3-components of CEP, a localization of a maximal P3 peak. The motor reaction speed was more connected with the attention and the information processing speed, than with a visual-spatial orientation, whereas the fatigue more influenced on the speed of comparison and decision making, than on the attention. In 44 % of cases, the time of reply in tests were increased by a slowing down of assessment of a stimulus modality; in 24 % of cases, a long delay of the reply was connected, besides of a low speed of cognitive processes, with impairments of a working memory. The results obtained confirmed a significance of an integrated approach to understand reasons of changes of the cognitive efficacy and to assess adequately cognitive impairments in MS. Key words: neurocognitive computerized tests, cognitive efficacy, cognitive evoked potentials, multiple sclerosis

Cognitive impairment in multiple sclerosis: lessons from cerebrospinal fluid biomarkers.

Cognitive impairment is a common clinical manifestation of multiple sclerosis, but its pathophysiology is not completely understood. White and grey matter injury together with synaptic dysfunction do play a role. The measurement of biomarkers in the cerebrospinal fluid and the study of their association with cognitive impairment may provide interesting in vivo evidence of the biological mechanisms underlying multiple sclerosis-related cognitive impairment. So far, only a few studies on this topic have been published, giving interesting results that deserve further investigation. Cerebrospinal fluid biomarkers of different pathophysiological mechanisms seem to reflect different neuropsychological patterns of cognitive deficits in multiple sclerosis. The aim of this review is to discuss the studies that have correlated cerebrospinal fluid markers of immune, glial and neuronal pathology with cognitive impairment in multiple sclerosis. Although preliminary, these findings suggest that cerebrospinal fluid biomarkers show some correlation with cognitive performance in multiple sclerosis, thus providing interesting insights into the mechanisms underlying the involvement of specific cognitive domains.

Graph Theoretic Analysis of Brain Connectomics in Multiple Sclerosis: Reliability and Relationship with Cognition.

Research suggests that disruption of brain networks might explain cognitive deficits in multiple sclerosis (MS). The reliability and effectiveness of graph theoretic network metrics as measures of cognitive performance were tested in 37 people with MS and 23 controls. Specifically, relationships with cognitive performance (linear regression against the paced auditory serial addition test-3 seconds [PASAT-3], symbol digit modalities test [SDMT], and attention network test) and 1-month reliability (using the intraclass correlation coefficient [ICC]) of network metrics were measured using both resting-state functional and diffusion magnetic resonance imaging data. Cognitive impairment was directly related to measures of brain network segregation and inversely related to network integration (prediction of PASAT-3 by small worldness, modularity, characteristic path length, R2 = 0.55; prediction of SDMT by small worldness, global efficiency, and characteristic path length, R2 = 0.60). Reliability of the measures for 1 month in a subset of nine participants was mostly rated as good (ICC >0.6) for both controls and MS patients in both functional and diffusion data, but was highly dependent on the chosen parcellation and graph density, with the 0.2–0.5 density range being the most reliable. This suggests that disrupted network organization predicts cognitive impairment in MS and its measurement is reliable for a 1-month period. These new findings support the hypothesis of network disruption as a major determinant of cognitive deficits in MS and the future possibility of the application of derived metrics as surrogate outcomes in trials of therapies for cognitive impairment.

Cognitive processing speed deficits in multiple sclerosis: Dissociating sensorial and motor processing changes from cognitive processing speed

BackgroundThe assessment of cognitive information processing speed (IPS) is complicated in MS, with altered performance on tests such as the Symbol Digit Modalities Test (SDMT) potentially representing changes not only within cognitive networks but in the initial sensorial transmission of information to cognitive networks, and/or efferent transmission of the motor response. ObjectiveWe aimed to isolate and characterise cognitive IPS deficits in MS using ocular motor tasks; a prosaccade task (used to assess and control for sensorial and motor IPS) which was then used to adjust performance on the Simon task (cognitive IPS). MethodsAll participants (22 MS patients with early disease, 22 healthy controls) completed the ocular motor tasks and the SDMT. The Simon task assessed cognitive IPS by manipulating the relationship between a stimulus location and its associated response direction. Two trial types were interleaved: (1) congruent, where stimulus location = response direction; or (2) incongruent, where stimulus location ≠ response direction. RESULTS MS patients did not perform differently to controls on the SDMT. For OM tasks, when sensorial and motor IPS was controlled, MS patients had significantly slower cognitive IPS (incongruent trials only) and poorer conflict resolution. SDMT performance did not correlate with slower cognitive IPS in MS patients, highlighting the limitation of using SDMT performance to interpret cognitive IPS changes in patients with MS. ConclusionCognitive IPS deficits in MS patients are dissociable from changes in other processing stages, manifesting as impaired conflict resolution between automatic and non-automatic processes. Importantly, these results raise concerns about the SDMT as an accurate measure of cognitive IPS in MS.