Brain activity pattern changes after adaptive working memory training in multiple sclerosis

Cognitive impairment and related abnormal brain activity are common in people with multiple sclerosis (PwMS). Adaptive training based on working memory (WM) has been shown to ameliorate cognitive symptoms, although the effects at a neural level are unclear. The aim of this study was to expand the existing research on the effects of an adaptive WM rehabilitative intervention on brain functional activity in PwMS. A sample of eighteen PwMS performed an 8-week home-based cognitive rehabilitation treatment based on adaptive WM training. PwMS were assessed before and after treatment using a validated neuropsychological battery and undergoing an fMRI session while carrying out a cognitive task (i.e., Paced Visual Serial Addition Test - PVSAT). fMRI activations were compared to the activation pattern elicited by eighteen matched healthy subjects performing the same task. At baseline, we found abnormal brain activity during PVSAT in PwMS when compared to healthy subjects, with a pattern including several bilateral activation clusters. Following rehabilitation, PwMS improved cognitive performance, as evaluated by the neuropsychological battery, and showed a different activation map with clusters mainly located in the right cerebellum and in the left hemisphere. The only significant cluster in the right hemisphere was located in the inferior parietal lobule, and the BOLD signal extracted in this area significantly correlated with cognitive performance both before and after the treatment. We suggest that WM training can improve the cognitive performance and reduce the abnormal activation of PwMS by partially maintaining or even restoring brain cognitive function

Motor imagery as a function of disease severity in multiple sclerosis: An fMRI study

Motor imagery (MI) is defined as mental execution without any actual movement. While healthy adults usually show temporal equivalence, i.e., isochrony, between the mental simulation of an action and its actual performance, neurological disorders are associated with anisochrony. Unlike in patients with stroke and Parkinson disease, only a few studies have investigated differences of MI ability in multiple sclerosis (MS). However, the relationship among disease severity, anisochrony and brain activation patterns during MI has not been investigated yet. Here, we propose to investigate MI in MS patients using fMRI during a behavioral task executed with dominant/non-dominant hand and to evaluate whether anisochrony is associated with disease severity. Thirty-seven right-handed MS patients, 17 with clinically isolated syndrome (CIS) suggestive of MS and 20 with relapsing-remitting MS (RR-MS) and 20 right-handed healthy controls (HC) underwent fMRI during a motor task consisting in the actual or imaged movement of squeezing a foam ball with the dominant and non-dominant hand. The same tasks were performed outside the MRI room to record the number of actual and imagined ball squeezes, and calculate an Index of performance (IP) based on the ratio between actual and imagined movements. IP showed that a progressive loss of ability in simulating actions (i.e., anisochrony) more pronounced for non-dominant hand, was found as function of the disease course. Moreover, anisochrony was associated with activation of occipito-parieto-frontal areas that were more extensive at the early stages of the disease, probably in order to counteract the changes due to MS. However, the neural engagement of compensatory brain areas becomes more difficult with more challenging tasks, i.e., dominant vs. non-dominant hand, with a consequent deficit in behavioral performance. These results show a strict association between MI performance and disease severity, suggesting that, at early stages of the disease, anisochrony in MI could be considered as surrogate behavioral marker of MS severity

Upper limb motor rehabilitation impacts white matter microstructure in multiple sclerosis

Upper limb impairments can occur in patients with multiple sclerosis, affecting daily living activities; however there is at present no definite agreement on the best rehabilitation treatment strategy to pursue. Moreover, motor training has been shown to induce changes in white matter architecture in healthy subjects.This study aimed at evaluating the motor behavioral and white matter microstructural changes following a 2-month upper limb motor rehabilitation treatment based on task-oriented exercises in patients with multiple sclerosis.Thirty patients (18 females and 12 males; age. = 43.3. ±. 8.7. years) in a stable phase of the disease presenting with mild or moderate upper limb sensorimotor deficits were randomized into two groups of 15 patients each. Both groups underwent twenty 1-hour treatment sessions, three times a week. The "treatment group" received an active motor rehabilitation treatment, based on voluntary exercises including task-oriented exercises, while the "control group" underwent passive mobilization of the shoulder, elbow, wrist and fingers.Before and after the rehabilitation protocols, motor performance was evaluated in all patients with standard tests. Additionally, finger motor performance accuracy was assessed by an engineered glove.In the same sessions, every patient underwent diffusion tensor imaging to obtain parametric maps of fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. The mean value of each parameter was separately calculated within regions of interest including the fiber bundles connecting brain areas involved in voluntary movement control: the corpus callosum, the corticospinal tracts and the superior longitudinal fasciculi.The two rehabilitation protocols induced similar effects on unimanual motor performance, but the bimanual coordination task revealed that the residual coordination abilities were maintained in the treated patients while they significantly worsened in the control group (p. = 0.002). Further, in the treatment group white matter integrity in the corpus callosum and corticospinal tracts was preserved while a microstructural integrity worsening was found in the control group (fractional anisotropy of the corpus callosum and corticospinal tracts: p. = 0.033 and p. = 0.022; radial diffusivity of the corpus callosum and corticospinal tracts: p. = 0.004 and p. = 0.008). Conversely, a significant increase of radial diffusivity was observed in the superior longitudinal fasciculi in both groups (p. = 0.02), indicating lack of treatment effects on this structure, showing damage progression likely due to a demyelination process.All these findings indicate the importance of administering, when possible, a rehabilitation treatment consisting of voluntary movements. We also demonstrated that the beneficial effects of a rehabilitation treatment are task-dependent and selective in their target; this becomes crucial towards the implementation of tailored rehabilitative approaches. © 2013 The Authors

The hidden information in patient-reported outcomes and clinician-assessed outcomes: multiple sclerosis as a proof of concept of a machine learning approach

Machine learning (ML) applied to patient-reported (PROs) and clinical-assessed outcomes (CAOs) could favour a more predictive and personalized medicine. Our aim was to confirm the important role of applying ML to PROs and CAOs of people with relapsing-remitting (RR) and secondary progressive (SP) form of multiple sclerosis (MS), to promptly identifying information useful to predict disease progression. For our analysis, a dataset of 3398 evaluations from 810 persons with MS (PwMS) was adopted. Three steps were provided: course classification; extraction of the most relevant predictors at the next time point; prediction if the patient will experience the transition from RR to SP at the next time point. The Current Course Assignment (CCA) step correctly assigned the current MS course with an accuracy of about 86.0%. The MS course at the next time point can be predicted using the predictors selected in CCA. PROs/CAOs Evolution Prediction (PEP) followed by Future Course Assignment (FCA) was able to foresee the course at the next time point with an accuracy of 82.6%. Our results suggest that PROs and CAOs could help the clinician decision-making in their practice

Associations between fatigue impact and physical and neurobehavioural factors: An exploration in people with progressive multiple sclerosis

Background: Fatigue is common in people with multiple sclerosis (MS). Understanding the relationship between fatigue, physical and neurobehavioural factors is important to inform future research and practice. Few studies explore this explicitly in people with progressive MS (pwPMS). // Objective: To explore relationships between self-reported fatigue, physical and neurobehavioural measures in a large, international progressive MS sample of cognitively impaired people recruited to the CogEx trial. // Methods: Baseline assessments of fatigue (Modified Fatigue Impact Scale; MFIS), aerobic capacity (VO2peak), time in moderate-vigorous physical activity (MVPA; accelerometery over seven-days), walking performance (6-minute walk test; 6MWT), self-reported walking difficulty (MS Walking Scale; MSWS-12), anxiety and depression (Hospital Anxiety and Depression Scale; HADS and Beck Depression Inventory-II; BDI-II), and disease impact (MS Impact Scale-29, MSIS-29) were assessed. Participants were categorised as fatigued (MFISTotal >=38) or non-fatigued (MFISTotal ≤38). // Statistical Analysis: Differences in individuals categorised as fatigued or non-fatigued were assessed (t-tests, chi square). Pearson's correlation and partial correlations (adjusted for EDSS score, country, sex, and depressive symptoms) determined associations with MFISTotal, MFISPhysical, MFISCognitive and MFISPsychosocial, and the other measures. Multivariable logistic regression evaluated the independent association of fatigue (categorised MFISTotal) with physical and neurobehavioural measures. // Results: The sample comprised 308 pwPMS (62 % female, 27 % primary progressive, 73 % secondary progressive), mean age 52.5 ± 7.2 yrs, median EDSS score 6.0 (4.5–6.5), mean MFISTotal 44.1 ± 17.1, with 67.2 % categorised as fatigued. Fatigued participants walked shorter distances (6MWT, p = 0.043), had worse MSWS-12 scores (p < 0.001), and lower average % in MVPA (p = 0.026). The magnitude of associations was mostly weak between MFISTotal and physical measures (r = 0.13 to 0.18), apart from the MSWS-12 where it was strong (r = 0.51). The magnitude of correlations were strong between the MFISTotal and neurobehavioural measures of anxiety (r = 0.56), depression (r = 0.59), and measures of disease impact (MSIS-physical r = 0.67; MSIS-mental r = 0.71). This pattern was broadly similar for the MSIF subscales. The multivariable model indicated a five-point increase in MSWS-12 was associated with a 14 % increase in the odds of being fatigued (OR [95 %CI]: 1.14 [1.07–1.22], p < 0.0001) // Conclusion: Management of fatigue should consider both physical and neurobehavioural factors, in cognitively impaired persons with progressive MS

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

BACKGROUND AND OBJECTIVES: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. METHODS: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score &gt; 3 or at least 1 comorbidity, lower risk: EDSS score 64 3 and no comorbidities) by the \u3c72 test, and the risk excess was quantified by risk ratios (RRs). RESULTS: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p &lt; 0.001), RR = 2.19 for ICU admission (p &lt; 0.001), and RR = 2.43 for death (p &lt; 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). DISCUSSION: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon

Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy

Background In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection.Methods This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose.Findings 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p &lt; 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p &lt; 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave.Interpretation The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response. Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/

Antibody response elicited by the SARS-CoV-2 vaccine booster in patients with multiple sclerosis: Who gains from it?

Background and purpose: Although two doses of COVID-19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease-modifying therapies (DMTs) showed less efficient responses. Methods: This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS. Results: Four hundred seventy-three pwMS were analyzed. Compared to untreated patients, there was a 50-fold decrease (95% confidence interval [CI] = 14.3–100.0, p &lt; 0.001) in serum SARS-CoV-2 antibody levels in those on rituximab, a 20-fold decrease (95% CI = 8.3–50.0, p &lt; 0.001) in those on ocrelizumab, and a 2.3-fold decrease (95% CI = 1.2–4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti-CD20 drugs rituximab and ocrelizumab showed a 2.3-fold lower gain (95% CI = 1.4–3.8, p = 0.001), whereas those on fingolimod showed a 1.7-fold higher gain (95% CI = 1.1–2.7, p = 0.012), compared to patients treated with other DMTs. Conclusions: All pwMS increased their serum SARS-CoV-2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (&gt;659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff

Adaptive robot training for the treatment of incoordination in Multiple Sclerosis

<p>Abstract</p> <p>Background</p> <p>Cerebellar symptoms are extremely disabling and are common in Multiple Sclerosis (MS) subjects. In this feasibility study, we developed and tested a robot therapy protocol, aimed at the rehabilitation of incoordination in MS subjects.</p> <p>Methods</p> <p>Eight subjects with clinically defined MS performed planar reaching movements while grasping the handle of a robotic manipulandum, which generated forces that either reduced (error-reducing, ER) or enhanced (error-enhancing, EE) the curvature of their movements, assessed at the beginning of each session. The protocol was designed to adapt to the individual subjects' impairments, as well as to improvements between sessions (if any). Each subject went through a total of eight training sessions. To compare the effect of the two variants of the training protocol (ER and EE), we used a cross-over design consisting of two blocks of sessions (four ER and four EE; 2 sessions/week), separated by a 2-weeks rest period. The order of application of ER and EE exercises was randomized across subjects. The primary outcome measure was the modification of the Nine Hole Peg Test (NHPT) score. Other clinical scales and movement kinematics were taken as secondary outcomes.</p> <p>Results</p> <p>Most subjects revealed a preserved ability to adapt to the robot-generated forces. No significant differences were observed in EE and ER training. However over sessions, subjects exhibited an average 24% decrease in their NHPT score. The other clinical scales showed small improvements for at least some of the subjects. After training, movements became smoother, and their curvature decreased significantly over sessions.</p> <p>Conclusions</p> <p>The results point to an improved coordination over sessions and suggest a potential benefit of a short-term, customized, and adaptive robot therapy for MS subjects.</p

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18\u20134.74, p = 0.015) with increased risk of severe COVID-19. Recent use (&lt;1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20\u201312.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780\u2013789