Eye movement desensitization and reprocessing for depressed individuals with multiple sclerosis: A pilot study.

BACKGROUND: Multiple studies have highlighted elevated rates of depression among individuals with Multiple Sclerosis (MS), with its associated symptoms posing a significant threat to overall well-being. Moreover, existing literature suggests a potential interconnection between depressive manifestations and the decline of physical functionalities in the context of MS. OBJECTIVE: to examine the viability of the Eye Movement Desensitization Reprocessing (EMDR) therapy protocol for the treatment of depressive disorders (DeprEND) for alleviating depression in individuals with MS. METHODS: We conducted a process-outcome study to examine the feasibilty and effectiveness DeprEND enrolling 13 individuals with MS and depressive symtpoms. Psychological and physical assessment pre-, post-intervention and 3-month follow-up were included. Pre- and post-magnetic resonance imaging (MRI) scans were conducted to analyze potential alterations in brain function. RESULTS: The EMDR DeprEND treatment showed a high level of adherence and feasibility. Significant reductions in depressive symptoms were found at post-intervention and at 3 months follow-up. No significant differences were observed in terms of physical symptoms. A significant modulation observed in parietal and premotor areas when examining negative valence stimuli post-treatment was found. CONCLUSION: for The EMDR DeprEND protocol may represent a feasible and cost-effective treatment for reducing depressive symptoms in MS patients and improving their mental well-being.

Increased Levels of Beta-Endorphin and Noradrenaline after a Brief High-Impact Multidimensional Rehabilitation Program in Multiple Sclerosis.

Finding new solutions for the management of multiple sclerosis (MS) is crucial: further research is needed to study the effect of non-pharmacological interventions on the symptoms and the course of the disease, especially on lifestyle. Benefits from a proper lifestyle are evident not only on a clinical level but also on immune and neuro-endocrine systems. A brief high-impact multidimensional rehabilitation program (b-HIPE) was proposed for a sample of people with MS (pwMS) with a medium level of disease disability. We tested the change on clinical parameters and quality of life (QoL) after participation in B-HIPE. We furthermore decided to measure beta-endorphin and catecholamines concentrations pre- and post-participation in the b-HIPE program, due to the relationship between these hormones and the immune system in neurodegenerative diseases. Our results showed that after the b-HIPE program, an improvement of clinical parameters and QoL occurred. Moreover, we found higher levels of beta-endorphin and noradrenaline after participation in the program. These findings highlight the importance of implementing lifestyle interventions in the clinical management of MS. Furthermore, we hypothesize that the B-HIPE program increased beta-endorphin and noradrenaline levels, helping to reduce the inflammation related to MS disease.

Effects of home-based virtual reality telerehabilitation system in people with multiple sclerosis: A randomized controlled trial.

BACKGROUND AND OBJECTIVE: Multiple sclerosis is an inflammatory and neurodegenerative disorder of the central nervous system that can lead to severe motor disability. The aim of this study was to verify the health care effects of an integrated telerehabilitation approach involving dual-domains (motor and cognitive) in people with multiple sclerosis using a virtual reality rehabilitation system compared to a home-based conventional rehabilitative intervention usual care for patient-relevant outcomes (motor, cognitive and participation). METHODS: This multicentre interventional, randomized controlled trial included 70 participants with multiple sclerosis, 35 in the telerehabilitation group (30 sessions of home-based virtual reality rehabilitation system training, five sessions for week each lasting 45 min) and 35 in the usual care group (30 sessions of conventional treatment, five sessions for week). Participants completed the assessment of motor, cognitive and participation outcomes at baseline and after 6 weeks of treatment. RESULTS: In total, 63.3% of the telerehabilitation group exhibited improvement in the physical domain of the quality of life (p = 0.045). The telerehabilitation group showed greater improvement than the usual care group in Mini-BESTest domains of balance (p = 0.014), postural control (p = 0.024), and dynamic walking (p = 0.020) at post-treatment. Higher adherence was registered for telerehabilitation compared with usual care (86.67% vs. 80.0%). DISCUSSION: This study provides evidence that people with multiple sclerosis can benefit from telerehabilitation treatment in the physical domain of the quality of life and motor symptoms. Moreover, considering the persistent COVID-19 emergency, telerehabilitation can represent an effective telemedicine solution for safely delivering effective rehabilitation care to people with multiple sclerosis. TRIAL REGISTRATION NUMBER AND TRIAL REGISTER: This trial was registered at ClinicalTrials.gov (NCT03444454).

An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients.

Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease's estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes-particularly mRNA transport-or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family.

Influence of a High-Impact Multidimensional Rehabilitation Program on the Gut Microbiota of Patients with Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative inflammatory condition mediated by autoreactive immune processes. Due to its potential to influence host immunity and gut-brain communication, the gut microbiota has been suggested to be involved in the onset and progression of MS. To date, there is no definitive cure for MS, and rehabilitation programs are of the utmost importance, especially in the later stages. However, only a few people generally participate due to poor support, knowledge, and motivation, and no information is available on gut microbiota changes. Herein we evaluated the potential of a brief high-impact multidimensional rehabilitation program (B-HIPE) in a leisure environment to affect the gut microbiota, mitigate MS symptoms and improve quality of life. B-HIPE resulted in modulation of the MS-typical dysbiosis, with reduced levels of pathobionts and the replenishment of beneficial short-chain fatty acid producers. This partial recovery of a eubiotic profile could help counteract the inflammatory tone typically observed in MS, as supported by reduced circulating lipopolysaccharide levels and decreased populations of pro-inflammatory lymphocytes. Improved physical performance and fatigue relief were also found. Our findings pave the way for integrating clinical practice with holistic approaches to mitigate MS symptoms and improve patients' quality of life.

Cancer risk for multiple sclerosis patients treated with azathioprine and disease-modifying therapies: an Italian observational study.

BACKGROUND: The risk of malignancy associated with sequential disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS) is uncertain. The aim of this study was to analyze the risk of cancer in patients with MS treated with azathioprine (AZA) and the influence of sequential DMTs on the risk. METHOD: We retrospectively enrolled a cohort of AZA-treated MS patients followed in two Italian centers from 1987 to 2019. The ratio between observed and expected cancers in the Italian general population was calculated as standardized incidence ratio (SIR). Associations between AZA and DMTs and cancer were estimated by Cox proportional hazards model. RESULTS: We identified 500 AZA-treated MS patients, followed for a median time of 9.7 (0.1-45.7) years: 61.8% of them were treated with DMTs. We found 22 cases of cancer (4.4%). The SIR was 1.14 (95% CI 0.98-1.29), not significantly increased in comparison with the general population. However, the risk was significantly higher in the quintiles of age 32-45, SIR 1.21 (95% CI 1.21-1.42), and 46-51, SIR 1.11 (95% CI 1.11-1.32) than in older cases. Age at AZA treatment onset was the only covariate significantly related to cancer incidence (HR = 1.049, 95% CI 1.007-1.093). The exposure to other DMTs did not modify the risk. CONCLUSION: The risk of malignancy in MS patients after AZA was similar to that of the general population and did not change with other DMTs sequential treatments. The increased risk in the younger ages should be considered in treatment assessment.

Alterations in Circulating Fatty Acid Are Associated With Gut Microbiota Dysbiosis and Inflammation in Multiple Sclerosis.

Background: Butyric acid (BA) is a short-chain fatty acid (SCFA) with anti-inflammatory properties, which promotes intestinal barrier function. Medium-chain fatty acids (MCFA), including caproic acid (CA), promote TH1 and TH17 differentiation, thus supporting inflammation. Aim: Since most SCFAs are absorbed in the cecum and colon, the measurement of BA in peripheral blood could provide information on the health status of the intestinal ecosystem. Additionally, given the different immunomodulatory properties of BA and CA the evaluation of their serum concentration, as well as their ratio could be as a simple and rapid biomarker of disease activity and/or treatment efficacy in MS. Methods: We evaluated serum BA and CA concentrations, immune parameters, intestinal barrier integrity and the gut microbiota composition in patients with multiple sclerosis (MS) comparing result to those obtained in healthy controls. Results: In MS, the concentration of BA was reduced and that of CA was increased. Concurrently, the microbiota was depleted of BA producers while it was enriched in mucin-degrading, pro-inflammatory components. The reduced serum concentration of BA seen in MS patients correlated with alterations of the barrier permeability, as evidenced by the higher plasma concentrations of lipopolysaccharide and intestinal fatty acid-binding protein, and inflammation. Specifically, CA was positively associated with CD4+/IFNγ+ T lymphocytes, and the BA/CA ratio correlated positively with CD4+/CD25high/Foxp3+ and negatively with CD4+/IFNγ+ T lymphocytes. Conclusion: The gut microbiota dysbiosis found in MS is possibly associated with alterations of the SCFA/MCFA ratio and of the intestinal barrier; this could explain the chronic inflammation that characterizes this disease. SCFA and MCFA quantification could be a simple biomarker to evaluate the efficacy of therapeutic and rehabilitation procedures in MS.

Theory of mind network in multiple Sclerosis: A double disconnection mechanism.

The relationship between cognitive and affective theory of mind (ToM), clinical variables, and brain tissue injury is still a subject of debate in multiple sclerosis (MS). By adopting a ToM Networks model, we investigated ToM performance, and brain imaging correlates in relapsing-remitting (RR) and progressive (Pr) MS. 16RR, 19Pr, and 21 healthy controls were assessed with both cognitive (CToM) and affective ToM (AToM) tests and neuropsychological tools and were evaluated with MRI. Cortical thickness, sub-cortical volumetry, and tract-based-spatial-statistics were analyzed. Our results reported a CToM deficit in Pr, correlated with attention. While no relation between gray matter and CToM was observed, a widespread correlation between CToM and normal-appearing white matter was found. In particular, we registered a significant positive correlation between CToM and fractional anisotropy in Superior and Inferior Longitudinal Fasciculus and right thalamic radiation tracts. Moreover, an inverse correlation between CToM and mean diffusivity of the right fronto-occipital fasciculus, bilateral superior longitudinal fasciculus, cortico-spinal, left uncinate, corpus callosum, and forceps minor tracts was also observed. This work highlighted a double disconnection mechanism in Pr MS affecting communication both (1) inside the ToM network and (2) between the ToM network and cognitive execution areas, likely explaining the deficit in cognitive ToM.

Cerebrovascular reactivity and its correlation with age in patients with multiple sclerosis.

We assessed cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) within gray matter (GM), normal appearing white matter (NAWM) and white matter (WM) lesions in a group of multiple sclerosis (MS) patients. Furthermore, correlations between CBF, CVR and age were investigated. 31 MS patients and 25 healthy controls (HC) were examined on a 1.5 T MRI scanner, using pseudo-continuous arterial spin labeling MRI. MS vs HC CBF and CVR differences were assessed in GM regions of interest (i.e. resting state networks and vascular territories), and within WM. Correlations between CBF/CVR and age were then computed for MS and HC groups. Whereas no significant CBF and CVR differences were observed between MS and HC in any of the considered brain areas, significantly lower CBF was found in WM lesions with respect to NAWM (p < 0.001) in MS patients. Furthermore, CVR was significantly correlated with age in HC, but not in MS patients. The relatively low-grade of inflammation of our MS cohort may be associated with the observed lack of significant CVR differences between MS patients and HC. The loss of correlation between CVR and age in the MS group suggests that CVR may be influenced by MS-related factors.

Integrated telerehabilitation approach in multiple sclerosis: A systematic review and meta-analysis.

INTRODUCTION: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system and a major cause of disability in young adults. Recently, there has been a growing interest in the development of innovative ways to deliver rehabilitation care outside of a hospital setting. The aim was to conduct a systematic review and a meta-analysis of the efficacy of an integrated telerehabilitation approach (ITA) on motor, cognitive and participation outcomes delivered to people with MS (pwMS). METHODS: We systematically searched for original manuscripts regarding ITA in pwMS. Efficacy on motor, cognitive and participation outcomes was measured as the standardized mean difference (Hedges' g) of pre and post training. RESULTS: Nine studies encompassing 716 pwMS diagnosis were included. The overall effect of ITA was: large for motor outcomes (g = 1.05; p = 0.013); small for cognitive performance outcomes (g = 0.16; p = 0.237); and small for participation outcomes (g = 0.15; p = 0.259). Domain-specific results showed that the effect on motor disability was large (g = 1.18), while on gait and balance was medium (g = 0.32 and g = 0.48, respectively). Moreover, all effects on single cognitive domains were small. Finally, among the single participation outcomes considered (depression, fatigue, daily functioning, quality of life and self-efficacy) only depression showed a nearly medium effect (g = 0.30). CONCLUSIONS: PwMS can benefit from ITA in the treatment of motor symptoms according to the current model of continuity of care. However, the low efficacy of ITA on cognition and participation domains suggests the necessity to develop intervention models that include a broader spectrum of needs and objectives.

Dissociative identity as a continuum from healthy mind to psychiatric disorders: Epistemological and neurophenomenological implications approached through hypnosis.

The topic of multiple personality, redefined as Dissociative Identity Disorders (DIDs) in the DSM-5, is an intriguing and still debated disorder with a long history and deep cultural and epistemological implications, extending up to the idea of possession. Hypnosis is an appealing and valuable model to manipulate subjective experience and get an insight on both the physiology and the pathophysiology of the mind-brain functioning; it and has been closely connected with DIDs and possession since its origin in 18th century and as recently proved the capacity to yield a loss of sense of agency, mimicking delusions of alien control and spirit possession. In this study we report on five very uncommon "hypnotic virtuosos" (HVs) free from any psychiatric disorder, spontaneously undergoing the emergence of multiple identities during neutral hypnosis; this allowed us to check the relationship between their experience and fMRI data. During hypnosis the subjects underwent spontaneous non-intrusive experiences of other selves which were not recalled after the end of the session, due to post-hypnotic amnesia. The fMRI showed a significant decrease of connectivity in the Default Mode Network (DMN) especially between the posterior cingulate cortex and the medial prefrontal cortex. Our results and their contrast with the available data on fMRI in DIDs allows to draw the hypothesis of a continuum between healthy mind - where multiple identities may coexist at unconscious level and may sometimes emerge to the consciousness - and DIDs, where multiple personalities emerge as dissociated, ostensibly autonomous components yielding impaired functioning, subject's loss of control and suffering. If this is the case, it seems more reasonable to refrain from seeking for a clear-cut limit between normality (anyway a conventional, statistical concept) and pathology, and accept a grey area in between, where ostensibly odd but non-pathological experiences may occur (including so-called non-ordinary mental expressions) without calling for treatment but, rather, for being properly understood.

A Deficit of CEACAM-1-Expressing T Lymphocytes Supports Inflammation in Primary Progressive Multiple Sclerosis.

The immune regulatory mechanisms that modulate Th1 and Th17 immune responses are altered in multiple sclerosis (MS). The inhibitory TIM-3/Gal-9 pathway, in particular, is impaired in primary progressive MS (PPMS). Recent results showed that carcinoembryonic Ag-related cell adhesion molecule 1 (CEACAM-1), a molecule expressed on activated T lymphocytes, endows TIM-3 with inhibitory function and facilitates the maturation and cell surface expression of TIM-3. We analyzed by flow cytometry CEACAM-1 expression on myelin basic protein (MBP)-stimulated CD4+ and CD8+ T lymphocytes of 56 MS patients with a diagnosis of either PPMS (n = 16), relapsing-remitting MS (n = 20), or benign MS (n = 20) and 40 age- and sex-matched healthy controls. The expression of TIM-3 and annexin V (AV) as well as the production of IFN-γ and the intracellular concentration of HLA-B-associated transcript 3 (Bat3), a molecular adaptor that binds the intracellular tail of TIM-3 promoting both proliferation and proinflammatory cytokine production, were analyzed as well in the same cells. Results showed the following in PPMS: 1) CD4+/CEACAM-1+, CD4+/TIM-3+, CD8+/TIM-3+, CD4+/CEACAM-1+/TIM-3+, and CD8+/CEACAM-1+/TIM-3+ T lymphocytes as well as CEACAM-1 mean fluorescence intensity on CD4+ T lymphocytes were significantly reduced; 2) apoptotic CD4+/AV+/CEACAM-1+ and CD8+/AV+/CEACAM-1+ T lymphocytes were significantly reduced; and 3) Bat3-expressing CD4+ and CD8+ T cells were significantly increased. Notably, a specular immunologic scenario was seen in benign MS. CEACAM-1 expression is reduced in PPMS; this exacerbates MBP-specific inflammatory T cell response and reduces the apoptosis of MBP-specific T lymphocytes, possibly as a consequence of the upregulation of Bat3 seen in these patients.

An ecological measure to screen executive functioning in MS: the Picture Interpretation Test (PIT) 360°.

Executive functions are crucial for performance of everyday activities. In Multiple Sclerosis (MS), executive dysfunctions can be apparent from the early onset of the disease. Technology-based time-efficient and resource-saving tools for early evaluation of executive functions using an ecological approach are needed to assess functional performance in real-life. The aim was to compare the efficiency of the Picture Interpretation Test 360° (PIT 360°) with traditional measures on executive dysfunction in Persons with Multiple Sclerosis (PwMS) and Healthy Controls (HC). Participants were 31 patients with Relapsing-Remitting MS (mean age = 44.323 ± 13.149; mean Expanded Disability Status Scale = 2) and 39 HC (mean age = 39.538 ± 15.728). All were tested with standard neuropsychological tests of executive functions, PIT 360°, and measures of user experience. While standard neuropsychological tests failed to differentiate between PwMS and HC group, the PIT 360° was successful in detecting executive dysfunction in PwMS. All participants reported the PIT 360° to be an engaging tool and endorsed positive reactions to their experience. Overall, the PIT 360° is a quick, sensitive, and ecological tool that captures real-world executive dysfunction in PwMS. This engaging measure is sensitive for the detection of executive deficits since the early phases of the disease.

Longitudinal associations between mindfulness and well-being in people with multiple sclerosis.

Background/Objective: Depression, anxiety, fatigue, and sleep problems are typical conditions reported in people with multiple sclerosis (MS), often resulting in a reduction of their quality of life (QOL) and well-being. Mindfulness is a multifaceted and complex construct that has been increasingly explored for its correlated to well-being. Despite preliminary evidence, longitudinal data about the impact of mindfulness on QOL in MS remain limited. In addition, Langerian mindfulness, one of the prominent approaches to mindfulness, is yet unexplored in this field. The study aims to examine the longitudinal relationships between two forms of mindfulness (Langerian and contemplative) and QOL, anxiety, depression, fatigue, and sleep. Method: Within a larger randomized controlled trial of an online mindfulness-based stress reduction intervention, a cohort of 156 people with MS was recruited and assessed for both mindfulness constructs, QOL, anxiety, depression, fatigue, and sleep problems. Assessments were repeated after 2 and after another 6 months. Results: Both mindfulness constructs were highly correlated with all investigated outcomes. Both Langerian and contemplative mindfulness predicted higher QOL, lower anxiety, depression, fatigue, and sleep, over time. Conclusions: In both approaches dispositional mindfulness is a protective factor against depression, anxiety, fatigue, and sleep in people with MS.

Antecedentes/Objetivo: La depresión, la ansiedad, la fatiga y los problemas para dormir son condiciones típicas en personas con esclerosis múltiple (EM), que a menudo conllevan una reducción de su calidad de vida (CV). El mindfulness es una construcción compleja y multifacética que ha sido cada vez más explorada por su correlación con el bienestar. Sin embargo, los datos longitudinales sobre el impacto del mindfulness en la calidad de vida en la EM siguen siendo limitados. Este estudio tiene como objetivo examinar las relaciones longitudinales entre dos formas de mindfulness con la calidad de vida, la ansiedad, la depresión, la fatiga y el sueño. Método: Se contó con una muestra de 156 personas con EM y se evaluaron los constructos de mindfulness, calidad de vida, ansiedad, depresión, fatiga y problemas de sueño. Las evaluaciones se repitieron después de 2 y 6 meses. Resultados: Ambos constructos de mindfulness estuvieron altamente correlacionados con todos los resultados investigados, y ambos predijeron mayor CV, menor ansiedad, depresión, fatiga y problemas de sueño con el tiempo. Conclusiones: El mindfulness es un factor de protección contra la depresión, la ansiedad, la fatiga y el sueño en personas con EM.

Longitudinal associations between mindfulness and well-being in people with multiple sclerosis / Asociaciones longitudinales entre el mindfulness y el bienestar en personas con esclerosis múltiple

Background/Objective: Depression, anxiety, fatigue, and sleep problems are typical conditions reported in people with multiple sclerosis (MS), often resulting in a reduction of their quality of life (QOL) and well-being. Mindfulness is a multifaceted and complex construct that has been increasingly explored for its correlated to well-being. Despite preliminary evidence, longitudinal data about the impact of mindfulness on QOL in MS remain limited. In addition, Langerian mindfulness, one of the prominent approaches to mindfulness, is yet unexplored in this field. The study aims to examine the longitudinal relationships between two forms of mindfulness (Langerian and contemplative) and QOL, anxiety, depression, fatigue, and sleep. Method: Within a larger randomized controlled trial of an online mindfulness-based stress reduction intervention, a cohort of 156 people with MS was recruited and assessed for both mindfulness constructs, QOL, anxiety, depression, fatigue, and sleep problems. Assessments were repeated after 2 and after another 6 months. Results: Both mindfulness constructs were highly correlated with all investigated outcomes. Both Langerian and contemplative mindfulness predicted higher QOL, lower anxiety, depression, fatigue, and sleep, over time. Conclusions: In both approaches dispositional mindfulness is a protective factor against depression, anxiety, fatigue, and sleep in people with MS

Antecedentes/Objetivo: La depresión, la ansiedad, la fatiga y los problemas para dormir son condiciones típicas en personas con esclerosis múltiple (EM), que a menudo conllevan una reducción de su calidad de vida (CV). El mindfulness es una construcción compleja y multifacética que ha sido cada vez más explorada por su correlación con el bienestar. Sin embargo, los datos longitudinales sobre el impacto del mindfulness en la calidad de vida en la EM siguen siendo limitados. Este estudio tiene como objetivo examinar las relaciones longitudinales entre dos formas de mindfulness con la calidad de vida, la ansiedad, la depresión, la fatiga y el sueño. Método: Se contó con una muestra de 156 personas con EM y se evaluaron los constructos de mindfulness, calidad de vida, ansiedad, depresión, fatiga y problemas de sueño. Las evaluaciones se repitieron después de 2 y 6 meses. Resultados: Ambos constructos de mindfulness estuvieron altamente correlacionados con todos los resultados investigados, y ambos predijeron mayor CV, menor ansiedad, depresión, fatiga y problemas de sueño con el tiempo. Conclusiones: El mindfulness es un factor de protección contra la depresión, la ansiedad, la fatiga y el sueño en personas con EM

Online meditation training for people with multiple sclerosis: A randomized controlled trial.

BACKGROUND: Multiple sclerosis (MS) has a relevant impact on quality of life (QOL) and is associated with increased risks of psychological morbidity. Mindfulness-based interventions (MBIs) are among the most studied interventions, although few well-conducted studies have tested them in this field. Furthermore, the participation in typical MBIs may be impaired by time and logistics. OBJECTIVE: We aimed to test the efficacy of an online MBI to improve QOL, psychological well-being, sleep, and fatigue. METHODS: We conducted a randomized controlled trial, in which 139 participants were randomly assigned to an MS-specific online mindfulness meditation intervention or to a psychoeducational (active control) group. Participants were assessed for QOL, depression, anxiety, sleep problems, and fatigue, at three different times: at recruitment, after 2 months, and after 6 months. RESULTS: In comparison to the control group, the experimental subjects reported higher QOL and lower depression, anxiety, and sleep problems at the end of intervention. However, after 6 months these group differences were no longer significant. CONCLUSION: An online MBI could be an effective psychological treatment for the promotion of well-being in MS in short-term. However, the lack of lasting effects requires the development of new strategies to support long-term changes.

Are Cerebral Perfusion and Atrophy Linked in Multiple Sclerosis? Evidence for a Multifactorial Approach to Assess Neurodegeneration.

BACKGROUND: Grey Matter (GM) atrophy has been extensively described in Multiple Sclerosis (MS) patients, while cerebral hypoperfusion has been less consistently reported. Since hypoperfusion might be related to atrophy, we evaluated the presence of both damages. OBJECTIVE: We aimed to assess if the regions of altered perfusion and atrophy overlapped with one another and if the two parameters were locally related. METHOD: 3D-T1 weighted and arterial spin labelling sequences were acquired using a 1.5T Magnetic Resonance Imaging scanner from 26 relapsing remitting MS patients and 26 Healthy Controls (HC). GM volume and Cerebral Blood Flow (CBF) differences and their correlation were tested with a voxel-wise approach. RESULTS: MS patients (41.4±12.5 years; 14 females) had a median [25th-75th percentile range] Expanded Disability Status Scale of 1.0[1.0-2.4] and a median [25th-75th percentile range] disease duration of 8.0 [4.0-16.5] years. HC were age- and sex-matched (43.9±17.4 years; 11 females). GM atrophy was detected for MS group in the right parahippocampal gyrus, thalami and left caudate (pFWE≤0.05). Areas of significant (after family-wise error -FWE- correction for multiple comparisons) (pFWE≤0.05) hypoperfusion were found for MS in the anterior cingulate and paracingulate gyri, supplementary motor cortex, precentral and superior frontal gyrus. GM volume and CBF showed a significant correlation (pFWE≤0.05) in the right lateral occipital cortex and precuneus in the MS group. CONCLUSIONS: GM atrophy and hypoperfusion in MS were located in different areas. Perfusion estimate might be used as a further marker of tissue damage, in addition to GM volume.

Monosodium Urate Crystals Activate the Inflammasome in Primary Progressive Multiple Sclerosis.

Inflammasome-driven inflammation is postulated to play a role in multiple sclerosis (MS), but there is no direct evidence that the nod-like receptor protein 3 (NLRP3) inflammasome is involved in MS pathogenesis. Uric acid was shown to be one of the "danger" signals involved in the activation of NLRP3 inflammasome; notably, the concentration of uric acid is increased in the serum and in the cerebrospinal fluid of MS individuals. To better investigate the role of the NLRP3 inflammasome in MS-associated inflammation, we primed with lipopolysaccharide and stimulated with monosodium urate crystals PBMCs of 41 MS patients with different disease phenotypes. Eleven individuals with primary progressive MS (PPMS), 10 individuals with stable relapsing-remitting MS (SMS), 10 individuals with acute relapsing-remitting MS (AMS), 10 individuals with benign MS were analyzed; 10 healthy controls were enrolled as well in the study. The expression of the NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), caspase-1, caspase-8, IL-1ß, and IL-18 inflammasome genes was evaluated by RT-PCR. NLRP3 and ASC-speck protein expression was analyzed by FlowSight AMNIS, whereas production of the pro-inflammatory cytokines IL-1ß and IL-18 and of caspase-1 and caspase-8 was measured by ELISA in supernatants. Results showed that uric acid serum concentration was significantly increased in PPMS; in these and in AMS patients, mRNA for NLRP3, ASC, and IL-18 was upregulated as well, but caspase-8 mRNA was upregulated only in PPMS. Expression of NLRP3 and ASC-speck protein was significantly increased in PPMS, SMS, and AMS patients, but IL-18 and caspase-8 production was significantly increased only in PPMS, in whom a direct correlation between hyperuricemia and caspase-8 was detected. The NLRP3/caspase-8 inflammasome pathway is activated in PPMS, possibly as a consequence of hyperuricemia. Therapeutic strategies reducing NLRP3 activation and/or lowering hyperuricemia could be useful in the therapy of PPMS.

Sympathetic skin response in multiple sclerosis: a meta-analysis of case-control studies.

The usefulness of sympathetic skin responses (SSR) in multiple sclerosis (MS) has been advocated by several studies in the last 20 years; however, due to a great heterogeneity of findings, a comprehensive meta-analysis of case-control studies is in order to pinpoint consistencies and investigate the causes of discrepancies. We searched MEDLINE, EMBASE and Cochrane databases for case-control studies comparing SSR absence frequency and latency between patients with MS and healthy controls. Thirteen eligible studies including 415 MS patients and 331 healthy controls were identified. The pooled analysis showed that SSR can be always obtained in healthy controls while 34% of patients had absent SSRs in at least one limb (95% CI 22-47%; p < 0.0001) but with considerable heterogeneity across studies (I 2 = 90.3%). Patients' age explained 22% of the overall variability and positive correlations were found with Expanded Disability Status Scale and disease duration. The pooled mean difference of SSR latency showed a significant increase in patients on both upper (193 ms; 95% CI 120-270 ms) and lower (350 ms; 95% CI 190-510 ms) extremities. We tested the discriminatory value of SSR latency thresholds defined as the 95% confidence interval (CI) upper bound of the healthy controls, and validated the results on a new dataset. The lower limb threshold of 1.964 s produces the best results in terms of sensitivity 0.86, specificity 0.67, positive predicted value 0.75 and negative predicted value 0.80. Despite a considerable heterogeneity of findings, there is evidence that SSR is a useful tool in MS.

Immunological and Clinical Effect of Diet Modulation of the Gut Microbiome in Multiple Sclerosis Patients: A Pilot Study.

Pathogenesis of autoimmune disorders, including multiple sclerosis (MS), has been linked to an alteration of the resident microbial commensal community and of the interplay between the microbiota and the immune system. Dietary components such as fiber, acting on microbiota composition, could, in principle, result in immune modulation and, thus, could be used to obtain beneficial outcomes for patients. We verified this hypothesis in a pilot study involving two groups of clinically similar relapsing-remitting (RR) MS patients who had undergone either a high-vegetable/low-protein diet (HV/LP diet group; N = 10) or a "Western Diet" (WD group; N = 10) for at least 12 months. Gut microbiota composition, analyzed by 16 S V4 rRNA gene sequencing and immunological profiles, was examined after a minimum of 12 months of diet. Results showed that, in the HV/LP diet group compared to the WD group: (1) Lachnospiraceae family was significantly more abundant; (2) IL-17-producing T CD4+ lymphocytes (p = 0.04) and PD-1 expressing T CD4+ lymphocytes (p = 0.0004) were significantly decreased; and (3) PD-L1 expressing monocytes (p = 0.009) were significantly increased. In the HV/LP diet group, positive correlations between Lachnospiraceae and both CD14+/IL-10+ and CD14+/TGFß+monocytes (RSp = 0.707, p = 0.05, and RSp = 0.73, p = 0.04, respectively), as well as between Lachnospiraceae and CD4+/CD25+/FoxP3+ T lymphocytes (RSp = 0.68, p = 0.02) were observed. Evaluation of clinical parameters showed that in the HV/LP diet group alone the relapse rate during the 12 months follow-up period and the Expanded Disability Status Scale score at the end of the study period were significantly reduced. Diet modulates dysbiosis and improves clinical parameters in MS patients by increasing anti-inflammatory circuits. Because Lachnospiraceae favor Treg differentiation as well as TGFß and IL-10 production this effect could be associated with an increase of these bacteria in the microbiota.