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.

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.

A Systematic Review of Cerebral Functional Near-Infrared Spectroscopy in Chronic Neurological Diseases-Actual Applications and Future Perspectives.

BACKGROUND: The management of people affected by age-related neurological disorders requires the adoption of targeted and cost-effective interventions to cope with chronicity. Therapy adaptation and rehabilitation represent major targets requiring long-term follow-up of neurodegeneration or, conversely, the promotion of neuroplasticity mechanisms. However, affordable and reliable neurophysiological correlates of cerebral activity to be used throughout treatment stages are often lacking. The aim of this systematic review is to highlight actual applications of functional Near-Infrared Spectroscopy (fNIRS) as a versatile optical neuroimaging technology for investigating cortical hemodynamic activity in the most common chronic neurological conditions. METHODS: We reviewed studies investigating fNIRS applications in Parkinson's Disease (PD), Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) as those focusing on motor and cognitive impairment in ageing and Multiple Sclerosis (MS) as the most common chronic neurological disease in young adults. The literature search was conducted on NCBI PubMed and Web of Science databases by PRISMA guidelines. RESULTS: We identified a total of 63 peer-reviewed articles. The AD spectrum is the most investigated pathology with 40 articles ranging from the traditional monitoring of tissue oxygenation to the analysis of functional resting-state conditions or cognitive functions by means of memory and verbal fluency tasks. Conversely, applications in PD (12 articles) and MS (11 articles) are mainly focused on the characterization of motor functions and their association with dual-task conditions. The most investigated cortical area is the prefrontal cortex, since reported to play an important role in age-related compensatory mechanism and neurofunctional changes associated to these chronic neurological conditions. Interestingly, only 9 articles applied a longitudinal approach. CONCLUSION: The results indicate that fNIRS is mainly employed for the cross-sectional characterization of the clinical phenotypes of these pathologies, whereas data on its utility for longitudinal monitoring as surrogate biomarkers of disease progression and rehabilitation effects are promising but still lacking.

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.

Brain networks construction using Bayes FDR and average power function.

Brain functional connectivity is a widely investigated topic in neuroscience. In recent years, the study of brain connectivity has been largely aided by graph theory. The link between time series recorded at multiple locations in the brain and the construction of a graph is usually an adjacency matrix. The latter converts a measure of the connectivity between two time series, typically a correlation coefficient, into a binary choice on whether the two brain locations are functionally connected or not. As a result, the choice of a threshold τ over the correlation coefficient is key. In the present work, we propose a multiple testing approach to the choice of τ that uses the Bayes false discovery rate and a new estimator of the statistical power called average power function to balance the two types of statistical error. We show that the proposed average power function estimator behaves well both in case of independence and weak dependence of the tests and it is reliable under several simulated dependence conditions. Moreover, we propose a robust method for the choice of τ using the 5% and 95% percentiles of the average power function and False Discovery Rate bootstrap distributions, respectively, to improve stability. We applied our approach to functional magnetic resonance imaging and high density electroencephalogram data.

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.

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.

Performance comparison between wrist and chest actigraphy in combination with heart rate variability for sleep classification.

The concurrent usage of actigraphy and heart rate variability (HRV) for sleep efficiency quantification is still matter of investigation. This study compared chest (CACT) and wrist (WACT) actigraphy (actigraphs positioned on chest and wrist, respectively) in combination with HRV for automatic sleep vs wake classification. Accelerometer and ECG signals were collected during polysomnographic studies (PSGs) including 18 individuals (25-53 years old) with no previous history of sleep disorders. Then, an experienced neurologist performed sleep staging on PSG data. Eleven features from HRV and accelerometry were extracted from series of different lengths. A support vector machine (SVM) was used to automatically distinguish sleep and wake. We found 7 min as the optimal signal length for classification, while maximizing specificity (wake detection). CACT and WACT provided similar accuracies (78% chest vs 77% wrist), larger than what yielded by HRV alone (66%). The addition of HRV to CACT reduced slightly the accuracy, while improving specificity (from 33% to 51%, p < 0.05). On the contrary, the concurrent usage of HRV and WACT did not provide statistically significant improvements over WACT. Then, a subset of features (3 from HRV + 1 from actigraphy) was selected by reducing redundancy using a strategy based on Spearman's correlation and area under the ROC curve. The usage of the reduced set of features and SVM classifier gave only slightly reduced classification performances, which did not differ from the full sets of features. The study opens interesting possibilities in the design of wearable devices for long-term monitoring of sleep at home.

Hypnotism as a Function of Trance State Effects, Expectancy, and Suggestibility: An Italian Replication.

Previous research using stepwise regression analyses found self-reported hypnotic depth (srHD) to be a function of suggestibility, trance state effects, and expectancy. This study sought to replicate and expand that research using a general state measure of hypnotic responsivity, the Phenomenology of Consciousness Inventory: Hypnotic Assessment Procedure (PCI-HAP). Ninety-five participants completed an Italian translation of the PCI-HAP, with srHD scores predicted from the PCI-HAP assessment items. The regression analysis replicated the previous research results. Additionally, stepwise regression analyses were able to predict the srHD score equally well using only the PCI dimension scores. These results not only replicated prior research but suggest how this methodology to assess hypnotic responsivity, when combined with more traditional neurophysiological and cognitive-behavioral methodologies, may allow for a more comprehensive understanding of that enigma called hypnosis.

A telemedicine meditation intervention for people with multiple sclerosis and their caregivers: study protocol for a randomized controlled trial.

BACKGROUND: Mindfulness-based interventions, modified and shortened versions of meditation teachings, have proved to be effective in the improvement of quality of life in many clinical conditions, including chronic diseases. Preliminary results available in the literature and in clinical experience indicate a high potential for this treatment for the reduction of psychological suffering in people with chronic diseases. METHODS/DESIGN: This randomized controlled trial will investigate the impact of a multiple sclerosis (MS) specific telemedicine meditation intervention on the quality of life of people with multiple sclerosis and their caregivers. This trial will recruit 120 patients, men and women, with a diagnosis of relapsing-remitting or secondary progressive MS and their caregivers to participate in a 2-month intervention. Patients will undergo assessments of quality of life, anxiety, depression, quality of sleep, mindfulness and fatigue levels conducted at baseline, at week 8 (conclusion of the intervention) and at week 27 (6 months follow-up). Caregivers will complete assessments conducted at the same time for the same areas, plus caregiver burden. The intervention condition will consist of 2 hours/week of online meditation in a group setting led by a trainer, plus 1 hour/week of individual exercises. The control condition will incorporate a psycho-education online program and will require the same contact time commitment as the intervention condition. DISCUSSION: Primary outcome measures will consist of assessments of quality of life, anxiety, and depression level. Assessments of mindfulness level, quality of sleep and fatigue level will be considered secondary outcome measures. This investigation will increase understanding of the role of meditation as part of a treatment plan for people with MS and their caregivers. Overall, this study design has the potential to lead to effective meditation intervention strategies for this population and improve their quality of life. TRIAL REGISTRATION: Clinical Trials Register NCT02364505. https://clinicaltrials.gov/ct2/show/NCT02364505.

The EP-score to assess treatment efficacy in RRMS patients: a preliminary study.

AIM OF THE STUDY: The aim of this retrospective study was to preliminarily assess whether the EP-score, a summary score derived from multimodal evoked potentials tests, might be used as a measure of treatment efficacy in multiple sclerosis (MS). MATERIALS AND METHODS: A sample of 56 relapsing remitting MS (RRMS) patients who at diagnosis started treatment with interferon ß (INFß, n = 19), glatiramer acetate (GA, n = 15) or refused any chronic treatment were assessed at baseline (before treatment) and at a median of 1.7 and 3.6 years thereafter. Outcome variables were Expanded Disability Status Scale (EDSS), EP-Score, visual evoked potentials (VEP) and somatosensory evoked potentials (SEP) scores measured as differences between baseline and follow-ups. Statistical differences between groups and follow-ups were assessed using non-parametric analyses. RESULTS: Treatment effects were not significant for EDSS both at the first and at the second follow-up, while a trend toward significance was observed in the EP-score only in the first follow-up (p = 0.07). Post-hoc analysis showed a greater decrease in median VEP-score for the IFNß group compared to the GA and DF groups at both the first and second follow-ups. CONCLUSIONS: We found no evidence that either INFß or GA significantly improved disability in RRMS patients. Using the EP-score as an outcome measure, we found that it was improved at both follow-ups in the INFß group mainly due to a decrease in the VEP-score. This finding supports the proposal to include the EP-score as an additional outcome variable in future studies of treatment efficacy in MS.

Exploring the predictive value of the evoked potentials score in MS within an appropriate patient population: a hint for an early identification of benign MS?

BACKGROUND: The prognostic value of evoked potentials (EPs) in multiple sclerosis (MS) has not been fully established. The correlations between the Expanded Disability Status Scale (EDSS) at First Neurological Evaluation (FNE) and the duration of the disease, as well as between EDSS and EPs, have influenced the outcome of most previous studies. To overcome this confounding relations, we propose to test the prognostic value of EPs within an appropriate patient population which should be based on patients with low EDSS at FNE and short disease duration. METHODS: We retrospectively selected a sample of 143 early relapsing remitting MS (RRMS) patients with an EDSS < 3.5 from a larger database spanning 20 years. By means of bivariate logistic regressions, the best predictors of worsening were selected among several demographic and clinical variables. The best multivariate logistic model was statistically validated and prospectively applied to 50 patients examined during 2009-2011. RESULTS: The Evoked Potentials score (EP score) and the Time to EDSS 2.0 (TT2) were the best predictors of worsening in our sample (Odds Ratio 1.10 and 0.82 respectively, p=0.001). Low EP score (below 15-20 points), short TT2 (lower than 3-5 years) and their interaction resulted to be the most useful for the identification of worsening patterns. Moreover, in patients with an EP score at FNE below 6 points and a TT2 greater than 3 years the probability of worsening was 10% after 4-5 years and rapidly decreased thereafter. CONCLUSIONS: In an appropriate population of early RRMS patients, the EP score at FNE is a good predictor of disability at low values as well as in combination with a rapid buildup of disability. Interestingly, an EP score at FNE under the median together with a clinical stability lasting more than 3 years turned out to be a protective pattern. This finding may contribute to an early identification of benign patients, well before the term required to diagnose Benign MS (BMS).

EEG evidence of posterior cortical disconnection in PD and related dementias.

Electroencephalogram (EEG) reactivity to eyes opening and 12-Hz photic stimulation was investigated in 14 healthy elderly subjects, 21 parkinsonian patients (PD), 7 demented parkinsonian patients (PDD), and 10 patients with Lewy body dementia (LBD) using global field synchronization (GFS). During eyes closed Theta GFS was increased in Parkinson's disease and patients and alpha1 GFS was decreased in LBD subjects. During 12-Hz intermittent photic stimulation (IPS), reactivity of posterior electrodes was decreased in PD and LBD patients. No reactivity was observed in PDD. Results are consistent with a graded posterior cortical disconnection in parkinsonian syndromes and with a model of dopamine-modulated thalamocortical interplay in visual processing.

Sleep disturbance and fatigue in mild relapsing remitting multiple sclerosis patients on chronic immunomodulant therapy: an actigraphic study.

BACKGROUND: Poor sleep is common in MS and it contributes to fatigue. The beta interferons produce systemic effects which may not adapt and may induce fatigue. OBJECTIVE: To verify whether subjective poor sleep and fatigue during chronic therapy correspond to reduced sleep efficiency obtained by actigraphy at home. METHODS: 42 ambulatory relapsing remitting MS patients with mild disability were monitored for at least 7 nights. Habitual sleep quality and fatigue were assessed with the MOS sleep measure and the Fatigue Severity Scale. Sleep logs provided daily sleep quality assessments during actigraphy at home. Patients were grouped according to their current treatment: no therapy, glatiramer acetate, IFNbeta 3 times a week, and IFNbeta once a week. RESULTS AND CONCLUSION: Sleep efficiency was reduced by an average of 5% in 2/3 of the nights following IFNbeta injections compared to the other nights, and daily sleep ratings correlated with actigraphy. Patients on glatiramer acetate also showed a lower sleep efficiency than patients without therapy. Actigraphy data were only modestly correlated with MOSsm scores, not with fatigue. Long term adaptation of sleep effects of immunomodulant agents is incomplete and needs to be considered in treatment planning and assessment of sleep in MS.

Vestibular evoked myogenic potentials in multiple sclerosis: a comparison between onset and definite cases.

Patients affected with multiple sclerosis (MS) frequently suffer from vestibular disorders due to vestibulospinal involvement. The vestibulospinal reflexes in these subjects can be well investigated through vestibular evoked myogenic potentials (VEMPs). Evoked by the acoustic stimulation of the saccular macula and mediated by the vestibulocollic reflex pathway, they are recorded using surface electromyographic electrodes from the ipsilateral sternocleidomastoid muscle tonically contracted. Abnormal findings (e.g., absence of response, prolonged latencies) disclose a lesion anywhere in the pathway. We examined VEMPs in 19 patients with definite MS (5 men, 14 women; age range, 31-59 years; mean age, 45 years) and compared them to VEMPs in 10 subjects with onset MS (2 men, 8 women; age range, 24-35 years; mean age, 29 years). VEMPs in definite MS subjects were abnormal in 14, absent (on the left side only) in 1, and normal in the remaining 4. In patients with onset MS, VEMPs were abnormal in 6. These results suggest that latencies of vestibulospinal reflexes can be remarkably delayed in MS at different stages of disease, whereas vestibulospinal involvement is more frequent in definite cases. To date, no study has yet investigated different VEMPs involvement at different stages of MS.