Fatigued Multiple Sclerosis Patients Research Articles

Functional connectivity modifications in monoaminergic circuits occur in fatigued MS patients treated with fampridine and amantadine.

Monoaminergic network dysfunction may have a role in multiple sclerosis (MS) fatigue pathogenesis. To investigate modifications of fatigue severity and resting state (RS) functional connectivity (FC) in monoaminergic networks of 45 fatigued MS patients after different symptomatic treatments. Patients were randomly, blindly assigned to fampridine (n = 15), amantadine (n = 15) or placebo (n = 15) treatment and underwent clinical and 3T-MRI evaluations at baseline (t0) and week 4 (w4), i.e. after four weeks of treatment. Fifteen healthy controls (HC) were enrolled. Dopamine-, noradrenaline- and serotonin-related RS FC was assessed by PET-guided constrained independent component analysis. At t0, MS patients showed widespread monoamine-related RS FC abnormalities. At w4, fatigue scores decreased in all groups (p = range < 0.001-0.002). Concomitantly, fampridine and amantadine patients showed increased insular RS FC in dopamine-related and noradrenaline-related networks (p < 0.001, uncorrected). Amantadine patients also showed increased RS FC of anterior cingulate cortex in dopamine-related and noradrenaline-related networks (p < 0.001, uncorrected). Placebo patients showed increased precuneus/middle cingulate RS FC in the noradrenaline-related network (p < 0.001, uncorrected). In fampridine and placebo patients, just tendencies towards correlations between RS FC and fatigue modifications were found. In MS patients, specific RS FC modifications in PET-guided monoaminergic networks were observed, concomitantly with fatigue improvements following treatment. EudraCT 2010-023678-38.

Functional Connectivity Modifications in Monoaminergic Circuits Occur in Fatigued MS Patients Treated With Fampridine and Amantadine (P10-3.008)

<h3>Objective:</h3> To investigate changes over time of fatigue severity and concomitant modifications of resting state (RS) functional connectivity (FC) in monoaminergic networks in 45 fatigued multiple sclerosis (MS) patients after different symptomatic treatments. <h3>Background:</h3> Fatigue is common and disabling in MS. Symptomatic treatments for fatigue rely on drugs reinforcing monoaminergic synaptic transmission, suggesting a role of monoaminergic network abnormalities in fatigue pathogenesis. <h3>Design/Methods:</h3> MS patients were randomly, blindly assigned to treatment with fampridine (n=15), amantadine (n=15) or placebo (n=15) and underwent clinical, neuropsychological and 3T RS fMRI at baseline (T0) and after four weeks (W4) of treatment. Fifteen matched healthy controls (HC) were acquired twice. Dopamine-, noradrenaline- and serotonin-related RS FC was derived by independent component analysis (ICA), constrained to PET atlases for dopamine, noradrenaline and serotonin transporters, obtained in HCs’ brain. Changes in modified fatigue impact scale (MFIS) score and monoaminergic-related RS FC were assessed. <h3>Results:</h3> MS patients showed baseline abnormalities <i>vs</i> HC in all three networks, with decreased monoamine-related RS FC in temporal, occipital, insular and cerebellar regions, and increased RS FC in frontal, parietal and subcortical areas. At W4, MFIS scores decreased in all patients’ groups, with no time-by-treatment interaction. At W4, fampridine and amantadine patients showed increased dopamine- and noradrenaline-related RS FC in the insular cortex, as well as increased serotonin-related RS FC in the precuneus/posterior cingulate cortex. Amantadine patients also showed increased dopamine- and noradrenaline-related RS FC in the anterior cingulate cortex (ACC). Conversely, placebo patients mostly showed increased noradrenaline-related RS FC in the precuneus and middle cingulate cortex. Fampridine and placebo groups showed trends towards significant correlations between RS FC modifications and MFIS improvements (r=−0.49: −0.52, p=0.07–0.08). <h3>Conclusions:</h3> Fatigue improved in all groups. Concomitant monoaminergic-related RS FC modifications were found in insular, ACC and parietal regions for fampridine and amantadine MS patients, and in medial parietal regions for placebo patients. <b>Disclosure:</b> Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Dr. Lamanna has nothing to disclose. Bruno Colombo has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis, Biogen, Sanofi Genzyme, TEVA and Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck . Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Effects on Corticospinal Tract Homology of Faremus Personalized Neuromodulation Relieving Fatigue in Multiple Sclerosis: A Proof-of-Concept Study

Fatigue in multiple sclerosis (MS) is a frequent and invalidating symptom, which can be relieved by non-invasive neuromodulation, which presents only negligible side effects. A 5-day transcranial direct-current stimulation, 15 min per day, anodically targeting the somatosensory representation of the whole body against a larger occipital cathode was efficacious against MS fatigue (fatigue relief in multiple sclerosis, Faremus treatment). The present proof-of-concept study tested the working hypothesis that Faremus S1 neuromodulation modifies the homology of the dominant and non-dominant corticospinal (CST) circuit recruitment. CST homology was assessed via the Fréchet distance between the morphologies of motor potentials (MEPs) evoked by transcranial magnetic stimulation in the homologous left- and right-hand muscles of 10 fatigued MS patients before and after Faremus. In the absence of any change in MEP features either as differences between the two body sides or as an effect of the treatment, Faremus changed in physiological direction the CST's homology. Faremus effects on homology were more evident than recruitment changes within the dominant and non-dominant sides. The Faremus-related CST changes extend the relevance of the balance between hemispheric homologs to the homology between body sides. With this work, we contribute to the development of new network-sensitive measures that can provide new insights into the mechanisms of neuronal functional patterning underlying relevant symptoms.

Normal Appearing White Matter N-Acetylaspartate Changes Impact on Fatigue in Multiple Sclerosis

Background: Fatigue is one of the most frequent complaints presented by multiple sclerosis patients. Fatigue may be multifactorial. Proton magnetic resonance spectroscopy studies have shown significant reductions in N-acetylaspartate/creatine ratios in multiple brain regions among fatigued multiple sclerosis patients in comparison to non-fatigued multiple sclerosis patients, suggesting axonal loss as a contributing factor. Females are twice as likely to develop the disease. Aim: To evaluate gender variability in fatigue scores in relapsing-remitting multiple sclerosis patients. To explore potential gender differences in metabolite profiles of normal appearing white matter. To correlate metabolite changes distribution with fatigue severity and to evaluate the gender impact. Methods: We enrolled 50 relapsing-remitting multiple sclerosis patients on disease modifying treatment and 28 healthy controls. All participants underwent proton magnetic resonance spectroscopy of normal appearing white matter corresponding regions and fatigue severity evaluation. Results: We found higher fatigue scores in the multiple sclerosis group, due to greater severity in female subjects. We found a significant decrease of N-acetylaspartate/creatine ratio with increase in N-acetylaspartate, choline, and creatine levels in multiple sclerosis subjects. N-acetylaspartate and choline levels were significantly higher in the multiple sclerosis males. Female multiple sclerosis patients presented with lower N-acetylaspartate levels than healthy controls and greater increases in Fatigue Severity Scale score. Regression analysis revealed metabolite specific relationships between fatigue against metabolite variables. Conclusion: Proton magnetic resonance spectroscopy registered differences in metabolite profiles in normal appearing white matter male and female multiple sclerosis subjects. We might presume gender dependent specifiers in metabolite profiles in relapsing- remitting multiple sclerosis. They impact fatigue severity. N- acetyaspartate might be crucial contributor in central fatigue in multiple sclerosis. Bioenergetic role of N-acetylaspartate needs further collaborative research on genetics and electrical properties of neurons to reveal the underlying mechanism of fatigue and conductivity deterioration.

Fatigue, insomnia and daytime sleepiness in multiple sclerosis versus narcolepsy.

In multiple sclerosis (MS), fatigue is the most prevalent cause of impaired ability to work. In narcolepsy, daytime sleepiness is the main symptom but some studies indicate fatigue being present. We aimed to assess fatigue and associated features in patients with MS or narcolepsy and healthy controls and to assess whether clinical parameters separate fatigued (MS-F) and non-fatigued MS patients (MS-NoF). In this non-interventional cross-sectional study, we recruited 34 MS patients, 15 narcolepsy type 1 patients and 17 healthy controls. An interviewer administered the Fatigue Severity Scale (FSS), the Insomnia Severity Index (ISI), the Epworth Sleepiness Scale, the Patient Health Questionnaire-9 and the Saltin-Grimby Physical Activity Level Scale. Information about clinical parameters and current treatments was collected. In its fatigue profile, MS-F resembled the narcolepsy group rather than MS-NoF, which resembled the healthy control group. ISI alone was significantly associated with FSS, and only in MS-NoF and healthy controls; in MS-F and the narcolepsy group, no variable was associated with FSS. Months since diagnosis was the only clinical variable significantly separating MS-F from MS-NoF. In MS, disease duration correlated with fatigue. No clinical variables correlated with fatigue in the narcolepsy group. Fatigued MS patients resemble narcolepsy patients more than they resemble non-fatigued MS patients, who resemble healthy controls. Insomnia is the main factor associated with fatigue in MS, while disease duration is the only clinical variable separating fatigued and non-fatigued MS patients. In fatigued patients, variance in fatigue cannot be explained by insomnia, daytime sleepiness, depression or level of exercise.

Bifrontal transcranial direct current stimulation modulates fatigue in multiple sclerosis: a randomized sham-controlled study.

Fatigue is a frequent and debilitating symptom in patients with central nervous system diseases. Up to 90% of patients with multiple sclerosis (MS) suffer from fatigue that drastically affects the quality of life. MS patients also complain of anxiety and depressive symptoms and these three manifestations tend to cluster together in this clinical population. The objective of this work was to assess the effects of transcranial direct stimulation (tDCS), a noninvasive brain stimulation technique, on fatigue as well as anxiety and depressive symptoms. Eleven fatigued MS patients randomly received two blocks (active and sham tDCS) of five consecutive daily sessions of bifrontal tDCS (anode/cathode over the left/right prefrontal cortices, respectively) in a crossover manner, separated by a 3-week washout interval. Evaluation took place at day 1, day 5 (right after each block) and 1 week later. Active but not sham tDCS resulted in a significant improvement of fatigue at day 5 (p < 0.05), an effect that seems to last at least 1 week following the stimulation (p = 0.05). Active tDCS also significantly improved anxiety symptoms, but the effect emerged 1 week later (p < 0.05). No significant effects were obtained regarding depression (p > 0.05). Bifrontal tDCS seems to modulate fatigue in PwMS. The observed anxiolytic effects could constitute delayed after effects of tDCS or might be mediated by fatigue improvement. These findings merit to be addressed in large-scale controlled trials.

Personalized, bilateral whole-body somatosensory cortex stimulation to relieve fatigue in multiple sclerosis

Background: The patients suffering from multiple sclerosis (MS) often consider fatigue the most debilitating symptom they experience, but conventional medicine currently offers poorly efficacious therapies. Objective: We executed a replication study of an innovative approach for relieving MS fatigue. Methods: According to the sample size estimate, we recruited 10 fatigued MS patients who received 5-day transcranial direct current stimulation (tDCS) in a randomized, double-blind, Sham-controlled, crossover study, with modified Fatigue Impact Scale (mFIS) score reduction at the end of the treatment as primary outcome. A personalized anodal electrode, shaped on the magnetic resonance imaging (MRI)-derived individual cortical folding, targeted the bilateral whole-body primary somatosensory cortex (S1) with an occipital cathode. Results: The amelioration of fatigue symptoms after Real stimulation (40% of baseline) was significantly larger than after Sham stimulation (14%, p = 0.012). Anodal whole body S1 induced a significant fatigue reduction in mildly disabled MS patients when the fatigue-related symptoms severely hampered their quality of life. Conclusion: This second result in an independent group of patients supports the idea that neuromodulation interventions that properly select a personalized target might be a suitable non-pharmacological treatment for MS fatigue.

Abnormal functional connectivity of thalamic sub-regions contributes to fatigue in multiple sclerosis

Objective: To investigate sub-regional thalamic resting-state (RS) functional connectivity (FC) abnormalities in multiple sclerosis (MS) and their correlation with fatigue and its subcomponents (physical, cognitive, and psychosocial). Methods: From 122 MS patients and 94 healthy controls, 5 thalamic sub-regions (frontal, motor, postcentral, occipital, temporal) were parcellated based on their cortico-thalamic structural connectivity and used for a seed-based RS FC analysis. Abnormalities of thalamic RS FC in MS patients and their correlation with Modified Fatigue Impact Scale (MFIS) were assessed. Results: Compared to controls and non-fatigued MS (n = 86), fatigued MS patients (n = 36) showed thalamic RS FC abnormalities with middle frontal gyrus, sensorimotor network, precuneus, insula, and cerebellum, which correlated with global MFIS. Higher thalamic RS FC with precuneus and lower RS FC with posterior cerebellum correlated with cognitive MFIS. Higher thalamic RS FC with sensorimotor network in frontal-, motor-, and temporal thalamic sub-regions correlated with physical and psychosocial MFIS. Reduced thalamic RS FC with right insula in motor-, postcentral-, and occipital thalamic sub-regions correlated with psychosocial fatigue. Conclusion: Regional thalamic RS FC abnormalities with different cortical regions, including the frontal lobe, sensorimotor network, precuneus, insular cortices, and cerebellum contribute to fatigue in MS. Abnormal RS FC of selected thalamo-cortical connections explains different components of fatigue.

Simple index of functional connectivity at rest in Multiple Sclerosis fatigue.

To investigate the EEG-derived functional connectivity at rest (FCR) patterns of fatigued Multiple Sclerosis (MS) patients in order to find good parameters for a future EEG-Neurofeedback intervention to reduce their fatigue symptoms. We evaluated FCR between hemispheric homologous areas, via spectral coherence between pairs of corresponding left and right bipolar derivations, in the Theta, Alpha and Beta bands. We estimated FCR in 18MS patients with different levels of fatigue and minimal clinical severity and in 11 age and gender matched healthy controls. We used correlation analysis to assess the relationship between the fatigue scores and the FCR values differing between fatigued MS patients and controls. Among FCR values differing between fatigued MS patients and controls, fatigue symptoms increased with higher Beta temporo-parietal FCR (p=0.00004). Also, positive correlations were found between the fatigue levels and the fronto-frontal FCR in Beta and Theta bands (p=0.0002 and p=0.001 respectively). We propose that a future EEG-Neurofeedback system against MS fatigue would train patients to decrease voluntarily the beta coherence between the homologous temporo-parietal areas. We extracted a feature for building an EEG-Neurofeedback system against fatigue in MS.

P071 tDCS effects over the left DLPFC versus the right PPC in multiple sclerosis fatigue

Background Fatigue is a frequent and debilitating symptom in patients with multiple sclerosis (MS). Its classical treatments are still faced with limited benefits and numerous side effects. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique currently investigated in treating MS related symptoms. Objective The primary objective of this study was to evaluate the tDCS effects on MS fatigue. The secondary outcomes included the assessment of its effects on mood and attention symptoms, commonly encountered in MS. Methods 10 fatigued MS patients were enrolled in a double-blind, sham-controlled, and cross-over study. Each patient randomly received three anodal tDCS blocks: active stimulation over the left dorsolateral prefrontal cortex (DLPFC), active stimulation of the right posterior parietal cortex (PPC), and sham stimulation over either cortical site. To note, both cortical targets are key components in MS fatigue networks. tDCS blocks consisted of five consecutive daily sessions and were held apart by a washout interval of three weeks. Results Only active left DLPFC stimulation significantly ameliorated fatigue. Mood improvement was exclusively obtained following active right PPC stimulation. Neither intervention had effects on attention. Conclusion This small-scale study supports the role of left prefrontal anodal tDCS in treating MS fatigue. The lack of effects on attention might be related to the heterogeneity of the studied cohort, the relatively small sample size, the adapted stimulation parameters and the short protocol duration.

Effects of left DLPFC versus right PPC tDCS on multiple sclerosis fatigue

Background and objectiveFatigue is a frequent and debilitating symptom in patients with multiple sclerosis (MS). Its classical treatments are still faced with limited benefits and numerous side effects. Hence, we aimed to evaluate the effects of transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique, on such a challenging symptom. Our secondary outcomes included the assessment of tDCS impact on mood and attentional performance. MethodsTen fatigued MS patients were enrolled in a double-blind, sham-controlled, and cross-over study. Each patient randomly received three anodal tDCS blocks: active stimulation over the left dorsolateral prefrontal cortex (DLPFC), active stimulation over the right posterior parietal cortex (PPC), and sham stimulation over either cortical site. Both cortical targets are key components in the MS fatigue networks. The blocks consisted of five consecutive daily sessions and were held apart by a washout interval of three weeks. ResultsOnly active left DLPFC stimulation significantly ameliorated fatigue. Mood improvement was exclusively obtained following active right PPC stimulation. Neither intervention had effects on attention. ConclusionOur study supports the role of anodal tDCS over the left prefrontal in treating MS fatigue. The lack of tDCS effects on attention might be related to the heterogeneity of the studied cohort, the relatively small sample size, the protocol design and duration. Modifying these variables and coupling tDCS with neuroimaging might improve the clinical outcomes and enhance our understanding of the tDCS mechanism of actions.

Counteracting Fatigue in Multiple Sclerosis with Right Parietal Anodal Transcranial Direct Current Stimulation.

Fatigue in multiple sclerosis (MS) patients appears to correlate with vigilance decrement as reflected in an increase in reaction time (RT) and errors with prolonged time-on-task. The aim of this study was to investigate whether anodal transcranial direct current stimulation (tDCS) over the right parietal or frontal cortex counteracts fatigue-associated vigilance decrement and subjective fatigue. In study I, a randomized double-blind placebo-controlled study, anodal tDCS (1.5 mA) was delivered to the right parietal cortex or the right frontal cortex of 52 healthy participants during the first 20 min of a 40-min lasting visual vigilance task. Study II, also a randomized double-blind placebo-controlled study, investigated the effect of anodal tDCS (1.5 mA) over the right parietal cortex in 46 MS patients experiencing cognitive fatigue. tDCS was delivered for 20 min before patients performed a 20-min lasting visual vigilance task. Study I showed that right parietal stimulation, but not right frontal stimulation, counteracts the increase in RT associated with vigilance decrement. Hence, only right parietal stimulation was applied to the MS patients in study II. Stimulation had a significant effect on vigilance decrement in mildly to moderately cognitively fatigued MS patients. Vigilance testing significantly increased the feeling of fatigue independent of stimulation. Anodal tDCS over the right parietal cortex can counteract the increase in RTs during vigilance performance, but not the increase in subjective fatigue. This finding is compatible with our model of fatigue in MS, suggesting a dissociation between the feeling and the behavioral characteristics of fatigue.

Dilated perivascular spaces and fatigue: is there a link? Magnetic resonance retrospective 3Tesla study.

Fatigue (F) is a common, inexplicable, and disabling symptom in multiple sclerosis (MS) patients. The purpose of this study was to evaluate a possible correlation between fatigue and morpho-volumetric features and site of dilated perivascular spaces (dPS), visible on 3T magnetic resonance (MR) in fatigued multiple sclerosis patients (FMS). We studied 82 relapsing remitting (RR) FMS patients and 43 HC, matched for age, sex, and education. F was assessed by the Fatigue Severity Scale (FSS). To evaluate a possible correlation between degree of F and characteristics of dPS, patients were divided in two groups: more (mFMS) (FSS ≥ 5; n = 30) and less fatigued (lFMS) (FSS ≥ 4; n = 52), compared to a matched healthy control (HC) subject group. The MR study was performed with 3T scanner by SpinEcho T1, Fast-SpinEcho DP-T2, FLAIR, and 3D FSPGR T1 sequences. dPS volumes were measured with Medical Image Processing Analysis and Visualization (MIPAV); Global Cerebral Atrophy (GCA), expressed as Brain Parenchymal Fraction (BPF), was assessed by FSL SIENAX. The t test showed significantly increased dPS number (p = 0.021) in FMS patients (mFMS p = 0.0024 and lFMS p = 0.033) compared to HC. Pearson correlation revealed a significant correlation between dPS number and FSS (r = 0.208 p = 0.051). Furthermore, the chi-squared test confirms the intragroup (HC, mFMS, lFMS) differences about dPS location (p = 0.01) and size (p = 0.0001). Our study confirms that PS in MS patients presents with different volumetric and site characteristics as compared to HC; moreover, F severity significantly correlates with dPS number, site, and size.

Event-related potentials and cognitive performance in multiple sclerosis patients with fatigue

The aim of this study was to evaluate event-related potentials (ERP) and cognition in multiple sclerosis (MS) patients with regard to fatigue and disease-related variables. The study comprised 86 MS patients and 40 controls. Fatigue was assessed using the Fatigue Severity Scale (FSS/FSS-5) and the Modified Fatigue Impact Scale (MFIS/MFISmod). N200 and P300 components of auditory ERP were analyzed. Cognition was evaluated by means of Brief Repeatable Battery of Neuropsychological Tests (BRBNT). The results of ERP and BRBNT were compared between non-fatigued, moderately and severely fatigued MS patients and controls. P300 latency was significantly longer in the whole MS group and in the fatigued patients than in the controls. A positive correlation was found between P300 latency and MFIS/MFISmod results, independent from age and MS-related variables. The fatigued patients scored less than non-fatigued ones in tests evaluating memory, visuomotor abilities and attention. Results of these tests correlated significantly with fatigue measures, independently from MS-related variables. Fatigue in MS patients showed significant relationships with impairment within the memory and attention domains. Parameters of auditory ERP, as electrophysiological biomarkers of cognitive performance, were not independently linked to fatigue.

Multiple sclerosis fatigue relief by bilateral somatosensory cortex neuromodulation

Multiple sclerosis-related fatigue is highly common and often refractory to medical therapy. Ten fatigued multiple sclerosis patients received two blocks of 5-day anodal bilateral primary somatosensory areas transcranial direct current stimulation in a randomized, doubleblind sham-controlled, cross-over study. The real neuromodulation by a personalized electrode, shaped on the MRderived primary somatosensory cortical strip, reduced fatigue in all patients, by 26% in average ( p = 0.002), which did not change after sham ( p = 0.901). Anodal tDCS over bilateral somatosensory areas was able to relief fatigue in mildly disabled MS patients, when the fatigue related symptoms severely hamper their quality of life. These small-scale study results support the concept that interventions modifying the sensorimotor network activity balances could be a suitable non-pharmacological treatment for multiple sclerosis fatigue.

Atrophy of reward-related striatal structures in fatigued MS patients is independent of physical disability

Background: MRI studies have shown gray-matter abnormalities in fatigued multiple sclerosis (MS) patients. However, given that physical disability is highly correlated to MS fatigue, it is often difficult to disentangle its effect in these MRI findings. Objective: The objective of this research paper is to investigate gray-matter damage in mildly disabled MS patients, addressing which variables were better related to fatigue while controlling for physical disability and depression. Methods: Forty-nine relapsing–remitting MS (RRMS) patients and 30 controls underwent MRI (3T). Fatigue was assessed using the Fatigue Severity Scale (FSS). Multivariate logistic regression was performed to assess the contribution of clinical and MRI metrics to fatigue. Statistical analyses were performed controlling for disability and depression. Results: Fatigue was present in 22 (44.9%) patients. FSS score was highly correlated with EDSS (p = 0.00001). Patients with fatigue had lower brain cortical and subcortical gray-matter volumes. However, after controlling for EDSS, only the caudate and the accumbens volumes remained statistically significant. Conclusions: Fatigued MS patients have a global cortical and subcortical gray-matter atrophy that seems largely related to higher physical disability. However, striatal structures involved in effort-reward functions exhibited smaller volumes in fatigued patients, independently of physical disability and depressive symptoms, supporting the theory of cortico-striatal network impairment in MS fatigue.

Brain Plasticity Effects of Neuromodulation Against Multiple Sclerosis Fatigue.

We recently reported on the efficacy of a personalized transcranial direct current stimulation (tDCS) treatment in reducing multiple sclerosis (MS) fatigue. The result supports the notion that interventions targeted at modifying abnormal excitability within the sensorimotor network could represent valid non-pharmacological treatments. The present work aimed at assessing whether the mentioned intervention also induces changes in the excitability of sensorimotor cortical areas. Two separate groups of fatigued MS patients were given a 5-day tDCS treatments targeting, respectively, the whole body somatosensory areas (S1wb) and the hand sensorimotor areas (SM1hand). The study had a double blind, sham-controlled, randomized, cross-over (Real vs. Sham) design. Before and after each treatment, we measured fatigue levels (by the modified fatigue impact scale, mFIS), motor evoked potentials (MEPs) in response to transcranial magnetic stimulation and somatosensory evoked potentials (SEPs) in response to median nerve stimulation. We took MEPs and SEPs as measures of the excitability of the primary motor area (M1) and the primary somatosensory area (S1), respectively. The Real S1wb treatment produced a 27% reduction of the mFIS baseline level, while the SM1hand treatment showed no difference between Real and Sham stimulations. M1 excitability increased on average 6% of the baseline in the S1wb group and 40% in the SM1hand group. Observed SEP changes were not significant and we found no association between M1 excitability changes and mFIS decrease. The tDCS treatment was more effective against MS fatigue when the electrode was focused on the bilateral whole body somatosensory area. Changes in S1 and M1 excitability did not correlate with symptoms amelioration. The neuromodulation treatment that proved effective against MS fatigue induced only minor variations of the motor cortex excitability, not enough to explain the beneficial effects of the intervention.

Assessment of visual and auditory evoked potentials in multiple sclerosis patients with and without fatigue.

The aim of the study was to evaluate visual and brainstem auditory evoked potentials (VEP, BAEP) in multiple sclerosis (MS) patients with regards to fatigue and disease-related variables. The study comprised 86 MS patients and 40 controls. Fatigue was assessed using the Fatigue Severity Scale (FSS/FSS-5) and the Modified Fatigue Impact Scale (MFIS). Latencies and amplitudes of the P100 component of VEP and the I–V components of BAEP were analyzed. The results of EP were compared between non-fatigued, moderately and severely fatigued MS patients and controls. P100 latency was increased and amplitude decreased in moderately and severely fatigued MS subjects. The latency of the V component of BAEP and interlatencies I-III-V were increased in severely fatigued patients. The amplitude of the V component was lowered in fatigued patients. VEP and BAEP abnormalities were usually one-sided. Interocular P100 latency difference tended to correlate with FSS/FSS-5. The parameters of VEP and BAEP correlated with functional system scores but not with MS duration, overall degree of disability or its progression over time. Significant, usually asymmetrical VEP and BAEP abnormalities were found in fatigued MS patients, with no relationships to disease-related variables. EP may be considered an electrophysiological marker of fatigue in MS patients.

A wireless body measurement system to study fatigue in multiple sclerosis

Fatigue is reported as the most common symptom by patients with multiple sclerosis (MS). The physiological and functional parameters related to fatigue in MS patients are currently not well established. A new wearable wireless body measurement system, named Fatigue Monitoring System (FAMOS), was developed to study fatigue in MS. It can continuously measure electrocardiogram, body-skin temperature, electromyogram and motions of feet. The goal of this study is to test the ability of distinguishing fatigued MS patients from healthy subjects by the use of FAMOS. This paper presents the realization of the measurement system including the design of both hardware and dedicated signal processing algorithms. Twenty-six participants including 17 MS patients with fatigue and 9 sex- and age-matched healthy controls were included in the study for continuous 24 h monitoring. The preliminary results show significant differences between fatigued MS patients and healthy controls. In conclusion, the FAMOS enables continuous data acquisition and estimation of multiple physiological and functional parameters. It provides a new, flexible and objective approach to study fatigue in MS, which can distinguish between fatigued MS patients and healthy controls. The usability and reliability of the FAMOS should however be further improved and validated through larger clinical trials.

Fatigued patients with multiple sclerosis can be discriminated from healthy controls by the recordings of a newly developed measurement system (FAMOS): a pilot study

Purpose: To explore the difference between fatigued patients with multiple sclerosis (MS) and matched healthy controls by applying a newly developed physiological and functional data recording system. Methods: A portable wireless measurement system, named FAtigue MOnitoring System (FAMOS), has been developed, which can continuously measure electrocardiogram (ECG), body skin temperature, electromyogram, and motion parameters. In a pilot study, 17 fatigued MS patients (fatigue severity scale (FSS) = 53.9 SD 5.4) and 9 healthy matched controls (FSS = 27.2 SD 6.8) were recruited and monitored by FAMOS during the execution of functional (36 m walk test, 5- and 50-repetition sit-to-stand test) and cognitive (short-term memory tests) tests. Furthermore, oxygen saturation (SPO2) was measured during the functional and cognitive tests and during rest periods between these tests. Results: Recordings from FAMOS indicate that fatigued MS patients have reduced standard deviation (SD) of the heart rate (HR) during the short-term memory test, reduced high frequency (HF) component power spectrum (representing parasympathetic activation) at rest after walk test, and higher ratio of low frequency (LF) to HF (LF/HF) during 50-repetition sit-to-stand test. Conclusions: FAMOS recordings can discriminate fatigued MS patients from healthy controls. The data indicate that fatigued MS patients have vagus nerve dysfunction during cognitive tests and disturbed sympathovagal balance during stressful physical tests.Implications for RehabilitationFatigue is reported as the most common symptom by patients with multiple sclerosis, but the mechanism of this symptom is still not clearly understood.Wireless body sensor networks is one of the most promising concepts for healthcare and rehabilitation providing long-term health monitoring of subjects under conditions without constraining the subjects’ normal daily activities, but such system has not been used in the study of fatigue in MS.The main findings of this pilot study were that FAMOS can discriminate fatigued MS patients from healthy controls, and recordings extracted from specific monitoring periods indicate autonomic dysfunction in MS patients characterized by primary fatigue.