Effects on Motor Control of Personalized Neuromodulation Against Multiple Sclerosis Fatigue.

Fatigue is a hidden symptom of Multiple Sclerosis (MS) disease that nevertheless impacts severely on patients' everyday life. Evidence indicates the involvement of the sensorimotor network and its inter-nodes communication at the basis of this symptom. Two randomized controlled trials (RCTs) showed that the personalized neuromodulation called Fatigue Relief in Multiple Sclerosis (FaReMuS) efficaciously fights multiple sclerosis (MS) fatigue. By this Proof of Concept study, we tested whether FaReMuS reverts the alteration of the brain-muscular synchronization previously observed occurring with fatigue. The cortico muscular coherence (CMC) was studied in 11 patients before and after FaReMuS, a 5-day tDCS (1.5 mA, 15 min per day) anodal over the whole body's somatosensory representation (S1) via a personalized MRI-based electrode (35 cm2) against the occipital cathode (70 cm2). Before FaReMuS, the CMC was observed at a mean frequency of 31.5 ± 1.6 Hz (gamma-band) and positively correlated with the level of fatigue (p = .027). After FaReMuS, fatigue reduced in average of 28% ± 33% the baseline level, and the CMC frequency reduced to 26.6 ± 1.5 Hz (p = .022), thus forthcoming the physiological beta-band as observed in healthy people. The personalized S1 neuromodulation treatment, ameliorating the central-peripheral communication that subtends simple everyday movements, supports the appropriateness of neuromodulations aiming at increasing the parietal excitability in fighting MS fatigue. The relationship between central-peripheral features and fatigue profile strengthens a central more than peripheral origin of the symptom.

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.

Executive functioning in relapsing-remitting multiple sclerosis patients without cognitive impairment: A task-switching protocol.

BACKGROUND: Cognitive dysfunction affects 40%-65% of multiple sclerosis (MS) patients, most often affecting information processing speed and working memory, mediated by the pre-frontal cortex (PFC). OBJECTIVE: Our study aimed to investigate PFC functioning through a task-switching protocol in relapsing-remitting multiple sclerosis (RRMS) patients without cognitive impairment. METHODS: A total of 24 RRMS patients and 25 controls were enrolled. Two different tasks were performed in rapid and random succession, so that the task was either changed from one trial to the next one (switch trials) or repeated (repetition trials). Switch trials are usually slower than repetitions, causing a so-called switch cost (SC). RESULTS: Patients had worse performance than controls only in the switch trials, as indicated by increased SC and reaction times. Moreover, patients showed a reduced ability to reconfigure the task-set for the execution of a new task and to disengage from the previous one. CONCLUSION: Our results showed a primary deficit in executive control processes involved in the task-switching performance in RRMS patients without cognitive impairment. This deficit may depend on the functional impairment of the PFC, which is essential to adjust behaviour rapidly and flexibly in response to environmental changes, representing one of the most sophisticated human abilities.

Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS) in the Italian population.

Cognitive dysfunction involves 40-65 % of multiple sclerosis (MS) patients. It can be detected in all MS phenotypes from the early stages of the disease, and it tends to progress over time. Minimal Assessment of Cognitive Function in MS (MACFIMS) has been proved to be the most sensitive and comprehensive battery available for MS cognitive assessment in the English population. In Italy, MACFIMS applicability is limited in everyday clinical practice since the overall validity of this battery in the Italian MS population has never been demonstrated. The aim of this study was to translate/cross-culturally adapt and validate an Italian version of the MACFIMS. A total of 130 MS patients and 60 healthy controls (HCs) were enrolled and evaluated with an Italian version of the MACFIMS. All tests discriminated MS patients from HCs; according to the literature, approximately more than half of MS patients (70.8 %) exhibit cognitive impairment. Principal component analysis showed four distinct components: visual-spatial memory/processing speed, working memory, executive functions and verbal memory. Our study is the first to validate an Italian version of the MACFIMS. Several aspects of validity have been demonstrated: criterion and, partially, construct. Future work will investigate the longitudinal course of neuropsychological dysfunction in Italian MS patients using these measures.

Tissue factor as a potential coagulative/vascular marker in relapsing-remitting multiple sclerosis.

Objectives: Recent studies supported coagulation involvement in multiple sclerosis, an inflammatory-demyelinating and degenerative disease of the central nervous system. The main objectives of this observational study were to identify the most specific pro-coagulative/vascular factors for multiple sclerosis pathogenesis and to correlate them with brain hemodynamic abnormalities. Methods: We compared i) serum/plasma levels of complement(C)/coagulation/vascular factors, viral/microbiological assays, fat-soluble vitamins and lymphocyte count among people with multiple sclerosis sampled in a clinical remission (n=30; 23F/7M, 40 ± 8.14 years) or a relapse (n=30; 24F/6M, age 41 ± 10.74 years) and age/sex-matched controls (n=30; 23F/7M, 40 ± 8.38 years); ii) brain hemodynamic metrics at dynamic susceptibility contrast-enhanced 3T-MRI during relapse and remission, and iii) laboratory data with MRI perfusion metrics and clinical features of people with multiple sclerosis. Two models by Partial Least Squares Discriminant Analysis were performed using two groups as input: (1) multiple sclerosis vs. controls, and (2) relapsing vs. remitting multiple sclerosis. Results: Compared to controls, multiple sclerosis patients had a higher Body-Mass-Index, Protein-C and activated-C9; and a lower activated-C4. Levels of Tissue-Factor, Tie-2 and P-Selectin/CD62P were lower in relapse compared to remission and HC, whereas Angiopoietin-I was higher in relapsing vs. remitting multiple sclerosis. A lower number of total lymphocytes was found in relapsing multiple sclerosis vs. remitting multiple sclerosis and controls. Cerebral-Blood-Volume was lower in normal-appearing white matter and left caudatum while Cerebral-Blood-Flow was inferior in bilateral putamen in relapsing versus remitting multiple sclerosis. The mean-transit-time of gadolinium-enhancing lesions negatively correlated with Tissue-Factor. The top-5 discriminating variables for model (1) were: EBV-EBNA-1 IgG, Body-Mass-Index, Protein-C, activated-C4 and Tissue-Factor whereas for model (2) were: Tissue-Factor, Angiopoietin-I, MCHC, Vitamin A and T-CD3. Conclusion: Tissue-factor was one of the top-5 variables in the models discriminating either multiple sclerosis from controls or multiple sclerosis relapse from remission and correlated with mean-transit-time of gadolinium-enhancing lesions. Tissue-factor appears a promising pro-coagulative/vascular biomarker and a possible therapeutic target in relapsing-remitting multiple sclerosis. Clinical trial registration: ClinicalTrials.gov, identifier NCT04380220.

Home treatment against fatigue in multiple sclerosis by a personalized, bilateral whole-body somatosensory cortex stimulation.

BACKGROUND: Fatigue in multiple sclerosis (MS) is a highly invalidating symptom with no pharmacological efficacious therapies, which furthermore present frequent severe side effects. In two previous randomized controlled trials we observed the efficacy of a personalized neuromodulation treatment consisting of a personalized transcranial Direct Current Stimulation (tDCS) for 15 min per day for 5 days (Faremus). METHODS: By this medical-device phase II study, we aimed at assessing the feasibility, acceptance, safety and efficacy of Faremus treatment when applied at patients' home. We considered the efficacy as primary outcome assessed by a reduction of fatigue levels measured by Modified Fatigue Impact Scale (mFIS) scored before and after the treatment. Primary outcome determined the sample size estimate. Individual ad-hoc questionnaires quantified the acceptance, safety and side effects during the treatment. RESULTS: All 15 patients completed the treatment, reporting optimal acceptance and safety on using Faremus at their home without side-effects. The treatment ameliorated fatigue symptoms more than 20% of baseline in 10 out of the 15 patients and of 37% on average, with a corresponding effect size 1.21. CONCLUSIONS: Faremus personalized electroceutical intervention, a 5-days anodal tDCS over the bilateral whole-body somatosensory cortex, is well accepted and can be feasibly, safely, and efficaciously applied at patients' home, offering a comfortable treatment by reducing the need to travel when fatigue-related symptoms hamper the quality of life.

Real world experience with teriflunomide in multiple sclerosis: the TER-Italy study.

OBJECTIVE: To identify baseline factors associated with disease activity in patients with relapsing-remitting multiple sclerosis (RRMS) under teriflunomide treatment. METHODS: This was an independent, multi-centre, retrospective post-marketing study. We analysed data of 1,507 patients who started teriflunomide since October 2014 and were regularly followed in 28 Centres in Italy. We reported the proportions of patients who discontinued treatment (after excluding 32 lost to follow-up) and who experienced clinical disease activity, i.e., relapse(s) and/or confirmed disability worsening, as assessed by the Expanded Disability Status Scale (EDSS). Decision tree-based analysis was performed to identify baseline factors associated with clinical disease activity during teriflunomide treatment. RESULTS: At database lock (September 2020), approximately 29% of patients (430 out of 1,475) discontinued teriflunomide because of disease activity (~ 46%), adverse events (~ 37%), poor tolerability (~ 15%), pregnancy planning (~ 2%). Approximately 28% of patients experienced disease activity over a median follow-up of 2.75 years: ~ 9% had relapses but not disability worsening; ~ 13% had isolated disability worsening; ~ 6% had both relapses and disability worsening. The most important baseline factor associated with disease activity (especially disability worsening) was an EDSS > 4.0 (p < 0.001). In patients with moderate disability level (EDSS 2.0-4.0), disease activity occurred more frequently in case of ≥ 1 pre-treatment relapses (p = 0.025). In patients with milder disability level (EDSS < 2.0), disease activity occurred more frequently after previous exposure to ≥ 2 disease-modifying treatments (p = 0.007). CONCLUSIONS: Our study suggests a place-in-therapy for teriflunomide in naïve patients with mild disability level or in those who switched their initial treatment for poor tolerability. Adverse events related with teriflunomide were consistent with literature data, without any new safety concern.

Oxidative Stress Related to Iron Metabolism in Relapsing Remitting Multiple Sclerosis Patients With Low Disability.

Oxidative status may play a role in chronic inflammation and neurodegeneration which are considered critical etiopathogenetic factors in Multiple Sclerosis (MS), both in the early phase of the disease and in the progressive one. The aim of this study is to explore oxidative status related to iron metabolism in peripheral blood of stable Relapsing-Remitting MS with low disability. We studied 60 Relapsing-Remitting MS patients (age 37.2 ± 9.06, EDSS median 1.0), and 40 healthy controls (age 40.3 ± 10.86). We measured total hydroperoxides (dROMs test) and Total Antioxidant Status (TAS), along with the iron metabolism biomarkers: Iron (Fe), ferritin (Ferr), transferrin (Tf), transferrin saturation (Tfsat), and ceruloplasmin (Cp) panel biomarkers [concentration (iCp) and enzymatic activity (eCp), copper (Cu), ceruloplasmin specific activity (eCp:iCp), copper to ceruloplasmin ratio (Cu:Cp), non-ceruloplasmin copper (nCp-Cu)]. We computed also the Cp:Tf ratio as an index of oxidative stress related to iron metabolism. We found lower TAS levels in MS patients than in healthy controls (CTRL) and normal reference level and higher dROMs and Cp:Tf ratio in MS than in healthy controls. Cp and Cu were higher in MS while biomarkers of iron metabolism were not different between patients and controls. Both in controls and MS, dROMs correlated with iCp (CTRL r = 0.821, p < 0.001; MS r = 0.775 p < 0.001) and eCp (CTRL r = 0.734, p < 0.001; MS r = 0.820 p < 0.001). Moreover, only in MS group iCp correlated negatively with Tfsat (r = -0.257, p = 0.047). Dividing MS patients in "untreated" group and "treated" group, we found a significant difference in Fe values [F(2, 97) = 10.136, p < 0.001]; in particular "MS untreated" showed higher mean values (mean = 114.5, SD = 39.37 µg/dL) than CTRL (mean 78.6, SD = 27.55 µg/dL p = 0.001) and "MS treated" (mean = 72.4, SD = 38.08 µg/dL; p < 0.001). Moreover, "MS untreated" showed significantly higher values of Cp:Tf (mean = 10.19, SD = 1.77∗10-2; p = 0.015), than CTRL (mean = 9.03, SD = 1.46 ∗10-2). These results suggest that chronic oxidative stress is relevant also in the remitting phase of the disease in patients with low disability and short disease duration. Therefore, treatment with antioxidants may be beneficial also in the early stage of the disease to preserve neuronal reserve.

Brain Plasticity Effects of Neuromodulation Against Multiple Sclerosis Fatigue.

RATIONALE: 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. OBJECTIVE: The present work aimed at assessing whether the mentioned intervention also induces changes in the excitability of sensorimotor cortical areas. METHOD: 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. RESULTS: 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. CONCLUSION: 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. SIGNIFICANCE: 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.

Specific forms of neural activity associated with tactile space awareness.

Left tactile extinction, in which a left tactile stimulus fails to access consciousness only when a right stimulus is presented simultaneously, offers a model for studying tactile awareness from its transitory absence. Pairs of transcranial magnetic stimuli (TMS) on the parietal cortex inhibit contralateral tactile perception when separated by an interval of 1 ms. We have applied this technique on the left parietal cortex of right brain damaged (RBD) patients and normal subjects and have shown a selective lack of paired TMS inhibitory effects on right tactile perception of patients during bimanual stimulation. TMS effects were normal during unimanual right stimulation. These results suggest the presence of a specific pattern of inhibitory/excitatory interactions in parietal brain areas as critical for tactile awareness.

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, double-blind sham-controlled, cross-over study. The real neuromodulation by a personalized electrode, shaped on the MR-derived 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.

Imagery-induced cortical excitability changes in stroke: a transcranial magnetic stimulation study.

Focal transcranial magnetic stimulation (TMS) was employed in a population of hemiparetic stroke patients in a post-acute stage to map out the abductor digiti minimi (ADM) muscle cortical representation of the affected (AH) and unaffected (UH) hemisphere at rest, during motor imagery and during voluntary contraction. Imagery induced an enhancement of the ADM map area and volume in both hemispheres in a way which partly corrected the abnormal asymmetry between AH and UH motor output seen in rest condition. The voluntary contraction was the task provoking maximal facilitation in the UH, whereas a similar degree of facilitation was obtained during voluntary contraction and motor imagery in the AH. We argued that motor imagery could induce a pronounced motor output enhancement in the hemisphere affected by stroke. Further, we demonstrated that imagery-induced excitability changes were specific for the muscle 'prime mover' for the imagined movement, while no differences were observed with respect to the stroke lesion locations. Present findings demonstrated that motor imagery significantly enhanced the cortical excitability of the hemisphere affected by stroke in a post-acute stage. Further studies are needed to correlate these cortical excitability changes with short-term plasticity therefore prompting motor imagery as a 'cortical reservoir' in post-stroke motor rehabilitation.