Anna Ghazaryan

Cortico-muscular coherence as an index of fatigue in multiple sclerosis

Background: Highly common in multiple sclerosis (MS), fatigue severely impacts patients’ daily lives. Previous findings of altered connectivity patterns led to the hypothesis that the distortion of functional connections within the brain-muscle circuit plays a crucial pathogenic role. Objective: The objective of this paper is to identify markers sensitive to fatigue in multiple sclerosis. Methods: Structural (magnetic resonance imaging with assessment of thalamic volume and cortical thickness of the primary sensorimotor areas) and functional (cortico-muscular coherence (CMC) from simultaneous electroencephalo- and surface electromyographic recordings during a weak handgrip task) measures were used on 20 mildly disabled MS patients (relapsing–remitting course, Expanded Disability Status Scale score ≤ 2) who were recruited in two fatigue-dependent groups according to the Modified Fatigue Index Scale (MFIS) score. Results: The two groups were similar in terms of demographic, clinical and imaging features, as well as task execution accuracy and weariness. In the absence of any fatigue-dependent brain and muscular oscillatory activity alterations, CMC worked at higher frequencies as fatigue increased, explaining 67% of MFIS variance (p=.002). Conclusion: Brain-muscle functional connectivity emerged as a sensitive marker of phenomena related to the origin of MS fatigue, impacting central-peripheral communication well before the appearance of any impairment in the communicating nodes.

Oral fingolimod reduces glutamate-mediated intracortical excitability in relapsing-remitting multiple sclerosis

OBJECTIVE Fingolimod is an effective disease modifying therapy for multiple sclerosis (MS). Beyond its main action on peripheral lymphocytes, several noteworthy side effects have been demonstrated in vitro, among which modulation of neural excitability. Our aim was to explore cortical excitability in vivo in patients treated with fingolimod 0.5mg/day. METHODS Paired-pulse TMS was applied on the left primary motor cortex in 13 patients affected by relapsing-remitting MS, the day before the first dose of fingolimod (T0) and 60days later (T1). Resting motor threshold, baseline motor evoked potentials, short interval intracortical inhibition (at 1, 3, 5ms) and intracortical facilitation (at 7, 9, 11 and 13ms) were estimated at T0 and T1. RESULTS Intracortical facilitation was reduced at T1, without any changes in short interval intracortical inhibition. CONCLUSIONS Fingolimod selectively reduced intracortical facilitation, which is mainly mediated by glutamate. SIGNIFICANCE This is the first in vivo confirmation of the effects of fingolimod on glutamatergic drive in treated humans. Our results suggest a novel neuromodulatory activity of fingolimod with potential effect on glutamate-mediated excitotoxicity in vivo, as already seen in animal models.

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.

Functional and structural balances of homologous sensorimotor regions in multiple sclerosis fatigue

Fatigue in multiple sclerosis (MS) is a highly disabling symptom. Among the central mechanisms behind it, an involvement of sensorimotor networks is clearly evident from structural and functional studies. We aimed at assessing whether functional/structural balances of homologous sensorimotor regions—known to be crucial for sensorimotor networks effectiveness—decrease with MS fatigue increase. Functional connectivity measures at rest and during a simple motor task (weak handgrip of either the right or left hand) were derived from primary sensorimotor areas electroencephalographic recordings in 27 mildly disabled MS patients. Structural MRI-derived inter-hemispheric asymmetries included the cortical thickness of Rolandic regions and the volume of thalami. Fatigue symptoms increased together with the functional inter-hemispheric imbalance of sensorimotor homologous areas activities at rest and during movement, in absence of any appreciable parenchymal asymmetries. This finding supports the development of compensative interventions that may revert these neuronal activity imbalances to relieve fatigue in MS.

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.

P17.11 Neuroanatomic and functional profile of fatigue in multiple sclerosis: an integrated morphofunctional study

E. Cases Rodríguez1, J. Miró Lladó2, M. Veciana De Las Heras1, I. Moreno Gómez1, J.P. Pérez1, M.A. Macau2, S. Fernández Fernández2, M.M. Santurino Plaza2, J. Mora Salvadó3, S. Castañer Llanes4, M. Falip Centellas2 1Neurophysiology department. Neurology Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 2Epilepsy Unit. Neurology Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 3Spect Unit. Nuclear Medicine Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 4IDI: Image Diagnostic Institute. Hospital Universitari de Bellvitge, Barcelona, Spain

P17.12 Inter-hemispheric connectivity in multiple sclerosis: an integrative electrophysiological-structural study

E. Cases Rodríguez1, J. Miró Lladó2, M. Veciana De Las Heras1, I. Moreno Gómez1, J.P. Pérez1, M.A. Macau2, S. Fernández Fernández2, M.M. Santurino Plaza2, J. Mora Salvadó3, S. Castañer Llanes4, M. Falip Centellas2 1Neurophysiology department. Neurology Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 2Epilepsy Unit. Neurology Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 3Spect Unit. Nuclear Medicine Service. Hospital Universitari de Bellvitge, Barcelona, Spain, 4IDI: Image Diagnostic Institute. Hospital Universitari de Bellvitge, Barcelona, Spain