Search

Introduction: Fatigue is one of the most disabling symptoms of multiple sclerosis (MS), and effective treatments are lacking. Amantadine is one of the most used treatments, although its efficacy is under debate. Transcranial magnetic stimulation (TMS) is a promising intervention that has shown positive effects in some preliminary investigations. We aim to investigate the effect of 6 weeks of amantadine and/or TMS in fatigue due to MS., Methods and Analysis: The study is a national, multicentre, phase 3, randomised, double-blind, cross-over, placebo-controlled and sham-controlled clinical trial. Adult patients with relapsing-remitting MS, Expanded Disability Status Scale score of 1.5-4.5 and Fatigue Severity Score>4 are eligible for the trial. Participants will be randomised to one of the sequences of the study. Each sequence consists of four periods of 6 weeks of treatment and three washout periods of 12-18 weeks. All patients will receive all the combinations of therapies. The primary outcome is the Modified Fatigue Impact Scale. The secondary outcomes are the Symbol Digit Modalities Test (cognition), Beck Depression Inventory-II (depressive symptoms) and Short-Survey 12 (quality of life). Safety and cost-effectiveness will also be evaluated. An exploratory substudy including MRI and blood biomarkers will be conducted., Ethics and Dissemination: The study is approved by the Ethics Committee of the Hospital Clinico San Carlos and the Spanish Agency of Medications and Medical Devices. All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences., Trial Registration Number: EudraCT 2021-004868-95; NCT05809414., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The present report focuses on evaluating the neurocognitive consequences of the correct or incorrect spatial prediction induced by a spatial cue. Positions in the vertical meridian were cued in order to evaluate the cognitive consequences in the processing of the validly (VC) or invalidly cued (IC) targets. The behavioural responses and the 64 EEG channel were recorded. The late endogenous event-related potential (ERP) induced by target stimuli in VC and IC targets were compared in voltage amplitude, voltage and current source density topographies. The P3a and a late positive complex, possibly P3b were increased in a statistically significant manner in the IC targets with regard to the VC targets. The previous result suggests that subjects prepare to accomplish the task upon specification of the cue, and when the IC target appeared it is treated as a low probability stimulus in a similar manner to deviant stimuli in odd-ball paradigms.

The contingent negative variation (CNV), and the associated event-related desynchronization (ERD) on motor areas and sensory areas, and increase of alpha in the ipsilateral to the cued stimulus side, are different brain signals that reflect motor, sensory, and cognitive activations related to the expectancy of the next stimulus. However, the possibility of an overall change in EEG oscillatory activity during expectancy periods has not been directly addressed. The present report tests whether the background oscillatory activity is modulated by a warning signal. During the expectancy period, the power spectral density (PSD) between 0 and 42.9 Hz--including delta, theta, alpha, beta, and gamma--decreased with respect to the baseline. These results suggest that during expectancy periods there is a generalised decrease in the oscillatory activity, and that reduction of the EEG power would facilitate the phasic and oscillatory neural activities triggered by the next target stimulus.