DOI: 10.6084/m9.figshare.26527351.v1
title: A 12-week in-phase bilateral upper limb exercise protocol promoted neuroplastic and clinical changes in people with relapsing remitting multiple sclerosis

description: Relapsing-Remitting Multiple Sclerosis manifests various motor symptoms including impairments in corticospinal tract integrity, whose symptoms can be assessed using transcranial magnetic stimulation. Several factors, such as exercise and interlimb coordination, can influence the corticospinal plasticity. Previous studies reported that the greatest improvement in corticospinal plasticity occurred during in-phase bilateral exercises, yet the effect of in-phase bilateral exercise on corticospinal plasticity in Multiple Sclerosis remains unclear.<i> </i>Our aim was to investigate the effects of in-phase bilateral exercises on central motor conduction time, motor evoked potential amplitude and latency, motor threshold and clinical measures.Five people were randomized and recruited in this single case concurrent multiple baseline design study. The intervention lasted for 12 consecutive weeks (30-60 minutes /session x 3 sessions / week) and included in-phase bilateral upper limb movements, adapted to different sports activities and to functional motor training. To define the functional relation between the intervention and the results, we conducted a visual analysis. If a potential sizeable effect was observed, we subsequently performed a statistical analysis.We assessed the corticospinal plasticity using single pulse TMS. Using electromyography (EMG) signals from an upper limb muscle, we collected Motor Evoked Potentials (MEPs), which were used to calculate all corticospinal excitability measures. To ensure methodological consistency, we collected all data by performing the same methodological procedures for both conditions (i.e., corticospinal excitability measures bilaterally) - one side per assessment- across participants and across all time points.<b>TMS assessment</b>We assessed bilateral corticospinal excitability measures. We applied TMS single pulses via figure-eight coil (C-B60; inner diameter: 35mm, outer diameter: 75mm), connected to the MagPro R20 (MagVenture User Guide, United Kingdom edition, MagVenture A/S, Denmark). The coil was oriented tangentially over the contralateral motor area of the brain, relative to the target muscle (i.e., APB), with a posterolateral handle pointing in approximately 45 degrees angle to the sagittal plane inducing posterior-anterior current in the brain.For the TMS procedures, we first found the optimal stimulation site (i.e., hot-spot), next we determined the resting motor threshold and then we applied a bout of single pulses using suprathreshold stimulation. To determine hot-spot (i.e., the spot in which the largest response of the target muscle is elicited), we delivered single pulses at low intensities (e.g., ~20% maximum stimulator output) and gradually increased it by 1-5% maximum stimulator output until we reached the intensity that elicited three consecutive MEPs with peak-to-peak amplitude greater than 50mV. Then, we marked the position of the coil on the skull with a water-resistant ink, to determine the resting motor threshold of the target muscle. Resting motor threshold is the minimum stimulation intensity needed to produce MEPs of the target muscle. To identify the resting motor threshold, we employed an adaptive threshold-hunting method, the Motor Threshold Assessment Tool (MTAT 2.0) (available at http://clinicalresearcher.org/software.htm). The specific method has the advantage of speed without losing accuracy when compared to the relative-frequency methods based on the Rossini–Rothwell, although both methods have similar precision. Then, to quantify the MEPs-derived measures of interest (i.e., MEPs amplitude and latency), we applied 30 suprathreshold stimuli at 120% of the resting motor threshold.<b>Clinical assessment</b>Two physiotherapists independently performed all clinical assessments to each participant, with the exact same methodological procedures, to ensure validity of the results. Clinical assessments included the Mini Balance Evaluation Systems Test (MiniBEST), Six Spot Step Test (SSST), Action Research Arm Test (ARAT), Hand Held Dynamometer (HHD), Symbol Digit Modalities Test (SDMT), Modified Fatigue Impact Scale (MFIS).Results demonstrated bilateral reduction of the motor threshold alongside with improvement of all clinical measures, but not in any other corticospinal plasticity measures. Our preliminary findings suggest that in-phase bilateral exercise affects motor threshold in people with Relapsing-Remitting Multiple Sclerosis. Therefore, this measure could potentially serve as a proxy for detecting corticospinal plasticity in this cohort. However, future studies with larger sample sizes should validate the effect of in-phase bilateral exercise on the corticospinal plasticity and clinical measures in this cohort.