Relapsing-remitting multiple sclerosis (RRMS) is associated with changes of the corticospinal tract integrity, which is quantified by means of corticospinal plasticity. Several factors, such as exercise and interlimb coordination can influence such corticospinal plasticity. Previous work in healthy and in stroke participants showed that the greatest improvement of corticospinal plasticity occurred during in-phase bilateral arm exercises. Here, the investigators propose a concurrent multiple baseline design study which has the advantage to verify the cause-effect inference by the staggered duration through separate baseline phases. The proposed study includes five people with RRMS, who will follow an intervention protocol which includes in-phase bilateral movements of the upper limbs, adapted to different sports activities and to functional training. The aim of the study is to investigate the effects of in-phase bilateral exercises on corticospinal plasticity and on clinical measures, using transcranial magnetic stimulation and standardized clinical assessment. To meet quality standards, the present study has been designed and will be conducted according to the "What Works Clearinghouse" criteria for single case studies.

Relapsing-remitting multiple sclerosis (RRMS) is the most common type of multiple sclerosis characterized by periods of relapses and generating various motor symptoms. These symptoms are associated with the corticospinal tract integrity neuroplasticity. The corticospinal tract is one of the major motor descending pathways providing voluntary motor function in humans. The neuroplasticity of the corticospinal tract, as defined by changes in neuron structure or function detected either directly from measures of individual neurons or inferred from measures taken across populations of neurons, is an essential factor that predicts clinical recovery in the post-relapse stage of people with RRMS. Corticospinal plasticity can be probed using Transcranial Magnetic Stimulation (TMS) and characterized via certain TMS-specific neurophysiological measures. Corticospinal plasticity is exercise-dependent and influenced by various factors, such as aerobic exercise, resistance training, as well as interlimb coordination. Previous studies that assessed corticospinal plasticity using TMS in healthy participants and in chronic stroke survivors, reported that interlimb coordination and especially in-phase bilateral movement has the strongest effect on corticospinal plasticity.

Despite the broad literature on the effects of different types of exercises on the neuroplasticity in people with RRMS, it is unclear whether in-phase bilateral exercises can promote motor related neuroplastic changes in RRMS. In light of evidence that people with RRMS have bilateral cortical lesions, which cause bilateral changes of corticospinal tract integrity, these findings raise the question about the effects of in-phase bilateral exercises on corticospinal plasticity. Such effects would provide strong evidence about whether exercise, in particular in-phase bilateral exercise, can influence the corticospinal plasticity in RRMS.

The aim of this concurrent multiple baseline design study is to investigate the effects of in-phase bilateral exercises on corticospinal plasticity and on clinical measures using TMS and standardized clinical assessment, in five people with RRMS. The intervention protocol will last for 12 consecutive weeks (30-60 minutes /session x 3 sessions/week) and include in-phase bilateral movements of the upper limbs, adapted to different sports activities and to functional training.

To define functional relation between the intervention and the results on corticospinal plasticity (i.e., resting motor threshold, motor evoked potential amplitude, latency) and on clinical measures (i.e., balance, gait, bilateral hand dexterity and strength, cognitive function), the investigators will perform a visual analysis followed by multilevel modelling and the single case educational design specific mean difference in order to estimate the magnitude of the effect size across cases.

Visual analysis will conducted first, in order to determine whether there is a functional relationship between the intervention and the outcome measures. During the visual analysis, six features of the research design graphed data will be examined: level, trend, stability, immediacy of the effect, overlap, and consistency. Over the within-phase examination an evaluation of level, trend and stability will be examined. Level will be reported from the mean score of each dependent variable and trend will determine whether the data points are monotonically decreased or increased. Stability will be estimated based on the percentage of data points falling within 15% of the phase median, if this is higher than 80% then we assume that this criterion is met. Additionally, over the between-phase examination an evaluation of overlapping data among baseline and intervention phases, consistency of data patterns and immediacy of effect will be performed. The Percentage of Non-overlapping Data index will be used to quantify the proportion of data points in the intervention phase that do not overlap with the baseline phase and the test statistic will be calculated using the Improvement Rate Difference as an effect size index. Immediacy of the effect will be examined by comparing changes in level between the last three data points of one phase and the three first data points of the next phase. Furthermore, consistency of data patterns involves the observation of the data from all phases within the same condition, with greater consistency expressing greater causal relation. Each feature will be assessed individually and collectively across to all participants and to all phases. Consequently, if the intervention protocol is the sole determinant of improvement, the investigators expect to find indicators of improvement only at the intervention phase.

Secondly, a quantitative analysis methods will conducted so to evaluate the magnitude of the intervention effect, provided there is evidence from the visual analysis. The investigators will perform all neurophysiological and clinical assessments to each participant according to the number of data points during each phase (i.e., baseline, intervention, follow up). In order to estimate the individual-level effect sizes, three different methods will be used, as suggested by 'What Works Clearinghouse', the standardized mean difference (Cohen's d), the standardized mean difference with correction for small sample sizes (Hedges' g) and piecewise regression analysis which does not only reflect the immediate intervention effect, but also the intervention effect across time. Multilevel modelling, which is recommended by the 'What Works Clearinghouse' and the single case educational design, specific mean difference index will be used to estimate the magnitude of the effect across cases and compared to the effect obtained by the single level estimates. All tests will be two sided. Statistical analysis will be performed using the statistical software R (https://www.r-project.org/).

Inclusion Criteria:

• Diagnosed with relapsing remitting multiple sclerosis
• Expanded Disability Status Scale score between three and five
• Aged between 30 and 70 years
• Relapse within 30 days
• Mini Mental State of Examination score between 24 and 30 (no cognitive impairment)

Exclusion Criteria:

• Metal implants
• History of any disease affecting the central nervous system other than multiple sclerosis
• History of cardiovascular disease
• Mental disorders
• Severe orthopedic disorders
• Pregnancy
• Visual deficit
• Hearing impairments,
• Εpileptic seizures
• Spasticity level on upper or lower limbs more than 1+ (slight increase in muscle tone) according to Modified Ashworth Scale

Participants are people with multiple sclerosis according inclusion/exclusion criteria.

Investigators are health professionals (i.e., physiotherapist, sports scientist, neuropsychologist, neurologist, biostastician).