In-phase Bilateral Exercises in People With Relapsing Remitting Multiple Sclerosis
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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/).
    

Intervention name(s): In-phase Bilateral Exercises of the upper limbs
Intervention type(s): Behavioral
Intervention description(s): The intervention protocol consists of in-phase bilateral exercises for the upper limbs, which are adapted to different sport activities and to fitness functional exercises, organized in a circuit training. Specifically, each session will consist of 1-3 sets, consisting of 10-15 repetitions of 9 different exercises targeting large muscle groups of the upper limbs.
The specific exercises will include sports activities of basic technical skills of basketball (e.g., different types of passing, catching and throwing the ball) and volleyball (e.g., different types of passing and receiving the ball), whereas the fitness exercises will include shoulder rows, shoulder lateral raises, elbow flexions, elbow extensions, using resistance elastic bands, as well as exercises with the patients' own body weight (e.g., pushups, TRX).
The intervention phase for each participant will consist of 12 consecutive weeks, for 3 times per week, 30-60 minutes each session.
Intervention model: Single Group Assignment
Intervention model description: The study follows a concurrent multiple baseline design across subjects, which involves five people with RRMS that will be managed as five different case studies. The specific design has the advantage to verify the cause-effect inference clearly by the staggered duration through separate baseline phases
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: transcranial magnetic stimulation; multiple sclerosis; exercise