The goal of this clinical trial is to learn if a comprehensive rehabilitation programme can improve physical function, reduce fatigue, and raise quality of life in adults aged 18-65 with multiple sclerosis (MS). The study will also look at whether the programme leads to changes in brain function using magnetic resonance imaging (MRI). The main questions it aims to answer are:

• Does the programme lower the overall impact of MS on daily life?
• Does the programme improve walking, balance, and hand function?
• Does the programme reduce the impact of fatigue?
• Are there changes in brain connections after the programme?

Each participant serves as their own comparison. They are tested 3 times: 2 months before the programme starts (T0), right before it starts (T1), and after 2 months of intensive treatment (T2). The period between T0 and T1, when no treatment is given, shows each person's natural changes over time.

Participants will:

• Attend individual physiotherapy twice a week for 2 months, then 3 follow-up sessions over the next month
• Take part in 3 group movement-awareness sessions
• Take part in 3 group psychotherapy sessions focused on stress management and relaxation
• Receive written nutritional guidance for autoimmune conditions

Tests include physical assessments, questionnaires about fatigue and quality of life, tremor measurement, and brain MRI scans.

The results may help improve rehabilitation care for people with MS and support their ability to stay active in everyday and working life.

Scientific Rationale

The management of multiple sclerosis (MS) increasingly emphasises non-pharmacological approaches, as available pharmacological treatments have limited effect on existing damage to motor and cognitive systems. Neuroplasticity - the brain's ability to adapt and restore its functions - represents a key mechanism of functional recovery that can be stimulated through targeted rehabilitation. Functional magnetic resonance imaging (fMRI) enables the assessment of these neuroplastic processes and helps identify the relationship between changes in brain connectivity and clinical improvement. Review articles confirm that targeted motor and cognitive rehabilitation in MS modifies clinical function and leads to measurable changes in brain activity and structural connectivity, indicating neuroplasticity activation.

Among rehabilitation approaches, facilitation-based physiotherapy holds particular promise for stimulating neuroplasticity, as it directly targets activation of the central nervous system. The efficacy of one such method (Motor Programme Activating Therapy) has been demonstrated through fMRI (reorganisation of brain activity and connectivity) and clinical tests. Comprehensive rehabilitation should also encompass psychological and behavioural support, as psychotherapy helps manage stress, supports treatment adherence, and positively influences quality of life.

Pilot Study and Rationale for the Present Project

The research team validated a comprehensive therapeutic programme in a pilot study involving 20 newly diagnosed individuals with MS (Hruskova et al., 2024, Front Neurol). The pilot showed significant reduction in fatigue and an increase in life satisfaction, with effects persisting for 12 months. However, these results are based on a smaller sample focused on early-stage disease.

The present project extends this work to people with established clinical manifestations of MS (EDSS 2-6), a population in which rehabilitative care is often fragmented and delivered without a unified methodological framework. The programme has been adapted for this population based on feedback from participants, therapists, and statistical analysis of pilot data. This type of comprehensive, multidisciplinary intervention has not been systematically validated in persons with established MS symptoms in the Czech Republic or internationally.

The programme was developed by two physiotherapists with long-standing experience in MS physiotherapy. Both authors comprehensively analysed the factors influencing the disease course and the effectiveness of physiotherapy in their doctoral theses. The programme was previously piloted under the title "Comprehensive Therapeutic Programme for People with MS", under the auspices of the Ministry of Health of the Czech Republic, with 20 participants with established MS manifestations, and was refined for this study.

Study Sites

Clinical assessments take place at the Department of Rehabilitation Medicine, University Hospital Kralovske Vinohrady (FNKV), Prague. The therapeutic programme is delivered at Olsanska Polyclinic, Prague. fMRI examinations are carried out at the Institute for Clinical and Experimental Medicine (IKEM), Prague.

Intervention Details

Individual Physiotherapy: Conducted according to predetermined procedures but led individually according to each participant's specific symptoms. Therapists use reflexive, mobilisation, and soft tissue techniques to prepare the body for activation of correct postural and motor programmes. For neuromuscular activation, Motor Programme Activating Therapy and Dynamic Neuromuscular Stabilisation are primarily used, along with principles of the Feldenkrais Method. Sessions last 50 minutes, twice weekly for 8 weeks, followed by 3 maintenance sessions at progressively extended intervals during weeks 9-12. Each participant works with two alternating therapists to maintain continuity and diversity of approach.

Group Movement Awareness: Three sessions in a small group (6-8 participants) using Awareness Through Movement (ATM), part of the Feldenkrais Method. Participants perform slow, mindful movements according to verbal instructions, alternating with guided rest. The specific ATM lesson is chosen by the therapist based on the group's needs and abilities.

Group Psychotherapy: Three 60-minute small-group sessions focusing on maintaining mental wellbeing, stress management, and strengthening motivation during treatment. Sessions include practical demonstrations of relaxation techniques with the opportunity to practise and share personal experiences in a safe group environment. Content reflects participants' individual needs, including possible gender-related differences in coping with stress.

Nutritional Recommendations: Evidence-based recommendations for autoimmune diseases, provided online or in written form.

Data Collection

Basic data include biological sex and gender, age, anthropometric measures, limb dominance, time since diagnosis, MS type, EDSS, recent rehabilitation and pharmacological treatment history, fall frequency, use of assistive devices, and social situation (caregiving responsibilities, workload, social support).

Functioning, activities, and contextual factors are assessed using the Brief ICF Core Set for Multiple Sclerosis (Czech translation, UZIS), supplemented by categories for fine motor skills and upper limb control. ICF assessment is conducted through a structured interview by an independent examiner, integrating clinical test results, questionnaire responses, and specialist input. ICF is assessed at T0 and T2 only.

The fMRI protocol includes resting-state fMRI (functional connectivity), stimulation fMRI (video-watching paradigm and simple motor task), and diffusion-weighted imaging (tractography). Total examination time is approximately 50 minutes. Analysis follows methodology previously standardised by the research team (Prochazkova et al., 2020, Eur J Phys Rehabil Med; Miznerova et al., 2025, BMJ Open).

Sample Size

The sample of 45 participants was determined on the basis of a power analysis using pilot study data. In the pilot (n=20), no statistically significant improvement was demonstrated for the Modified Fatigue Impact Scale (MFIS), unlike other measured parameters (SD of post-pre difference: 8.6). The minimal clinically important difference (MCID) for MFIS in MS is 4 points; at α=0.05 and 1-β=0.80, the required sample size is 38 pairs of measurements. Enrollment of 45 provides a margin for potential dropout.

Statistical Analysis

Data will be pseudo-anonymised and linked into a unified database using unique participant codes. Descriptive statistics will include means with standard deviations, medians with interquartile ranges, and absolute and relative frequencies. Where warranted by distributional asymmetry, data transformations will be applied (e.g., reciprocal transformation for timed tests).

The intervention effect will be evaluated using paired tests (t-test, Wilcoxon) comparing T1-T2 change against T0-T1 change. Stability during the control period will be assessed using the Intraclass Correlation Coefficient. All three time points will be incorporated into mixed regression models (repeated measures) for more precise estimation of the intervention effect against spontaneous variability during the control period.

fMRI data will be correlated with clinical and questionnaire data using Pearson/Spearman correlation coefficients and visualised through heatmaps. Regression models will identify potential effect modifiers. ICF data will be used to examine concordance between ICF qualifier ratings and scores from clinical tests and questionnaires (ICF linkage), contributing to the validation of ICF-based assessment in the Czech MS population and providing a detailed overview of functions, activities, and participation amenable to therapy. Benjamini-Hochberg correction for multiple comparisons will be applied where necessary. All analyses will be conducted in R.

Personalised Feedback

Each participant will receive a personalised client card presenting their measurements and changes in a clear visual format. Pilot study feedback indicated that access to individual results motivates participants and increases satisfaction.

Objectives

1. Demonstrate that the programme improves motor functions, tremor, and balance.
2. Verify that the programme positively influences psychological functioning, fatigue, and quality of life.
3. Demonstrate, using fMRI, that the intervention modulates neuroplastic processes.
4. Determine whether clinical changes correlate with fMRI changes.
5. Assess gender-related differences in clinical presentation, functional capacity, and response to the intervention.

Primary Research Question

Does intensive specialised physiotherapy combined with psychotherapeutic support have a measurable impact on motor, cognitive, and psychological functions and on brain neuroplasticity in people with multiple sclerosis?

The anticipated results may constitute an argument for expanding therapeutic options within MS management and provide a basis for discussions with health insurers regarding the reimbursement of comparable rehabilitation programmes.

Inclusion Criteria:

• Unambiguous clinical diagnosis of multiple sclerosis (any subtype, including relapsing-remitting, secondary progressive, and primary progressive)
• Age 18-65 years
• Predominantly motor disability with Expanded Disability Status Scale (EDSS) 2-6
• No relapse within the past month
• Able to attend outpatient physiotherapy regularly and motivated to participate in the programme
• Able and willing to complete 3 sets of clinical examinations and 3 MRI examinations

Exclusion Criteria:

• Conditions impairing mobility (e.g., severe injuries, orthopaedic problems, other neurological conditions)
• Acute inflammatory conditions or infections at the time of programme initiation that could affect the results or safety of the participant
• Change or planned change of treatment (including disease-modifying therapy or corticosteroid therapy) within the past month or during the programme
• Contraindications to MRI examination (e.g., first-trimester pregnancy, presence of a pacemaker, defibrillator, older metallic joint replacements, or other metallic implants)
• Long-term planned absence during the programme (e.g., holiday, surgical procedure)

The IPD sharing plan is being finalized as part of the Data Management Plan (DMP), which is currently being prepared in accordance with FAIR principles, as required by the funding programme (Operational Programme Jan Amos Komenský, OP JAK). The final decision on the scope, timing, and access procedures for sharing individual participant data will be made in alignment with the approved DMP, the informed consent provisions, and applicable data protection legislation (GDPR). This record will be updated accordingly before the primary completion date.