The Effects of a 12-week In-phase Bilateral Exercise Programme on the Corticospinal Plasticity in People With Progressive Multiple Sclerosis

Progressive Multiple Sclerosis (MS) is a chronic neurological condition characterized by gradual worsening of neurological function due to damage to the central nervous system. Individuals with progressive forms of MS often experience increasing difficulties with movement, balance, muscle strength, hand function, and cognitive performance. Although disease-modifying medications can reduce inflammatory activity, they have limited effects on the neurodegenerative processes that drive disease progression. For this reason, rehabilitation approaches that promote neuroplasticity-the brain's ability to reorganize and adapt-are considered an important complementary strategy for improving function and quality of life in people with progressive MS.

This study investigates whether a structured exercise program based on coordinated bilateral upper-limb movements can enhance corticospinal plasticity and improve clinical outcomes in people with progressive MS. The corticospinal tract is a major neural pathway responsible for voluntary movement, and damage to this pathway contributes significantly to motor impairment in MS. However, some remaining neural connections may still retain the ability to adapt through activity-dependent plasticity. The study examines whether targeted exercise can stimulate these mechanisms.

Five participants diagnosed with either primary progressive or secondary progressive MS took part in the study. The research used a single-case experimental design with a concurrent multiple baseline approach, in which each participant served as their own control. During an initial baseline period, repeated measurements were collected without intervention to establish stable reference values. The exercise intervention was then introduced at different time points for each participant.

The intervention consisted of a 12-week in-phase bilateral upper-limb exercise program performed three times per week. The training included coordinated movements of both arms performed simultaneously, such as adapted sport-related exercises, functional strengthening activities, and proprioceptive neuromuscular facilitation patterns. Sessions lasted approximately 30-60 minutes and were designed to provide a high number of repetitions while maintaining a safe intensity level.

The primary outcome of the study was corticospinal excitability, measured using transcranial magnetic stimulation (TMS). Specifically, the study evaluated the active motor threshold, a neurophysiological measure reflecting the responsiveness of motor pathways in the brain. Secondary outcomes assessed potential functional changes in walking ability, balance, manual dexterity, upper-limb strength, cognitive processing speed, fatigue, and health-related quality of life.

By combining neurophysiological measurements with clinical assessments, this study aims to determine whether coordinated bilateral exercise can induce measurable changes in brain excitability and functional performance in individuals with progressive MS. The findings may provide preliminary evidence supporting the use of targeted exercise interventions as part of comprehensive neurorehabilitation strategies for people living with progressive MS.

• In-Phase Bilateral Upper Limb Exercise Program (Other): The intervention consisted of a 12-week structured exercise program based on in-phase bilateral upper-limb movements, performed three times per week. During these movements, homologous muscles of both arms were activated simultaneously to promote coordinated bilateral motor activity. Each session lasted approximately 30-60 minutes and included a circuit of functional exercises, adapted sport-related movements (such as basketball chest and overhead passes), resistance exercises for finger flexion and extension, and proprioceptive neuromuscular facilitation patterns. The exercises targeted major upper-limb muscle groups and were performed with a high number of repetitions to promote activity-dependent neuroplasticity. Exercise intensity was monitored using heart rate measurements and maintained below 75% of the participant's age-predicted maximum heart rate to avoid aerobic training intensity. The program was designed to stimulate corticospinal plasticity and improve motor and functional

Primary outcomes

• Active Motor Threshold [12 weeks]: Active Motor Threshold (aMT) will be assessed using transcranial magnetic stimulation (TMS) over the primary motor cortex during a low-level voluntary contraction of the abductor pollicis brevis (APB) muscle. Surface electromyography (EMG) will be used to record motor evoked potentials (MEPs). The aMT is defined as the minimum stimulation intensity required to elicit motor evoked potentials with an amplitude ≥200 µV in the active muscle. The outcome will be reported as stimulation intensity expressed as a percentage of maximum stimulator output (%MSO). Lower values indicate greater corticospinal excitability.

Secondary outcomes

• Clinical Tests [12 weeks]: Secondary outcome measures assessed potential functional and clinical changes associated with the exercise intervention. Walking ability was evaluated using the Timed 25-Foot Walk Test, in which participants walked a 25-foot distance as quickly and safely as possible and the average time of two trials was recorded, with shorter times indicating better mobility. Dynamic balance and postural control were measured using the Mini Balance Evaluation Systems Test (Mini-BEST), a 14-item clinical assessment in which higher scores reflect better balance performance. Manual dexterity was assessed using the Purdue Pegboard Test, which measures fine motor coordination by requiring participants to place small pins into holes on a pegboard using one hand, the other hand, or both hands simultaneously within a limited time. Upper-limb muscle strength was evaluated using a handheld dynamometer during maximal isometric contractions of major upper-limb muscle groups. Cognitive processing speed was asses

Sex: All, ages: 30 Years to 75 Years

Inclusion Criteria:

* Diagnosis of Primary Progressive Multiple Sclerosis (PPMS) or Secondary Progressive Multiple Sclerosis (SPMS)
* Age between 30 and 75 years
* Expanded Disability Status Scale (EDSS) score between 5 and 7
* Ability to understand study procedures and provide informed consent
* Ability to safely participate in an exercise program involving coordinated upper-limb movements

Exclusion Criteria:

* Presence of other neurological diseases affecting the central nervous system (e.g., Parkinson's disease, stroke)
* Metallic implants in the brain contraindicating transcranial magnetic stimulation (TMS)
* History of significant cardiovascular disease (e.g., heart failure, aneurysm)
* History of epilepsy or seizures
* Severe orthopedic disorders (e.g., recent fractures, spine surgery, severe musculoskeletal injury)
* Pregnancy during the study period
* Severe visual impairments (e.g., optic neuritis, diplopia)
* Severe hearing impairments (e.g., deafness)
* Severe spasticity greater than grade 1+ on the Modified Ashworth Scale
* Severe psychiatric disorders (e.g., schizophrenia)