Participants in the multimodal exercise training group will be given a treatment protocol consisting of aerobic exercise and strengthening exercises in the presence of a physiotherapist for a total of 12 weeks, 3 days a week for 1 hour.

Participants in the control group will be put on the waiting list after all assessment methods have been applied and will be re-evaluated at the end of 12 weeks.

The exercise training consisting of aerobic, strengthening and balance exercises will be applied for 12 weeks/3days for 1hour. One day of the exercise training will be performed in a clinical environment with a physiotherapist, and the other 2 days of the week, participants will be asked to apply asynchronous video-based telerehabilitation over the internet in their own homes. The asynchronous video-based telerehabilitation application will be performed through an account created specifically for the participant on the "www.telenororehab.com" website. The exercise program will be created according to the individual's condition and progression will be provided every 3 weeks. Patients who do not attend 3 consecutive sessions will be excluded from the study.

The Multiple Sclerosis Functional Composite Test evaluates disease activity through three sections: cognitive status, and upper and lower extremity function. The Paced Auditory Serial Addition Test (PASAT) measures auditory processing speed, attention, flexibility, and calculation by having the patient add numbers presented at three-second intervals. The score is based on correct answers, with a maximum of 60 points. The Timed 25 Foot Walking Test (T25FWT) assesses lower extremity function by recording the time (in seconds) taken to walk 7.62 meters as quickly and safely as possible, with the average of two trials used for scoring. The 9-Hole Peg Test (9DPT) evaluates upper extremity function by having the patient place and remove nine pegs as quickly as possible, with scores based on the average of two trials for each hand.

fMRI is a non-invasive method that allows the examination of central nervous system function and the identification of abnormal activation patterns and/or functional connectivity caused by diseases (Rocca et al 2024).In our study, functional MRI evaluations are planned to be performed using parallel imaging sequences with a 3 T Siemens device with a 32-channel head coil. High-resolution (1 x 1 x 1 mm isotropic) sagittal 190 slices will be obtained with a T1-weighted imaging sequence (TR/TE: 7.7/3.7 ms;, FA: 8°; FOV: 256 x 256). Functional resting state data will be taken with a single-shot echo planar imaging (EPI) sequence consisting of 35 slices of 4 mm thickness, 300 dynamic shots (TR/TE: 2230/30 ms, FA: 77°; matrix: 80x80) and will last approximately 11 minutes. Before functional acquisition, magnetic field maps will be recorded in order to correct signal distortions caused by tissue inhomogeneities in the magnetic field during the analysis phase.

BDNF is a neurotrophin that affects the survival, growth and function of neurons in the central and peripheral nervous system, provides stabilization of synapses, and regulates synaptic function, axon and dendrite branching. In our study, Enzyme-Linked Immunosorbent Assay (ELISA) will be used to assess the BDNF levels of participants. All participants will be asked not to consume alcohol and caffeine in the last 12 hours before blood collection, not to take any anti-inflammatory drugs other than their routine treatments and not to exercise. The blood samples to be collected will be centrifuged and stored at -80 degrees in Eppendorf or Falcon tubes (15 ml) (Shobeiri et al 2022; Briken et al. 2016). After the treatments are completed, the blood taken will be analyzed by experienced technicians in the laboratory together with the blood taken before exercise training.

EDSS will be used to assess the disability level of the participants. The scale widely used to assess the level of disability in PwMS, evaluates 8 functional subsystems. These systems consist of pyramidal functions, cerebellar functions, brainstem functions, sensory functions, bladder-bowel functions, visual functions, cognitive functions, and other functions. The scale consists of a 20-category ordinal rating system ranging from 0 (normal neurological examination regardless of symptoms) to 10 (death due to MS), with 0.5-point increments starting from 1 (Kurtzke 1983).