Background: Corticospinal plasticity is impaired in MS. In-phase bilateral upper-limb exercises have been shown to improve corticospinal excitability in people with relapsing-remitting multiple sclerosis, but there is limited literature that supports the same conclusion for progressive multiple sclerosis. Therefore, our aim was to investigate whether a 12-week in-phase bilateral upper-limb exercise protocol could enhance corticospinal plasticity and improve clinical outcomes in people with progressive multiple sclerosis. Methods: Five participants (two females; age = 61 ± 12.04 years) with secondary or primary progressive multiple sclerosis were randomized and recruited in a single-case concurrent multiple-baseline design study. The exercise protocol lasted for 12 consecutive weeks (30–60 min/session × 3 sessions/week) and incorporated adapted sport-specific activities, functional training and proprioceptive neuromuscular facilitation exercises. To define the functional relationship between the intervention and the results, a visual analysis was conducted. A statistical analysis was performed when a potential sizeable effect was observed. Results: Statistically significant reductions in active motor threshold (primary outcome) were observed in two of the five participants for the left upper limb and in one of the five participants for the right upper limb. Statistically significant improvements were partially observed in muscle strength, pinch strength and cognitive processing speed. Conclusions: Based on the preliminary findings of the current study, in-phase bilateral upper-limb exercises may modulate corticospinal plasticity and improve clinical outcomes in people with progressive multiple sclerosis. However, larger studies are needed to reproduce these results and to establish the effects of in-phase bilateral exercise on both corticospinal plasticity and related clinical outcomes.

Transcranial ultrasonic stimulation (TUS) is emerging as a non-invasive neuromodulatory technique capable of delivering millimeter-precision stimulation at whole-brain depths. Research efforts have increasingly focused on its translational potential. Promising data have been reported across several disease populations, including Parkinson's disease and stroke, paving the way for clinical applications of TUS. Clinical studies to date, however, show substantial variability in transducer fixation, targeting approaches, and acoustic parameters. This limits the interpretability and comparability of results. Existing methodological guides address human TUS in general but do not focus on applications in neurological populations. This experimental protocol presents a standardized yet adaptable framework for applying TUS to neurological cohorts such as stroke. It offers detailed guidance on: (1) essential and optional hardware components in the context of therapy-oriented TUS; (2) hardware settings and parameter selection, including strategies to minimize auditory confounds; (3) calibration and quality assurance procedures to ensure the transducer delivers waveforms as specified; (4) targeting approaches based on simulation or non-simulation methods for accurate localization of TUS focus/foci to the intended anatomical region(s); (5) methodology adaption for clinical populations; and (6) outcome measures for clinical TUS, encompassing safety assessments and surrogate outcome measures such as corticospinal excitability and motor sequence learning. This protocol is designed as a replicable, modular resource. It accommodates both novice users (seeking a practical entry point into patient-based TUS) and experienced researchers (aiming to align with emerging scientific and methodological standards). The goal is to support the growing clinical interest in TUS and to facilitate clinically translatable, reproducible, and comparable results across research groups and patient populations.

Transcranial ultrasonic stimulation (TUS) is emerging as a non-invasive neuromodulatory technique capable of delivering millimeter-precision stimulation at whole-brain depths. Research efforts have increasingly focused on its translational potential. Promising data have been reported across several disease populations, including Parkinson's disease and stroke, paving the way for clinical applications of TUS. Clinical studies to date, however, show substantial variability in transducer fixation, targeting approaches, and acoustic parameters. This limits the interpretability and comparability of results. Existing methodological guides address human TUS in general but do not focus on applications in neurological populations. This experimental protocol presents a standardized yet adaptable framework for applying TUS to neurological cohorts such as stroke. It offers detailed guidance on: (1) essential and optional hardware components in the context of therapy-oriented TUS; (2) hardware settings and parameter selection, including strategies to minimize auditory confounds; (3) calibration and quality assurance procedures to ensure the transducer delivers waveforms as specified; (4) targeting approaches based on simulation or non-simulation methods for accurate localization of TUS focus/foci to the intended anatomical region(s); (5) methodology adaption for clinical populations; and (6) outcome measures for clinical TUS, encompassing safety assessments and surrogate outcome measures such as corticospinal excitability and motor sequence learning. This protocol is designed as a replicable, modular resource. It accommodates both novice users (seeking a practical entry point into patient-based TUS) and experienced researchers (aiming to align with emerging scientific and methodological standards). The goal is to support the growing clinical interest in TUS and to facilitate clinically translatable, reproducible, and comparable results across research groups and patient populations.