Cerebellar Paired Associative Stimulation Enhances Motor Learning and Modulates Cerebellar Output in a Timing- and...

Cerebellar paired associative stimulation (cPAS) is a non-invasive neuromodulation protocol that combines peripheral nerve stimulation with cerebellar transcranial magnetic stimulation to induce plasticity in the cerebellar-cortical pathway. Previous evidence suggested that cPAS delivered at a 25ms interstimulus interval (cPAS25) can modulate cerebellar-primary motor cortex connectivity, as reflected by changes in cerebellar-brain inhibition (CBI). However, its behavioural relevance remains unclear. To investigate this issue, we conducted two experiments in young healthy adults using a within-subject crossover design to compare the effects of cPAS25 and a temporally mismatched control (cPAS10). In Experiment 1, participants received cPAS followed by a visuomotor sequence learning task, with motor performance assessed via movement time, error rate, and a composite skill index. CBI and motor evoked potentials (MEPs) were recorded at baseline, post-stimulation, and after task completion. In Experiment 2, a subset of participants received cPAS without the task to isolate its neurophysiological effects. cPAS25 significantly improved motor learning compared to cPAS10, as shown by a greater increase in skill index. It also reduced CBI, but this effect was observed only when cPAS was not followed by motor practice, suggesting a task-sensitive interaction. MEP amplitudes remained unchanged, indicating selective modulation of cerebellar output. These results support a timing-dependent, context-sensitive mechanism of cerebellar plasticity. cPAS25 can enhance motor learning and modulate cerebellar-cortical connectivity, although effects may not summate when paired with motor practice. These findings highlight the translational potential of cPAS25 as a precision neuromodulatory approach to enhance motor learning and rehabilitation by targeting cerebellar circuits.