Cerebellar Paired Associative Stimulation Enhances Motor Learning and Modulates Cerebellar Output in a Timing- and Task-Dependent Manner

Abstract

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.

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