Motor cortex excitability in restless legs syndrome: A systematic review and insights into pathophysiology via transcranial magnetic stimulation

Restless Legs Syndrome (RLS) is a neurological disorder characterized by a complex and only partially understood pathophysiology. Numerous studies have investigated motor cortex excitability in RLS using transcranial magnetic stimulation (TMS), but a comprehensive systematic review assessing their methodological quality and synthesizing their findings is lacking. A systematic search of PubMed focused on various TMS parameters, including resting and active motor thresholds, motor evoked potential characteristics, contralateral and ipsilateral silent periods, and multiple measures of intracortical inhibition and facilitation. The quality of each study was evaluated using custom checklists and the modified Newcastle-Ottawa Quality Assessment Scale. Out of the studies screened, 21 (comprising 319 RLS patients and 278 healthy controls) met the inclusion criteria. Despite considerable variability in TMS methodologies—such as differences in the muscles tested, interstimulus intervals, testing timing, and the potential confounding effects of medications—a consistent finding was a reduction in short-interval intracortical inhibition, a key indicator of central inhibitory GABAergic activity. Additionally, altered post-exercise facilitation and delayed facilitation suggest abnormal motor plasticity in RLS patients. These findings suggest that despite the methodological heterogeneity, TMS abnormalities may play a crucial role in the pathophysiology of RLS. In this context, RLS symptoms are likely to originate at different levels within a complex neural network, ultimately leading to altered, possibly transient and circadian, excitability in a multifaceted neurophysiological system. While further rigorous research and reproducible evidence are needed, these insights may contribute to the identification of new diagnostic markers and the development of innovative therapeutic strategies for RLS.