Central and peripheral excitability in restless limbs syndrome

Restless limbs syndrome (RLS) is a neurological disorder characterized by an uncontrollable urge to move the limbs. Although it affects up to 10% of the general population, its underlying mechanisms remain poorly understood. Neurophysiological excitability testing may help elucidate mechanisms related to sensorimotor integration, axonal ion channel dysfunction and impaired neural inhibition. This study aimed to assess both CNS and PNS function by examining cortical, spinal and peripheral nerve excitability within the same individuals for the first time. To investigate potential widespread excitability changes in RLS, we specifically analysed hand muscles, offering new insights into the extent of neural involvement beyond the lower limbs. The study included 56 RLS patients, divided into treated and untreated groups, along with 32 healthy controls. Notably, none of the patients experienced symptoms in their hands. Cortical excitability was assessed via threshold-tracking transcranial magnetic stimulation (TMS) to evaluate intracortical inhibition and facilitation. Sensory-motor integration was measured via long-latency reflexes (LLRs), while spinal cord excitability was assessed using F-waves, H-reflexes and RIII-reflexes. Axonal excitability was examined using the extended TRONDNF protocol. TMS revealed a significant reduction in short-interval intracortical inhibition (SICI) in patients, particularly at inter-stimulus intervals (ISIs) of 2.5 and 3 ms. When averaging across ISIs from 1 to 7 ms, patients on medication exhibited significantly less inhibition compared to healthy controls. Long-interval intracortical inhibition (LICI) was also reduced at ISIs of 150 and 200 ms, while facilitation parameters remained within normal ranges. Patients exhibited increased amplitude of the second component of the LLR recorded from the abductor pollicis brevis, whereas RIII reflex measurements showed no significant differences. Axonal excitability testing revealed a graded increase in hyperpolarization-activated currents in patients with more severe symptoms. The observed reductions in SICI and LICI suggest impaired intracortical inhibition in the M1 hand area, offering indirect evidence of cortical dysfunction in regions clinically unaffected by the disease. The increased LLR amplitudes further indicate altered sensorimotor integration at the cortical level, whereas the absence of significant changes in RIII reflexes suggests that segmental spinal dysfunction within the pain pathway of the upper limbs is unlikely. Finally, axonal excitability findings point to a potential role of hyperpolarization-activated currents in either contributing to or predisposing individuals to RLS symptoms.