Cortical spectral rebalancing underlies pregabalin's efficacy in restless legs syndrome

Abstract

Restless legs syndrome afflicts nearly half of all patients with end-stage renal disease, imposing profound burdens through relentless insomnia and functional decline. Dopaminergic agents--the established first-line therapy--trigger augmentation, a paradoxical intensification of symptoms that leaves patients worse than when they began treatment. The resultant therapeutic impasse has left a vulnerable population without effective recourse. Here we demonstrate that pregabalin, an 2{delta} calcium channel ligand with established renal safety, provides robust and sustained symptom relief in a randomized, placebo-controlled trial of dialysis patients with uremic restless legs syndrome. Clinical benefits emerged rapidly and intensified over three months, with pregabalin-treated patients showing more than twofold greater likelihood of categorical improvement in disease severity. In complementary animal electrophysiology experiments, pregabalin distinctively suppressed cortical hyperarousal--a hallmark of restless legs syndrome--by rebalancing low- and high-frequency oscillatory activity patterns, particularly in motor regions. This neural signature closely resembled that of gabapentin, another therapeutically effective 2{delta} ligand, suggesting convergent mechanisms. Beyond establishing pregabalin as an urgently needed alternative to dopaminergic therapy, our results demonstrate that cortical oscillatory profiling can reveal mechanistic convergence among candidate therapeutics, offering a rational preclinical screening strategy for neurological disorders before exposure of high-risk patient populations to experimental interventions. This framework may accelerate therapeutic discovery while reducing clinical trial risks in vulnerable populations.