Thalamic glutamate/glutamine in restless legs syndrome

Objective: To evaluate possible abnormal increase in thalamic glutamate/glutamine levels for restless legs syndrome (RLS) indicating increased glutamatergic activity producing arousal that at night disrupts and shortens sleep. Methods: 1H MRS of the right thalamus was performed using a 1.5 T GE MRI scanner and the PROBE-P (PRESS) on 28 patients with RLS and 20 matched controls. The Glx signal (combination of mostly glutamate [Glu] and glutamine [Gln]) was assessed as a ratio to the total creatine (Cr). This study tested 2 primary hypotheses: 1) higher thalamic Glx/Cr for patients with RLS than controls; 2) thalamic Glx/Cr correlates with increased wake during the sleep period. Results: The Glx/Cr was higher for patients with RLS than controls (mean ± SD 1.20 ± 0.73 vs 0.80 ± 0.39, t = 2.2, p = 0.016) and correlated significantly with the wake time during the sleep period ( r = 0.61, p = 0.007) and all other RLS-related polysomnographic sleep variables ( p < 0.05) except for periodic leg movements during sleep (PLMS)/hour. Conclusions: The primary findings introduce 2 new related dimensions to RLS: abnormalities in a major nondopaminergic neurologic system and the arousal disturbance of sleep. The strong relation of the arousal sleep disturbance to glutamate and the lack of relation to the PLMS motor features of RLS contrasts with the reverse for dopamine of a limited relation to arousal sleep disturbance but strong relation to PLMS. Understanding this dichotomy and the interaction of these 2 differing systems may be important for understanding RLS neurobiology and developing better treatments for RLS. Cho= : choline-containing compounds; Cr= : creatine/phosphocreatine; Gln= : glutamine; Glu= : glutamate; Glx= : glutamine plus glutamate; 1H MRS= : proton magnetic resonance spectroscopy; mI= : myo-inositol; NAA= : N -acetylaspartate; PLMS= : periodic leg movements during sleep; PSG= : polysomnography; RLS= : restless legs syndrome; SWS= : slow-wave sleep; VMB= : ventral midbrain; WDSP= : wake during the sleep period