Clinical Trial: Glutamate, Hyperarousal and Restless Legs Syndrome

Study Status: Completed
Recruit Status: Completed
Study Type: Observational

Official Title: Glutamate, Hyperarousal and Restless Legs Syndrome

Brief Summary:

Restless Legs Syndrome (RLS) research has focused on the sensory features and failed to address an important aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss without significant excessive daytime sleepiness. This hyperarousal produces RLS symptoms by overwhelming the normal inhibitory processes needed to decrease sensory and motor cortical activity for resting and sleep. Thus the hyperarousal produces both the RLS need to move when trying to rest and the inability to maintain sleep. The biological consequences of this hyperarousal process on sleep (increased wake time) and cortical excitability (as demonstrated by transcranial magnetic stimulation (TMS)) are postulated to reflect increased degree of excitatory glutamatergic activity, and therefore affected brain regions will show relatively increased glutamate (Glu) and glutamine (Gln) on MR spectroscopy (MRS). Changes in inhibitory activity and GABA may also occur, but less significantly than the increase in Glu/Gln. Our pilot MRS data discovered a new abnormality in RLS: increased Thalamic Glx (Glu + Gln) that correlated well with sleep measures of hyperarousal. Glx levels are not specific for the neurotransmitter role of Glu.

In this project RLS and matching controls subjects will be studied using polysomnograms (PSG) and TMS and 7T MRI for MRS that provides accurate measurement of Gln levels, which reflect mostly neurotransmitter Glu activity. The first aim is to confirm that Gln is increased in the thalamus and to determine if this also occurs in the motor and sensory cortices. The relation between Glu, Gln and GABA will also be evaluated. Second, assessments will be made of the degree of relation between Gln increase and the hyperarousal effects on sleep and cortical excitability (TMS). This would demonstrate that abnormally increased Glu activity is primary to RLS hyperarousal and radically chang

Detailed Summary: Moderate to severe Restless Legs Syndrome (RLS) is a major public health problem, significantly affecting 1.5 to 3% of adult Americans (3 - 7 million), resulting in profound sleep loss and an urge to move during sitting or resting in the later part of the day. Work productivity is decreased by 20%, quality of life is as bad or worse than that for other chronic diseases, e.g. arthritis and diabetes, and there is increased cardio-vascular disease risk. Current approved dopaminergic treatments fail to improve sleep time, engender impulsive behaviors and may make RLS worse. New treatments and new research directions to find them are needed. The current research focus on the sensory features has failed to address an important aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss without significant excessive daytime sleepiness. This hyperarousal produces RLS symptoms by overwhelming the normal inhibitory processes needed to decrease sensory and motor cortical activity for resting and sleep. Thus the hyperarousal produces both the RLS need to move when trying to rest and the inability to maintain sleep. The biological consequences of this hyperarousal process on sleep (increased wake time) and cortical excitability (as demonstrated by transcranial magnetic stimulation (TMS)) are postulated to reflect increased degree of excitatory glutamatergic activity, and therefore affected brain regions will show relatively increased glutamate (Glu) and glutamine (Gln) on MR spectroscopy (MRS). Changes in inhibitory activity and GABA may also occur, but less significantly than the increase in Glu/Gln. Our pilot MRS data discovered a new abnormality in RLS: increased Thalamic Glx (Glu + Gln) that correlated well with sleep measures of hyperarousal. Glx levels are not specific for the neurotransmitter role of Glu. In this project RLS and matching controls subjects will be studied using polysomnograms (PSG) and TMS and 7T MRI for MRS that provides accurate measurement of Gl
Sponsor: Johns Hopkins University

Current Primary Outcome:

• MR Spectroscopy - Glutamate [ Time Frame: 2nd Day of Phase 2 ]
  Study of thalamic glutamate levels in the brain using MR Spectroscopy
• MR Spectroscopy - GABA [ Time Frame: 2nd Day of Phase 2 ]
  Study of thalamic GABA levels in the brain using MR Spectroscopy

Original Primary Outcome:

Current Secondary Outcome:

Original Secondary Outcome:

Information By: Johns Hopkins University

Dates:
Date Received: August 27, 2012
Date Started: August 2012
Date Completion:
Last Updated: February 28, 2017
Last Verified: February 2017