Elsevier

Sleep Medicine

Volume 15, Issue 10, October 2014, Pages 1225-1230
Sleep Medicine

Original Article
Restless legs syndrome and central nervous system gamma-aminobutyric acid: preliminary associations with periodic limb movements in sleep and restless leg syndrome symptom severity

https://doi.org/10.1016/j.sleep.2014.05.019Get rights and content

Highlights

  • First study to examine 1H-spectroscopy-derived levels of GABA in RLS.

  • No differences in GABA levels between patients with RLS and healthy controls.

  • Positive correlation of thalamic GABA with PLMI and self-reported RLS severity.

  • Negative correlation of cerebellar GABA with PLMI and self-reported RLS severity.

  • Elevated NAA levels in the ACC in RLS patients compared with controls.

Abstract

Background

Previous research has demonstrated abnormalities in glutamate and N-acetyl aspartate (NAA) in the thalamus in individuals with restless legs syndrome (RLS) compared with healthy matched controls. However, levels of these transmitters in other RLS-related brain areas and levels of the most common inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), have not been assessed.

Methods

This study examined GABA, glutamate, and NAA levels in the dorsal anterior cingulate cortex (ACC), thalamus and cerebellum with the use of proton magnetic resonance spectroscopy (1H-MRS) at 4 tesla (4 T) and Megapress difference-editing in 18 subjects with RLS and a matched control group without RLS. Actigraphy was performed on the nights before scans to assess periodic limb movements of sleep (PLMS).

Results

Levels of GABA, glutamate, and NAA were no different between RLS and control subjects in any of the three voxels of interest. However, GABA levels were positively correlated with both PLM indices and RLS severity in the thalamus and negatively with both of these measures in the cerebellum in RLS subjects. In addition, NAA levels were higher in the ACC in RLS than in controls.

Conclusion

Our preliminary data suggest that known cerebellar–thalamic interactions may modulate the intensity of RLS sensory and motor symptoms. In addition, anterior cingulate cortex may be associated with the affective components of the painful symptoms in this disorder.

Introduction

Restless legs syndrome (RLS) is characterized by an irresistible urge to move the legs, which is often associated with paresthesias. Central nervous systems (CNS) subserving sensory modulation, motor activity and pain appear to be altered in RLS [1]. In particular, leg discomfort and leg movements while awake in RLS are correlated with functional magnetic resonance imaging (fMRI)-related activation in the thalamus and cerebellum [2] , [3] . Similarly, enhanced dopaminergic binding [4] and a correlation of opioid binding with RLS disease severity [5] are seen in the thalamus in positron emission tomography (PET) studies in RLS. Ascending pain pathways project from the thalamus to the anterior cingulate cortex (ACC), which is involved in affective and cognitive aspects of pain [6]. ACC activity is abnormal in RLS by both fMRI [7] , [8]  and PET [4] , [5] .

Thalamic glutamate is 50% higher [9] and the neuronal marker N-acetyl aspartate (NAA) is reduced in the thalamus [10] in RLS using proton magnetic resonance spectroscopy (1H-MRS). To date, no study has reported levels of gamma-aminobutyric acid (GABA), the major CNS inhibitory neurotransmitter, in patients with RLS.

The primary aim of this study is to quantify GABA, glutamate, and NAA levels in the ACC, thalamus and cerebellum in patients with RLS and matched controls. Levels of these transmitters/metabolites will be correlated to RLS severity and to objective measures of sleep and leg movement activity.

Section snippets

Participants

Adult (aged >18 years) subjects were recruited from the greater Boston, MA, area from May 2010 to April 2012. RLS subjects met diagnostic criteria from the International RLS Study Group (IRLSSG) [11], had a history of RLS symptoms at least 15 nights in the previous month, or, if treated, this frequency of symptoms before treatment was started, and had a history of significant sleep disturbance due to RLS as indicated by a score of at least 2 on question 5 on the RLS severity scale. Age- and

Results

The RLS group (n = 18, all right-handed) was comprised of 10 women, with a mean age of 44.4 ± 15.0 (range, 18–64) years; the age- and sex-matched control group (one left-handed) had a mean age of 43.5 ± 14.3 (range, 19–64) years (Table 1). RLS subjects had duration of symptoms of 18.2 ± 16.1 years, with 14/18 reporting duration of symptoms ≥5 years (mean, 23.2 ± 15.8 years). Ten RLS subjects were taking medications for RLS prior to wash-out: eight on dopaminergic agonists, one on gabapentin and

Discussion

No group differences were found in GABA or glutamate levels between patients with RLS and matched healthy controls in the cerebellum, thalamus or ACC using 1H-MRS at 4 T. However, in exploratory analyses we did demonstrate relationships between GABA levels and both RLS severity and actigraphy-derived PLM indices in patients with RLS, with positive correlations observed in the thalamus and negative correlations in the cerebellum. In addition, NAA levels were elevated in the ACC in RLS patients

Funding sources

This research was supported by an investigator-initiated research grant from GlaxoSmithKline.

Conflicts of interest

The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2014.05.019.

. ICMJE Form for Disclosure of Potential Conflicts of Interest form.

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