Original ArticleRestless legs syndrome and central nervous system gamma-aminobutyric acid: preliminary associations with periodic limb movements in sleep and restless leg syndrome symptom severity
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.
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2020, Sleep MedicineCitation Excerpt :RLS/WED is a complex network disorder that likely spans from dopaminergic dysfunction [6–9] to multiple neurotransmitter systems [10]. It has also been suggested that RLS/WED may be caused by iron deficiency in the brain [11]; loss of inhibitory modulation over descending central motor pathways [12–15]; structural changes in the motor [16] and somatosensory cortices [17,18]; thalamic structural [19] and functional alterations [20–25]; cerebellar abnormalities [25–33]; dysfunctional connectivity between motor and sensory areas, as well as subtle abnormalities in white matter micro-organization [34]. Moreover, potential roles of central sensory processing deficits [32,35–37] and impaired sensorimotor integration [38–40] have been hypothesized as candidate causes of RLS/WED [10].