Original ArticleConnecting clinical aspects to corticomotor excitability in restless legs syndrome: a TMS study
Introduction
More than six million Americans suffer from moderate-to-severe restless legs syndrome (RLS). Many of these individuals report significant disability, reduced work productivity, diminished quality of life, and increased depression and anxiety [1], [2], [3], [4]. Clinical studies have reported that patients with RLS have a greater sustained alertness than expected for their degree of sleep loss [5]. This clinical feature is more or less similar to what has been postulated to underlie primary insomnia, where the term “hyperarousal” has been used to describe the increased wake time during the night without significant symptoms of daytime sleepiness. To date, RLS research has primarily focused on leg symptoms and movements and ignored the major RLS feature “hyperarousal” that may actually drive the primary symptoms [4].
Notably, RLS has been shown to be associated with increased excitability and reduced inhibition at different levels within the nervous system [6], [7], [8]. The use of transcranial magnetic stimulation (TMS) paired-pulse protocols to measure short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) [9], [10], [11], and intracortical facilitation (ICF) has allowed for the evaluation of intracortical excitatory and inhibitory circuitry in RLS. Most of the previous studies on RLS using TMS have reported diminished inhibition (reduced SICI), with one study reporting increased ICF, thus suggesting an overall increased excitability and supporting hyperarousal. However, among prior studies on RLS using TMS, not all have had consistent results and these studies have been limited regarding RLS populations, study methods, and sample sizes. Additionally, most prior TMS studies that reported increased corticomotor excitability in RLS were primarily focused on the motor cortex of the hand [8], [12], [13], [14], [15], [16]. There are only two studies that performed paired-pulse TMS [17], [18] in the leg, which is the primary appendage affected by RLS. Most of the previous studies also did not consider the clinical aspects of RLS. Thus, putative mechanisms regarding cortical excitability, particularly for the leg motor cortex, underlying RLS, and the relationship of cortical excitability with clinical aspects of RLS, remain unclear.
This study, therefore, studied corticomotor excitability in the primary motor cortex (M1) of the hand and leg, along with examining the relationship to the clinical aspects of RLS and sleep parameters. Participants with RLS were compared to age-matched healthy good sleeper control participants who did not have significant periodic limb movements during sleep (PLMS) or a family history of RLS. The paired-pulse TMS measures SICI and LICI (extending on previous work) [9], [10], [11], were evaluated. The study also evaluated ICF, which is believed to predominately reflect glutamatergic-mediated excitability along with GABAergic processes [19]. The study was designed to test the hypothesis of basic glutamate-hyperarousal process producing both disrupted sleep (increased wake time) and corticomotor excitability (as demonstrated by TMS).
Section snippets
Participants
This study was approved by the Johns Hopkins Medicine Institutional Review Board, and participants provided written consent and were compensated. Thirty-five participants (20 F; mean age: 59.23 ± 1.66 years; range: 42–78 years) affected by primary RLS (off medications) and 31 age-matched controls (19 F; mean age: 57.90 ± 1.50 years; range: 43–79 years) were included in the study. Both right- and left-handed participants were included, but all participants had strong hand dominance, and none
Day 1 and day 2: sleep studies
Study participants were admitted to the Clinical Research Unit, an inpatient research unit that includes the Center in Sleep Research and Education (CISRE), and they completed the study in the next three days (Fig. 1). Participants had height, weight, and vitals recorded, and premenopausal female participants completed a urine pregnancy test to rule out possible pregnancy cases. All participants underwent for two nights inpatient sleep monitoring that consisted of full PSG at CISRE. Bed times
Data analysis
MEP amplitudes were analyzed using MATLAB 2013a scripting to automate data extraction. Ratios of the conditioned pulse MEP amplitude to the test pulse MEP amplitude were calculated for SICI, LICI, and ICF measures. The primary hypothesis that RLS participants and controls showed significant differences in cortical excitability was evaluated for both the ratios of conditioned to test pulse MEP and the rMT. A secondary hypothesis of differences in excitability for augmented vs. nonaugmented
Results
There were no significant differences in age, ethnicity/race, or education level between controls and RLS groups that had the leg or hand TMS (Table 1). As expected, there were significant differences between controls and RLS groups for sleep assessments on PSQI score and PSG (Day 1 and Day 2) standard indices [ie, sleep efficiency, total sleep time, and wake after sleep onset (WASO); Table 1]. There were no significant differences in the Day 1 and Day 2 initial sleep latency between the
Summary
The results of this study support the putative altered corticomotor excitability in the neurobiology of RLS, which has generally been presented as an overall increase in corticomotor excitability. The two major TMS findings here, however, show an interesting difference between leg and hand excitability, with strong indications for increased corticomotor excitability in M1leg but decreased in M1hand. The increased M1leg corticomotor excitability is further supported by decreased rMT for the leg,
Conclusion
The present study fundamentally furthers understanding into the neurobiology of the corticomotor excitability of RLS. Specifically, M1 representation of the leg shows evident hyperexcitability that appears related to RLS disease severity. By contrast, the M1 hand in this study shows decreased excitability with no indication of the expected hyperarousal from RLS. This important difference provides insight into a significant and somewhat puzzling clinical feature, ie, RLS symptoms are limited to
Funding
This work was supported by a National Institutes of Health (NIH) grant – R01 NS075184. Sleep study data were collected and managed by the Center for Interdisciplinary Sleep Research and Education (cisre.jh.edu).
Acknowledgment
The authors thank the staff of the Clinical Research Unit at Johns Hopkins Bayview Medical Center and Ms. Paula David for her assistance in editing and formatting of this manuscript.
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