Sleep Medicine
Volume 11, Issue 1 , Pages 75-81, January 2010

Changes of cortical excitability after dopaminergic treatment in restless legs syndrome

  • Anna Scalise

      Affiliations

    • Department of Neurosciences, S. Maria della Misericordia University-Hospital, Udine, Italy
    • Corresponding Author InformationCorresponding author. Address: Department of Neurosciences, S. Maria della Misericordia Hospital, P.le S. Maria della Misericordia 15, 33100 Udine, Italy. Tel.: +39 0432552565; fax: +39 0432552719.
    • ,
  • Italo Pittaro-Cadore

      Affiliations

    • Department of Neurosciences, S. Maria della Misericordia University-Hospital, Udine, Italy
    • ,
  • Francesco Janes

      Affiliations

    • DPRSC, University of Udine, Italy
    • ,
  • Roberto Marinig

      Affiliations

    • Department of Neurosciences, S. Maria della Misericordia University-Hospital, Udine, Italy
    • ,
  • Gian Luigi Gigli

      Affiliations

    • DPRSC, University of Udine, Italy

Received 7 January 2009; received in revised form 27 April 2009; accepted 1 May 2009.

Article Outline

Abstract 

Objective

Dopaminergic pathways are most likely involved in the pathophysiology of restless legs syndrome (RLS). In previous investigations, an alteration of cortical excitability was suggested to be related to a dopaminergic dysfunction in RLS. The purpose of our study was to compare practice-dependent plasticity in RLS patients before and after a month of dopaminergic treatment.

Methods

Single-pulse transcranial magnetic stimulation (TMS) was used to define motor evoked potential (MEP) amplitude, motor threshold, and silent period (SP) as well. Subjects performed three exercise blocks (bimanual motor task). MEP amplitude, registered immediately after each exercise block and after a rest period, was compared to baseline. The time course of intra-cortical inhibition was tested using paired-pulse TMS at short inter-stimulus intervals. For the single-pulse TMS procedures, we enrolled 12 patients affected by primary RLS and 12 normal subjects. For the paired-pulse TMS procedures, only six patients underwent the examination. RLS patients underwent the examination in both pre- and post-dopaminergic treatment conditions.

Results

In RLS patients MEP amplitude increased after the rest period only in the post-treatment condition, showing a delayed facilitation. After exercise, MEP amplitude increased, but not enough to be significant, showing a positive trend but not a clear-cut post-exercise facilitation. In the pre-treatment condition instead, MEP amplitude did not change either after rest period or after exercise.

RLS patients showed a marked increase of the central motor inhibition, assessed by using paired-pulse TMS at short inter-stimulus intervals after pramipexole treatment. On the contrary, the duration of the SP did not change compared to the pre-treatment condition.

Conclusions

In RLS patients after dopaminergic treatment, the main finding was the changing of MEP amplitude after rest following a motor task. Since dopaminergic treatment can reverse delayed facilitation in RLS, we hypothesized that cortical plasticity related to dopaminergic systems may play a crucial role in RLS pathophysiology.

Keywords: Restless legs syndrome, Transcranial magnetic stimulation, Cortical plasticity, Cortical excitability, Delayed facilitation, Sleep, Dopamine, Movement disorders

 

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1. Introduction 

Patients affected by restless legs syndrome (RLS) usually complain of an unpleasant sensation in the legs and sometimes in the arms, which becomes evident during evening and night rest, associated with an irresistible urge to move. As no laboratory or RLS-specific clinical tests are available, diagnosis is based on the presence of specific clinical symptoms. Likewise, the exact pathophysiology of RLS still remains unknown [1], [2].

The dopaminergic system seems to be involved in the pathophysiology of RLS mainly because dopamine-receptor agonists can successfully treat the symptoms of RLS [2], [3], [4] and also because a variety of alterations in dopaminergic function has been demonstrated in RLS patients. Some of these alterations have also been found through positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) [5], [6]. These findings, however, are not peculiar in RLS; in fact, they can also be observed in other clinical conditions. Transcranial magnetic stimulation (TMS) may be used to study the movement-related cortical plasticity and the intra-cortical inhibition both in healthy and unhealthy subjects. In healthy subjects, motor evoked potential (MEP) amplitude increases immediately after a brief period of exercise (“post-exercise facilitation” phenomenon) and then increases again after a rest period of 15min following a defined motor task (“delayed facilitation” phenomenon) [7], [8], [9], [10]. The mechanism for post-exercise facilitation is thought to be due to a transient increase of excitability in the motor cortex [7], [8]. The delayed facilitation seems to reflect an intra-cortical synaptic reorganization consequent to the performance of repetitive motor tasks [9], [10]. Although the mechanism underlying this form of cortical plasticity remains to be determined, we suggested that the motor task could induce enduring changes in synaptic strength, in this way improving motor learning [9], [10]. In healthy subjects, the presentation of a conditioning TMS pulse shortly before a test pulse reduces MEP amplitude of the test pulse itself, which could be interpreted as an expression of the intra-cortical inhibition [11]. In addition, immediately after the MEP, muscle contraction is followed by a period of electrical silence that causes discontinuation of the ongoing EMG activity; this phenomenon is named “silent period.” The silent period may be considered an indicator of inhibitory activity within primary motor cortex [12], [13], [14]. A few studies have used TMS to investigate the central motor system in RLS patients [15], [16], [17], [18], [19], [20]. Despite some inconsistencies, the authors conclude that the pyramidal tract is intact in RLS patients, whereas the motor cortical excitability is altered, suggesting a cortical–subcortical origin of the disease. Methodological differences may account for some of the inconsistency among the studies. In particular, in our studies [19], [20], we showed some modifications in movement-related cortical plasticity and intra-cortical inhibition. In RLS patients, we demonstrated the absence of delayed facilitation, the absence of post-exercise facilitation, a shortening of the silent period and a reduction of intra-cortical inhibition as well.

We speculated that the above mentioned findings, identified in RLS patients by means of TMS, could be related to an alteration of the cortical plasticity resulting from a dopaminergic dysfunction [19].

We compared motor cortex excitability in RLS patients in basal condition and after a month of pramipexole therapy (a non-ergot dopaminergic agonist) to confirm these hypotheses and to determine whether dopaminergic treatment can restore normal TMS findings in RLS.

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2. Methods 

2.1. Patients 

Twelve right-handed patients (8 women and 4 men, mean age 52.67±10.9years), affected by primary (idiopathic) RLS, were included in our study and submitted to TMS. A complete neurophysiologic investigation (electromyography with nerve conduction study, F waves, soleus H reflex) was carried out in all patients in order to exclude peripheral nervous system involvement. All RLS patients fulfilled the criteria for a diagnosis of primary RLS according to the International RLS Study Group criteria [1], [2]. Patients had never previously taken any medications known to affect the TMS results; in particular, they had never been treated with dopaminergic or anti-dopaminergic drugs before the study. All patients had experienced symptoms compatible with a diagnosis of RLS for at least 1year. Pramipexole was administrated over a period of 4weeks. The starting dose was 0.125mg/day, which was then doubled in 1–2weeks (final dose 0.25mg/day). Patients received treatment once daily, 1 or 2h before bedtime. All patients tolerated the treatment without major adverse events or complaint. Signed informed consent forms were obtained from all subjects.

2.2. Controls 

A control group included 12 age- and sex-matched (6 women and 5 men, mean age 49.4±3.1years), right-handed normal subjects who were drug free with no history of neurologic problems or psychiatric illness.

2.3. Transcranial magnetic stimulation 

Transcranial magnetic stimulation (TMS) was performed with a MagLite-r25-Twin Top, Medtronic A/S biphasic stimulator (Copenhagen, Denmark) using single- and paired-pulse procedures. We stimulated the non-dominant hemisphere because we observed that delayed facilitation in healthy subjects is limited to this hemisphere (personal observations) [10] and also because an inter-hemispheric asymmetry in the excitability of cortical inhibitory mechanisms has been demonstrated [21].

According to the experimental design, the assessment of patients’ motor cortex excitability was performed separately in two different conditions: basal (pre-treatment condition) and after a month of dopaminergic therapy (after-treatment condition). In both conditions, in order to prevent the effect of circadian factors, evening somnolence, peak of RLS symptoms, and acute effect of pramipexole, the recording sessions were always performed late in the morning following a full night of spontaneous sleep. In order to avoid vigilance fluctuations, the subjects under TMS session were asked by the investigator to remain on alert with open eyes, but in a relaxed body condition.

The controls were studied only in basal condition.

2.4. Experimental procedures 

The TMS protocols we performed have already been described in detail in a recent paper [19].

In summary, the following three experimental sessions were performed for each condition (pre-treatment and post-treatment). (1) Evaluation of MEPs parameters: motor threshold, MEP amplitude, and silent-period duration were measured in response to single-pulse magnetic stimulation [12], [13], [19]. (2) Motor task: MEPs were recorded in response to single magnetic stimuli after a motor task [9], [10], [19], [20]. (3) Paired-pulse stimulation: the time course of intra-cortical motor activity was tested using pairs of magnetic stimuli (1–6-ms inter-stimulus intervals) [11], [19].

2.4.1. Single-pulse TMS: MEP amplitude, motor threshold, and silent period 

MEPs were recorded from the first dorsal interosseous muscle of the left non-dominant hand via surface electrodes applied in a belly-tendon montage. A round coil (90mm) was used, and the lateral edge was placed over the presumed hand area. The coil handle was held backward in a lateral (45°) direction from the inter-hemispheric line [11], [13], [19]. The optimal scalp position was determined by moving the coil in 1-cm steps over the presumed hand motor area. The site where the optimal MEP amplitude was elicited during muscle relaxation with the lowest threshold was marked and used for later testing. For motor threshold measurement, MEPs were recorded during relaxation of the target muscle [13], [16]. A moderate contraction allowed the detection of both MEP and silent-period parameters in the 500ms following TMS. Stimulus intensity during testing was determined by adding intensity equal to 5% of the maximum stimulus output above the motor threshold. The mean of three consecutive trials was used to define the following parameters:

•Motor threshold (%), defined as the intensity required to elicit detectable MEPs with amplitudes of 0.05–0.15mV in 50% of the stimuli. It was expressed as the percentage of the stimulator’s maximal output [13].

•MEP amplitude (mV), defined as the peak-to-peak amplitude between the largest negative and positive deflections following stimulus onset [13].

•Silent-period duration (ms), measured from the MEP to the rebound of voluntary electromyogram (EMG) activity (absolute duration of silent period) [14], [15], [19]. The EMG was recorded with 0.5-mV gain sensitivity, and the analysis time ranged from 200 to 500ms.

2.4.2. Single-TMS: MEPs to single stimuli after a bimanual motor task 

Motor cortex excitability was tested in three conditions: baseline, after exercise, and after rest [9], [10], [19], [20]. After each condition, three test pulses were presented at 2- to 3-s intervals (105% of motor threshold) during brief tonic contractions of the index finger onto the thumb. MEPs were measured from the first dorsal interosseous muscle of the left hand. During the baseline condition, subjects were tested after lying quietly and comfortably on a padded examination table for at least 30min. In the exercise condition, subjects performed bilateral, repetitive opening and closing movements of the index finger toward the thumb with both digits extended (3–4 movements per second). Subjects were given feedback if they performed too quickly or too slowly. Three different exercise periods (lasting 30, 60, and 90 s, respectively) were given to the subjects in progressive order (i.e., first session: 30 s; second session: 60 s; third session: 90 s). The inter-trial intervals between the different exercise blocks lasted about 1min. In the rest condition, TMS pulses were delivered after subjects had lain quietly and comfortably on a padded examination table for 15min without moving their fingers. The mean of the three MEPs obtained in each trial was used as a measure of MEP amplitude for the baseline period immediately after exercise (lasting 30, 60, and 90 s) and after the 15-min rest period. MEP amplitude of each exercise period and rest period was expressed as a percentage of the baseline MEP amplitudes. The subjects were instructed to perform the contraction of the target muscle with about 20% of their maximal force. We chose this level because TMS measures of post-exercise facilitation are similar when tested between 10% and 50% of the maximum force [7]. The ongoing EMG activity of the target muscle was monitored acoustically and visually on the oscilloscope. The investigators listened to the contractions and observed them, providing feedback to the subject if the level of EMG was judged to be either excessive or insufficient. The ongoing EMG activity during the task was similar in the groups.

2.4.3. Paired-pulse TMS: time course of intra-cortical inhibition 

Due to the lack of compliance for too long experimental procedures, only six of the 12 patients completed this part of the experimental study. MEPs were recorded through surface electrodes applied upon the opponent pollicis muscle, contra-lateral to the stimulated hemisphere, during complete relaxation of the target muscle. A focal butterfly-shaped coil was held tangential to the skull with the handle pointing backward at 45° lateral to the midline. Usually the “optimal” responses were elicited when the coil was placed 5–6cm along the coronal line from Cz point (10–20 International System). A conditioning-test design was used to investigate the time course of MEP inhibition. Paired stimuli were applied with conditioning pulses, delivered, respectively, 1, 2, 3, 4, 5, or 6ms before test stimulation. The intensity of the conditioning pulse was maintained below the threshold (70% of the individual resting motor threshold for evoking responses in contracted muscles). Test pulses were delivered above threshold (120–110% of the individual resting motor threshold for eliciting relaxed MEPs). In each block, test and conditioning pulses at the different inter-stimulus intervals were randomly mixed. Several blocks of trials were performed in order to achieve a complete set of inter-stimulus intervals. Each block included 16 trials, 8 having the test stimulus alone (unconditioned MEP) and 8 having pairs of conditioning-test pulses delivered at 1 of the 6 inter-stimulus intervals (conditioned MEP). The sequence began and ended with the unconditioned trials, with the conditioned MEP trials in between. Mean amplitude of unconditioned and conditioned MEPs were calculated separately for each inter-stimulus interval. The amplitude of conditioned MEPs was expressed as the percentage of unconditioned MEPs amplitude. The time course was defined as the mean amplitude variation of conditioned MEPs (expressed as the percentage of unconditioned MEPs amplitude) at each inter-stimulus interval.

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3. Data analysis 

3.1. Patients’ pre-treatment vs. post-treatment conditions 

3.1.1. Single-pulse TMS: MEPs, motor threshold, and silent period 

Pre-treatment vs. post-treatment differences regarding motor threshold, MEP amplitude, and silent-period duration were measured using paired t-tests.

3.1.2. Single-pulse TMS: MEPs after a bimanual motor task 

Single sample t-tests were performed for each time point in each condition in order to determine if MEP amplitudes were significantly different from baseline. Pre-treatment vs. post-treatment differences regarding MEP amplitude at the four time points along the motor task (baseline, immediately after each of the exercises and after rest) were measured using paired t-tests. Analysis of variance was performed by one-way ANOVA with repeated measures in order to evaluate the MEP amplitude changes along the motor task using the factors of conditions (pre-treatment vs. post-treatment) and time (baseline, immediately after each of the exercises and after rest).

3.1.3. Paired-pulse TMS: time course of intra-cortical inhibition 

Condition differences (pre-treatment vs. post-treatment) in the time course of cortical inhibition were assessed using a 2 (condition)×inter-stimulus interval (1, 2, 3, 4, 5, 6ms) repeated measure ANOVA. To examine the condition×time course interaction, separate ANOVA measures were performed for each condition using inter-stimulus interval as the within-condition factor.

Condition differences (pre-treatment vs. post-treatment) at each inter-stimulus interval were measured using paired t-tests.

3.2. Patients vs. controls 

3.2.1. Single-pulse TMS: MEPs, motor threshold, and silent period 

Controls vs. patient differences for each condition regarding motor threshold, MEP amplitude, and silent-period duration were measured using paired t-tests.

3.2.2. Single-pulse TMS: MEPs after a bimanual motor task 

Single sample t-tests were performed for each time point in the control group in order to determine if MEP amplitudes were significantly different from baseline. Controls vs. patient differences for each condition regarding MEP amplitude at the four time points along the motor task (baseline, immediately after each of the exercises and after rest) were measured using paired t-tests. Analysis of variance was performed by one-way ANOVA with repeated measures in order to evaluate the MEP amplitude changes along the motor task using the factor of time (baseline, immediately after each of the exercises and after rest).

The assumption of sphericity was evaluated using the Mauchly test, and a Huynh–Feldt correction was used when necessary. When the Huynh–Feldt correction was applied, the original degrees of freedom and corrected P-values were reported. Post hoc tests among the means were performed using paired t-tests adjusted for the number of comparisons (Fisher protected least significant difference).

Differences at P⩽0.05 were considered significant.

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4. Results 

4.1. Patients’ pre-treatment vs. post-treatment conditions 

4.1.1. Single-pulse TMS: MEPs, motor threshold, and silent period 

Comparisons between pre-treatment and post-treatment conditions showed no significant differences for motor threshold intensity (47.6±6% vs. 45.5±6.7%, respectively) (t=1.37, df=11; P=0.20) or MEP amplitude (7.5±2.57mV vs. 8.1±2.7mV, respectively) (t=1.16, df=11; P=0.27) or silent-period duration (62.0±21.9ms vs. 62.6±20.2ms, respectively) (t=1.73, df=8; P=0.87).

4.1.2. Single-pulse TMS: MEPs after a bimanual motor task 

MEP amplitudes in pre-treatment and post-treatment conditions at the four time points in the bimanual task conditions (30s, 60s, 90s, and 15-min rest) are shown in Fig. 1.

  • View full-size image.
  • Fig. 1. 

    Single-pulse transcranial magnetic stimulation (TMS). Motor evoked potential (MEP) amplitude elicited from the first dorsal interosseous muscle in the pre-treatment condition and in the post-treatment condition, tested at different times following a bimanual motor task. Note that only in the post-treatment condition is present a significant increment of MEP amplitude after the rest period (delayed facilitation). Standard error bars are shown.

The major findings were in the post-treatment condition MEP amplitudes after rest which showed a significant increase in amplitude (mean diff.=13.29% increase; df=11; t=2.96; P=0.01), indicating the presence of the delayed facilitation, and t-tests comparing the conditions at each time point showed significant differences in MEP amplitude in the after rest points (t=4.05, df=11; P<0.01), with larger MEPs in the post-treatment condition.

Besides, in the post-treatment, MEP amplitude was larger than baseline immediately after the 30-s (mean diff.=13.48% increase; df=11; t=1.84; P=0.09) and 60-s (mean diff.=9.67% increase; t=1.60; df=11; P=0.13) time periods, but insufficient to obtain statistical significance for post-exercise facilitation. There were no significant differences from baseline after the 90-s time period (mean diff.=0.19%; df=11; t=0.04; P=0.97).

In pre-treatment condition, MEP amplitude was not significantly different from baseline at any time point (Fig. 1), indicating an absence of post-exercise facilitation and delayed facilitation at the time periods tested.

Repeated ANOVA measures showed no significant main effect of condition (F(1,22) = 0.26; P=0.61).

4.1.3. Paired-pulse TMS: time course of intra-cortical inhibition 

MEP amplitudes to test stimuli as a function of inter-stimulus interval for both conditions are shown in Fig. 2. Repeated ANOVA measures showed a significant effect of condition (F(1,10)=17.33; P=0.002). In post-treatment condition, there was a significant effect of inter-stimulus interval (F(5,25)=3.95; P=0.009). By contrast, the pre-treatment condition showed no significant effect of inter-stimulus interval. Post hoc t-tests comparing the groups at each inter-stimulus interval showed significant group differences at 3-ms (t=4.79; df=5; P=0.005), and 4-ms (t=2.47; df=5; P=0.05) inter-stimulus intervals.

  • View full-size image.
  • Fig. 2. 

    Paired-pulse transcranial magnetic stimulation (TMS). The average time course at different inter-stimulus intervals (ISI) in the pre-treatment and post-treatment conditions. At each ISI, the size of the conditioned motor evoked potential (MEP) is expressed as a percentage of the size of the unconditioned MEP alone. Significant inhibition of the conditioned MEP is present only in the post-treatment condition. Standard error bars are shown.

4.2. Patients vs. controls 

4.2.1. Single-pulse TMS: MEPs, motor threshold, and silent period 

Comparisons between controls and patients in pre-treatment and post-treatment, respectively, showed no significant differences in age (t=1.1; df=11; P=0.29), motor threshold intensity (46.5±5.6% vs. 47.6±6%, and 46.5±5.6% vs. 45.5±6.7%, respectively) (t=0.55, df=11; P=0.58, and t=0.44, df=11; P=0.66), or MEP amplitude (7.23±1.17mV vs. 7.5±2.57mV, and 7.23±1.17mV vs. 8.1±2.7mV, respectively) (t=0.28, df=11; P=0.77, and t=0.99, df=11; P=0.34). But silent-period duration in the control group was significantly lengthened compared to the RLS patients in both conditions (83.1±13.2ms vs. 62.0±21.9ms, and 83.1±13.2ms vs. 62.6±20.2ms, respectively) (t=2.32, df=8; P=0.049, and t=2.38, df=8; P=0.044).

4.2.2. Single-pulse TMS: MEPs after a bimanual motor task 

Control subjects showed a significant effect of exercise time (F(4,40)=7.4; P<0.001). Post hoc t-tests comparing the groups at each time point showed significant differences in MEP amplitude in the rest block (t=4.1, df=20; P<0.01), with controls having larger MEPs than the RLS group in both conditions. In the control group, MEP amplitudes were significantly larger than baseline immediately after the 30-s (t=4.33, df=11; P=0.001) and 60-s (t=3.28, df=11; P=0.007) time periods, indicating post-exercise facilitation. There were no significant differences from baseline after the 90-s time period (t=0.69, df=11; P=0.95). For controls, MEP amplitudes after rest also showed a significant increase in amplitude (t=0.5, df=11; P<0.001), indicating delayed facilitation.

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5. Discussion 

5.1. Delayed facilitation and post-exercise facilitation 

The results obtained by comparing controls and patients confirm the findings of our previous paper [19]. The purpose of this study was to examine motor cortex excitability in RLS patients before and after a month of dopaminergic treatment. After treatment, the major finding was that MEP amplitude increased after a period of 15-min rest following the bimanual motor task, showing a significant delayed facilitation. In the post-treatment condition, after short blocks (30 and 60 s) of bimanual movements, the MEP amplitude increased, but not enough to be significant, so we did not find a clear post-exercise facilitation, but only a positive trend. The increase of MEP amplitude after treatment, although not significant, suggests that practice-dependent modifications of cortical excitability may be possible.

The physiology of delayed facilitation is not completely clarified, but it seems to involve enduring changes in synaptic strength. In fact, during a motor task, the repeated activation of excitatory synapses in the central nervous system may possibly change the neural circuit dynamics and modify cortical excitability [22], [23], [24], [25], [26]. The induced short-term potentiation, long-term potentiation, and/or unmasking of existing synapses onto motor cortex neurons represent the neural substrates of physiological learning processes, an important mechanism of practice-dependent plasticity [27].

Repetitive TMS (rTMS) and interventional-paired associative stimulation (IPAS) techniques can give the possibility of delivering tetanic stimulation to awaken healthy human subjects. The tetanic effect obtained in this way can induce long-lasting changes in motor cortical output, which is possibly linked to LTP-like plasticity processes. The amplitude of MEPs from the hand muscles as a result of rTMS and IPAS can significantly increase for many minutes [28], [29], [30]. Similarly, the motor task we adopted may repetitively activate the synapses in the central nervous system, inducing LTP-dependent process. Consequently, the delayed facilitation we observed may be the functional evidence of intra-cortical synaptic reorganization, a main mechanism for motor skill learning. The absence of a delayed facilitation in non-treated RLS patients has been interpreted as a reduction or alteration in cortical plasticity; instead the change in cortical excitability after a month of therapy suggests the dopaminergic treatment may restore a more effective movement-related cortical plasticity in RLS patients. As healthy controls were not treated with pramipexole, we cannot exclude the possibility that dopamine-agonists might increase the after-rest facilitation also in healthy subjects. To minimize this bias, patients were examined late in the morning, after wash-out of the drug from circulation. In this way, we hope to have avoided acute and direct effects of the drug.

5.2. Paired-pulse inhibition and silent-period duration (SP duration) 

Following pharmacological treatment, RLS patients show a marked increase of central motor inhibition, assessed by using paired-pulse TMS at short inter-stimulus intervals. On the contrary, the duration of the silent period from muscles of the upper limbs was unchanged in RLS patients after treatment compared to the pre-treatment condition. These results confirm the findings of a recent study by Nardone et al. [31]. Kutukcu et al. [32] demonstrated that SP duration, registered from the upper limb muscles in RLS patients after a month of dopaminergic treatment (levodopa or cabergoline or ropinirole), showed no significant difference, whereas SP duration registered from the lower limb muscles showed a significant prolongation. They did not find any difference in SP duration between upper and lower limbs at basal condition (drug free); the reason SP duration became longer after treatment only in the muscles of the legs remains unclear. Gosler and Liepert reported similar results in a recent paper [33]. They found that SP duration, registered from the anterior tibial muscle, can be normalized by carbergoline treatment only within the first 2weeks. Apparently, without justification, after 90days of therapy the SP tended to shorten again.

Our results support the hypothesis that the dopaminergic system plays a crucial role in the motor cortex inhibitory circuits, but different subtypes of inhibitory interneurons may be involved.

5.3. TMS findings, dopamine and RLS 

It is well known that dopamine-receptor agonists can successfully alleviate clinical symptoms of RLS [2], [3], [4]. Dopaminergic drugs are currently considered the first choice therapy for this illness. Treatment with dopamine agonists or l-dopa has been demonstrated to be able to regulate paired-pulse inhibition and lower limbs’ SP duration in RLS patients and in patients with Parkinson’s disease [30], [31], [32], [33], [34], [35]. Consequently, these findings confirm that the dopaminergic system could be implicated in the pathophysiology of RLS both directly, modulating the cortical excitability, and/or indirectly, by influencing GABAergic transmission [31]. Recent studies investigated whether RLS patients have alterations in H-reflexes. The authors found a diminished inhibition at spinal level in PLMD patients and suggested a functional role of dopamine in the spinal motor control mechanism [36].

Dopamine plays an important role in synaptic plasticity, involving motor cortex and regions of the basal ganglia [37], [38]. The dopaminergic neurotransmission is a major heterosynaptic input system able to affect the strength, specificity, and duration of formed memories [39], [40]. In the human motor cortex dopamine is a very important neuromodulator, influencing cognitive, emotional and motor processes. In particular, dopamine seems to be particularly necessary for consolidation of cognitive functions related to different kinds of neuroplasticity. The administration of levodopa in healthy subjects improves learning and memory formation by focusing synapse-specific excitability and enhancing neuroplasticity in cortical networks [41].

The brain synaptic plasticity in the corticostriatal circuit depends on the activation of dopamine receptors such as those in the prefrontal cortex, in the hippocampus and in the amygdala [42]. In patients with Parkinson’s disease, an impairment of dopaminergic-dependent synaptic plasticity has been supposed. Several authors reported that rTMS may improve contra-lateral hand function and increase cortical excitability in patients with Parkinson’s disease [43]. Ueki et al. [44] showed that the ratio of motor evoked potential amplitude before and after IPAS in Parkinson’s disease off-patients increased after dopamine replacement. Thus, they suggest that dopamine might modulate cortical plasticity, which could be related to higher order motor control, including motor learning. In particular, processes such as practice-dependent plasticity are enhanced by dopamine [45].

Despite the fact that systems of neurotransmission and CNS regions involved in the pathophysiology of RLS are different from ones involved in Parkinson’s disease, we believe the evidence of restoring delayed facilitation by dopaminergic treatment can support the theory that cortical plasticity related to dopaminergic pathways may play a crucial role in RLS pathophysiology.

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Addendum 

At the time this paper was sent for revision, an article by Rizzo et al. appeared on Movement Disorders showing that dopamine agonists are able to restore cortical plasticity in idiopathic RLS patients. Although the authors used a different TMS protocol (paired associative stimulation), their study confirms that long-term plasticity phenomena may be impaired in the motor cortex of RLS patients, with possible reversion to normality after dopaminergic treatment.

Rizzo V, Aricò I, Mastroeni C, Morgante F, Liotta G, Girlanda P, et al. Dopamine agonists restore cortical plasticity in patients with idiopathic restless legs syndrome. Mov Disord 2008 Dec 31.

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PII: S1389-9457(09)00222-6

doi:10.1016/j.sleep.2009.05.003

Sleep Medicine
Volume 11, Issue 1 , Pages 75-81, January 2010

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