Effects of Transcutaneous Spinal Direct Current Stimulation in Idiopathic Restless Legs Patients

Brain Stimulation 7 (2014) 636e642

Contents lists available at ScienceDirect

Brain Stimulation journal homepage: www.brainstimjrnl.com

Effects of Transcutaneous Spinal Direct Current Stimulation in Idiopathic Restless Legs Patients A.C. Heide a, T. Winkler d, H.J. Helms b, M.A. Nitsche a, C. Trenkwalder a, c, W. Paulus a, C.G. Bachmann a, e, * a

Department of Clinical Neurophysiology, University Medical Center, Göttingen, Germany Department of Medical Statistics, Georg August University, Göttingen, Germany Paracelsus-Elena Hospital, Kassel, Germany d Department of Neurology, University of Munich, Germany e Paracelsus Hospital Osnabrück, Germany b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 23 February 2014 Received in revised form 13 June 2014 Accepted 18 June 2014

Background: Transcutaneous spinal direct current stimulation (tsDCS) is a new non-invasive technique to modulate spinal cord activity. The pathophysiological concept of primary RLS proposes increased spinal excitability. Objective: This pilot study used tsDCS to reduce pathologically enhanced spinal excitability in RLS patients and to thereby ameliorate clinical symptoms. Methods: 20 patients with idiopathic RLS and 14 healthy subjects participated in this double-blinded, placebo-controlled study. All participants received one session of cathodal, anodal and sham stimulation of the thoracic spinal cord for 15 min (2.5 mA) each, in randomized order during their symptomatic phase in the evening. The soleus Hoffmann-reflex with Hmax/Mmax-ratio and seven different H2/H1ratios (of two H-reflex responses to double stimuli) were measured. The RLS symptoms were assessed by a visual analogue scale (VAS). All parameters were measured before and twice after tsDCS. Results: RLS patients showed increased H2/H1-ratios during their symptomatic phase in the evening. Application of anodal stimulation led to a decreased H2/H1-ratio for 0.2 and 0.3 s interstimulus intervals in patients. Furthermore, application of anodal and cathodal stimulation led to a reduction in restless legs symptoms on the VAS, whereas application of sham stimulation had no effects on either the VAS or on the H2/H1-ratio in patients. VAS changes did not correlate with changes of H2/H1-ratios. Conclusions: This is the first tsDCS study in idiopathic RLS, which resulted in short-lasting clinical improvement. Furthermore, our results support the pathophysiological concept of spinal cord hyperexcitability in primary RLS and provide the basis for a new non-pharmacological treatment tool. Ó 2014 Elsevier Inc. All rights reserved.

Keywords: Restless legs syndrome Spinal cord hyperexcitability Transcutaneous spinal direct current stimulation H-reflex

Introduction The pathophysiological concept of restless legs syndrome (RLS) hypothesizes an increased spinal excitability in RLS patients [1e6]. Rijsman and co-workers [7] describe increased H2/H1-ratios (measured from two H-reflex-responses to double stimuli with different interstimulus intervals) for the interstimulus intervals of 0.4, 0.3 and 0.2 s in eight patients with RLS and one patient with Periodic Limb Movement Disorder (PLMD). This disorder is characterized by periodic limb movements (PLM) in sleep > 15/h,

* Corresponding author. Department of Neurology, Paracelsus Klinik, Am Natruper Holz 69, D-49076 Osnabrück, Germany. Tel.: þ49 541 9663181; fax: þ49 541 9663089. E-mail addresses: [email protected], [email protected] (C.G. Bachmann). 1935-861X/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2014.06.008

reduced sleep quality and the exclusion of a clinical RLS or another secondary cause. Currently licensed dopaminergic therapy in RLS is complicated by the phenomenon of augmentation [8e11] as well as by constraining side effects of dopaminergic medication, such as impulse control disorders and weight gain [12,13]. Therefore, nonpharmacological therapeutic tools offering additional efficacy and fewer side effects may improve the therapeutical repertoire. Anodal transcranial direct current stimulation (tDCS) of the motor cortex is a well-established non-pharmacological method to alleviate chronic pain [14e17]. A few recently published studies indicate that transcutaneous spinal direct current stimulation (tsDCS) may be a non-invasive, painless way to reduce spinal cord excitability [18e21]. Our study assessed whether the application of tsDCS could become a suitable new therapeutic tool in the treatment of RLS

A.C. Heide et al. / Brain Stimulation 7 (2014) 636e642

patients. We especially asked if the application of anodal tsDCS is suited to reduce the severity of restless legs symptoms and if this potential alleviation is associated with inhibitory effects on spinal pathways, as measured by decreased H2/H1-ratios for the double stimulus intervals of 0.2, 0.3 and 0.4 s.

Methods Participants 20 patients with primary idiopathic RLS (mean age: 56.2  14.9 years, 15 female, 5 male, International Restless Legs Severity Scale (IRLSS) score: 27) from the movement disorders outpatient ward at the Department of Clinical Neurophysiology at the University Medical Center in Göttingen participated. Fourteen of the 20 patients received H-reflex-measurements (mean age 53.4  13.6 years, 9 female, 5 male, Table 1). The diagnosis of RLS was based on the four essential criteria defined by the International Restless Legs Syndrome Study Group [22,23]. For inclusion in the study all patients were classified as having RLS by experts (WP, CGB) in the field of RLS. All patients were also scored again on the IRLSS at the beginning of the study to assess general symptom severity. Secondary RLS (e.g. due to low ferritin, iron or B-vitamins) was excluded by neurological examination, blood tests and normal peripheral sensory and motor nerve conduction velocities. All patients had stopped their RLS medication or other CNS-affecting medication for at least five drug half-lives prior to the intervention. Since the patients mainly took low doses of medication, no tapering was required. During this off-medication period, patients took 100 mg of L-DOPA in the evening at bedtime. L-DOPA was stopped at least 24 h before and thus also more than 5 half-lives prior to the experiments [2]. The control group consisted of 14 gender- and age-matched healthy subjects (age: 52.8  14.1 years, 9 female, 5 male) without CNS-affecting medication, any central or PNS disorder in their history or a family history of RLS. The controls showed a normal neurological status.

637

All participants gave their written informed consent. The study was approved by the ethics committee of the University of Göttingen and conforms to the standards of the Declaration of Helsinki. Transcutaneous spinal direct current stimulation (tsDCS) TsDCS was conducted using a protocol similar to that of tsDCS studies published recently [18,21] to allow for methodological comparability [24]. The center of the electrode determining the polarity was placed over the thoracic spinal cord about 2 cm left paravertebrally and longitudinally to the Th11 level, and the return electrode was positioned over the right supraclavicular region. Both equally sized stimulation electrodes (Krauth*Timmermann DermaFlex, 5 cm9 cm) were coated with EEG paste. A current strength of 2.5 mA was applied for 900 s via a Neuro Conn DC Stimulator, which resulted in a current density of 0.056 mA/cm2 and a total delivered charge of 0.05 C/cm2. Sham tsDCS was achieved by turning off the stimulator after 40 s. Similar to numerous previous studies using transcranial DCS (tDCS) [16,17], the participants felt the same tingling sensation at the beginning of the stimulation [14] and, therefore, could not distinguish verum from sham stimulation, when asked after the intervention. Visual analogue scale (VAS) Patients were asked to rate their instantaneous restless legs symptom severity in the legs on the VAS from 0 (no symptoms) to 100 (worst symptoms ever) at all three time points (Experimental procedures, Fig. 1). H-reflex tests The soleus Hoffmann-reflex was measured by stimulating the tibial nerve in the popliteal fossa and recording the answers from surface electrodes on the soleus muscle. H-reflex measurements

Table 1 Demographic data of idiopathic RLS patients. Patient

Gender

Age at onset (years)

Duration (years)

IRLSS

Family history

RLS medication with total daily dose (mg)

Years of drug use at study entry

Hours off medication prior to the assessment

1 2 3 4 5 6 7

F F F M F F F

30 16 28 37 58 40 46

30 6 20 6 6 21 25

28 8 38 21 40 28 22

Yes Yes Yes Yes Unknown Yes Yes

8

F

18

44

31

No

9 10

F M

35 48

10 3

33 31

Yes Unknown

11 12 25 26

F M M M

58 32 48 10

6 20 20 27

23 24 33 37

Yes Yes Yes Yes

27 30

F F

49 44

26 25

23 30

Yes Yes

31

F

63

15

27

Yes

32 33

F F

39 34

30 18

26 21

Yes Yes

34

F

32

1,5

16

Yes

Ropinirole 0.5 None Ropinirole 0.5 Pramipexole 0.72 Rotigotine 3 Pramipexole 0.36 Ropinirole 3/ Tilidine þ Naloxone 50 þ 4, only 1/week Ropinirole 3/ Tilidine þ Naloxone 100 þ 4 Pramipexole 0.18 Trazodone n a/ Rotigotine 3 Trazodone 25 L-DOPA 100 L-DOPA 100 Rotigotine 2/ Tilidine 50 Ropinirole 2 Ropinirole 1.5/ L-DOPA 100, only 2/week Tilidine þ Naloxone 50 þ 4/ Pregabalin 75 Rotigotine 2 Ropinirole 2/ Tilidine þ Naloxone 50 þ 4 None

3 e 2 2.5 3/12 6 4 3 1/12 1/12 3 1½ 1/12 1/12 1 8 1/12 1/12 7 2 10 3 7 ½ 3 3 e

30 e 30 60 35 60 30 30 30 30 60 30 35 30 24 24 35 30 30 30 24 30 30 35 30 30 e

638

A.C. Heide et al. / Brain Stimulation 7 (2014) 636e642

Figure 1. Anodal, cathodal, sham tsDCS was applied over the thoracic spinal cord for 15 min (2.5 mA) in randomized order. At t0 (before tsDCS), at t1 (directly after tsDCS) and at t2 (30 min after tsDCS) RLS symptoms in patients were assessed by a visual analogue scale (VAS) and H-reflex parameters in patients and healthy controls.

were performed in 14 patients and 14 healthy controls at all three time points according to the protocol of Rijsman and co-workers [7]. We measured the amplitude of the maximal H-reflex answer and the maximal direct muscle potential through stimulation of the motor axons (Mmax) which defined the Hmax/Mmax-ratio. We also measured seven different H2/H1-ratios for seven different ISIs of 10; 1; 0.5; 0.4; 0.3; 0.2; 0.1 s. H2/H1-ratios are defined by the ratio of two H-reflex-answers H2 and H1 to double stimuli for different interstimulus intervals (ISIs) [7,25,26]. We elicited the H2/H1-ratios using the same current intensity as for the maximal H-reflexanswer [7]. Experimental procedures (Fig. 1) The subjects and the experimenter were fully blinded in a randomized double-blinded study design to each of the three stimulation modes. At least one week interval between each session was scheduled in order to avoid interference between stimulations. H-reflexes and VAS scores were measured at three points in time: before transcutaneous spinal stimulation (t0), immediately after termination of stimulation (t1) and 30 min after stimulation (t2). VAS measurements were performed before H-reflex measurements. Patients underwent H-reflex and VAS measurements, controls only received H-reflex measurements. During the tsDCS stimulation and VAS measurements the patients reclined on an examination couch and were asked not to move their legs voluntarily or perform any other action to get symptom release. Resting muscle activity was monitored with EMG surface electrodes on the soleus muscle, the same as for H-reflex measurements. After prior announcement, RLS symptom severity was assessed with VAS. The investigator sat next to the patient to observe the patient and monitor activity levels. All experimental sessions were performed during the patients’ symptomatic phase, i.e. between 4 pm and 2 am for all subjects [2].

VAS, Hmax/Mmax-ratio and normalized H2/H1-ratio for each ISI. In all analyses, the within-subject factors were time course (three levels: t0, t1, t2) and stimulation (three levels: anodal, cathodal, sham). We added the between-subjects factor group for the Hmax/Mmax-ratio (patient or control) and the H2/H1-ratios. If significant main effects were detected, post hoc tests were performed using paired Student’s t-tests with the BonferronieHolm adjustment. To test for significant differences in H2/H1-ratios between patients and controls before the tsDCS stimulation, repeated measure ANOVAs for t0 with the within-subject factor stimulation (three levels: anodal, cathodal, sham) and the between-subject factor group (patient or control) were performed for each of all seven ISIs. To exclude significant baseline differences at t0 between stimulation conditions, repeated measure ANOVAs for all dependent variables were performed as described above. H2/H1-ratios were normalized by dividing all values through t0-values. Results Apart from a slight sensation beneath the electrodes, in most cases only at the beginning of tsDCS, no side effects were reported by the subjects. According to our subjects, this sensation did not differ between the verum and sham stimulation conditions. For the results, we report means  standard deviation. H2/H1-ratios

Statistical analysis

Baseline H2/H1-ratios The repeated measure ANOVAs to test for group differences before tsDCS at t0 in all ISIs showed significant group effects in the H2/H1-ratios for the ISIs of 0.2, 0.3 and 0.4 s (Fig. 2). Significantly increased H2/H1-ratios in the patient group at t0 were found for ISIs of 0.2 s (patients: 1.2  0.7; controls: 0.6  0.3; P ¼ 0.002), 0.3 s (patients: 0.8  0.2; controls: 0.6  0.2; P ¼ 0.002) and 0.4 s (patients: 0.6  0.2; controls: 0.5  0.2; P ¼ 0.020).

The data were evaluated using the statistical software SPSS version 20 and Statistica 64 version 10 for the figures. Multifactorial repeated measures ANOVAs (Analysis of Variance) were used to analyze potential differences in the dependent variables

H2/H1-ratio alterations induced by tsDCS A three-way repeated measures ANOVA showed for the ISI of 0.2 s significant main effects of stimulation (P ¼ 0.027), significant interactions of ‘time  stimulation’ (P ¼ 0.016), ‘time  group’

A.C. Heide et al. / Brain Stimulation 7 (2014) 636e642

639

Figure 2. Mean baseline H2/H1-ratios and SEM at t0 (before application of tsDCS) in RLS patients and controls for all interstimulus intervals. The figure shows significantly* (P < 0.05) increased H2/H1-ratios in primary RLS for the interstimulus intervals of 0.2, 0.3 and 0.4 s in comparison to healthy controls.

(P ¼ 0.003) as well as a significant main effect of group (P ¼ 0.004) (Fig. 3A): In RLS patients, application of anodal tsDCS led to a significantly decreased H2/H1-ratio for ISI 0.2 s between t0 and t1 (decrease of 31.6%; P ¼ 0.005) and for t1 between the anodal and sham condition (decrease of 36.9%; P < 0.001). No significant time effects for cathodal or sham stimulation, nor significant stimulation effects for t2, were detected in RLS patients. In the control group, Student’s t-tests did not reveal any significant changes. For the ISI of 0.3 s, significant main effects of stimulation (P < 0.001) and significant interactions regarding ‘time  stimulation’ (P < 0.001) were found. Paired t-tests finally revealed a significantly decreased H2/H1-ratio for the ISI of 0.3 s in RLS patients after anodal tsDCS between t0 and t1 (decrease of 29.6%; P ¼ 0.002), but the P-value of the H2/H1-ratio in the anodal in comparison to the sham condition failed to reach the adjusted significance level (decrease of 38.1%; P ¼ 0.009 > P ¼ 0.007 for the adjusted significance level; not significant, Fig. 2b). No significant effects were detected in the control group. For the other ISIs the analysis did not reveal any significant main effects or interaction effects of time, stimulation and group (ISI of 0.1 s: Ptimestimulation ¼ 0.509, Ptimestimgroup ¼ 0.449; ISI of 0.4 s: Ptimestim ¼ 0.416, Ptimestimgroup ¼ 0.185; ISI of 0.5 s: Ptimestim ¼ 0.670, Ptimestimgroup ¼ 0.262; ISI of 1 s: Ptimestim ¼ 0.147, Ptimestimgroup ¼ 0.078; ISI of 10 s: Ptimestim ¼ 0.607, Ptimestimgroup ¼ 0.393). The analysis of the Hmax/Mmax-ratio did not show any significant changes which is consistent with previous findings [7,21]. VAS The two-way ANOVA for VAS performed with the data of 20 patients showed significant main effects for time (P < 0.001) and stimulation (P ¼ 0.003), as well as a significant interaction for ‘time  stimulation’ (P < 0.001) (Fig. 4). Sham stimulation and t0 condition (VAS-scores  SD, t0: anodal: 65.2  15.6; cathodal: 62.9  11.1; sham: 63.8  11.9) did not reveal any significant effects. Application of anodal tsDCS showed a significantly decreased VASscore between t0 (VAS-scores  SD, 65.2  15.5) and t1 (37.5  27.1; P < 0.001), and t0 and t2 (44.4  21.2; P < 0.001), whereas cathodal stimulation yielded significant effects only between t0 (62.9  11.1) and t1 (46.6  25.1; P ¼ 0.008), but not between t0 and t2 (56.8  23.2; P ¼ 0.176). The VAS-score was also significantly decreased for anodal stimulation in comparison to sham stimulation at t1 (sham: 66.3  18.6; anodal: 37.5  27.1; P < 0.001) and t2

Figure 3. Mean normalized H2/H1-ratios and SEM for ISI (interstimulus interval) of (A) 0.2 s and (B) 0.3 s before (t0), immediately after current offset (t1) and 30 min after tsDCS (t2) in RLS patients (no significant change was detected in the control group). A: ISI of 0.2 s: Application of anodal tsDCS led to a significantly* (P < 0.05) decreased H2/ H1-ratio in primary RLS patients at t1, whereas no significant change was observed for cathodal or sham stimulation. B: ISI of 0.3 s: Application of anodal tsDCS led to a significantly* (P < 0.05) decreased H2/H1-ratio in primary RLS patients during the time course (from t0 to t1) but not between stimulation conditions (anodal versus sham). No significant change was observed for cathodal or sham stimulation.

(sham: 59.9  17.3; anodal: 44.4  21.2; P ¼ 0.008), for cathodal in comparison to sham stimulation only for t1 (sham: 66.3  18.5; cathodal: 46.6  25.1; P ¼ 0.003), but not for t2 (sham: 59.9  17.3; cathodal: 56.8  23.2; P ¼ 0.501). The same analysis for VAS performed with all 14 patients who received the H-reflex-measurements revealed significant effects of time and stimulation for anodal tsDCS (P < 0.001), but not of cathodal or sham tsDCS. All RLS patients reported that tsDCS-induced release of RLS symptoms lasted for a few hours until their RLS symptoms required pharmacological treatment again: On the day following tsDCS all RLS patients receiving medication (18 of 20 patients) needed to restart their RLS medication. However, as the scope of this study was not to explore long-term effects of stimulation, this information was not quantitatively gathered using a validated scale, and is therefore preliminary. No significant correlation between symptom alleviation on the VAS and altered H2/H1-ratios for ISI of 0.2 s and 0.3 s was detected. The demographic data of those RLS patients (Table 1), who responded particularly well to treatment with tsDCS, did not reveal any specific characteristics of patients.

640

A.C. Heide et al. / Brain Stimulation 7 (2014) 636e642

spread [6]. Furthermore, Truini and co-workers [19] showed an inhibitory effect of anodal tsDCS on ascending nociceptive spinal pathways modulating laser-evoked potentials and increasing pain tolerance. Interestingly, Cogiamanian and co-workers [20] measured reduced amplitudes of posterior tibial nerve SEPs after application of anodal tsDCS at the thoracic level, whereas amplitudes of the median nerve SEPs remained unchanged. Clinical effects of tsDCS and neurophysiological background

Figure 4. Effect of tsDCS on VAS (Visual Analogue Scale: 0e100) in patients: Mean VAS e score (from 0 ¼ no RLS symptoms to 100 ¼ worst RLS symptoms ever had) and SEM before tsDCS (t0), immediately after current offset (t1) and after 30 min (t2): tsDCS led to a significant* (P < 0.05) decrease in symptoms on the VAS for anodal stimulation (t1 and t2) and for cathodal stimulation (only t1).

Discussion On the pathophysiological side our present study confirms the neurophysiological findings of Rijsman and co-workers [7], observed in RLS and PLMD patients, in patients with idiopathic restless legs syndrome: The results show a significantly increased H1/H2-ratio for ISI of 0.2, 0.3 s and 0.4 s in symptomatic patients in comparison with healthy controls at baseline. We were also able to show that application of anodal tsDCS led to a decrease of elevated H2/H1-ratios for ISI of 0.2 and 0.3 s in RLS patients, thus reflecting a decrease in spinal excitability after anodal tsDCS. In addition to this finding, we observed a significant alleviation of RLS symptoms on the VAS after anodal tsDCS and cathodal tsDCS. Nevertheless, treatment benefits do not significantly correlate with changes in spinal cord excitability. Comparison of baseline H2/H1-ratios between patients and controls As mentioned above, our results confirm the study of Rijsman and co-workers [7]. According to our findings and the findings of Rijsman and co-workers [7] in RLS and PLMD patients, Hmax/ Mmax-ratio did not differ between patients and healthy controls. We also found normal peripheral nerve conduction velocity and amplitudes, which all together argues against an isolated dysfunction of either Ia-afferents or alpha-motoneurons in RLS patients. Therefore, increased H2/H1-ratios in symptomatic RLS patients are likely to be caused by a compromised supraspinal inhibitory pathway projecting onto spinal motoneurons or on altered excitability in local spinal circuits. A similar mechanism is assumed to be responsible for increased H2/H1-ratios in patients with Parkinson’s disease [26]. Neurophysiological effects of tsDCS Anodal tsDCS led to significantly reduced H2/H1-ratios in RLS patients. This inhibitory effect may be caused by tDCS-induced modulation of activity in descending spinal tracts projecting onto alpha-motoneurons. Several studies support our results of an inhibitory effect of anodal tsDCS: Anodal tsDCS applied over the thoracic spinal cord has been shown to inhibit the nociceptive spinal flexion reflex in humans [18]. This reflex is pathologically enhanced in RLS patients, as reflected by lower thresholds and greater spatial

We assessed clinical effects of tsDCS on RLS symptoms via VAS: The patients were asked to report the instantaneous subjective severity of their sensory RLS symptoms. In general, sensory symptoms can also be measured using validated psychophysical tests such as quantitative sensory testing (QST). In primary RLS, QST revealed static mechanical hyperalgesia, hyperalgesia to blunt pressure and vibrotactile hyperesthesia [2]. Vibratory hyperesthesia as well as vibration sense is neuronally processed via the dorsal columns in the spinal cord, whereas hyperalgesia is processed via the spinothalamic tract. According to Clemens et al. [3]. RLS symptoms may be due to a dysfunction of inhibitory dopaminergic projections from hypothalamic area A11 to dorsal horn cells. This may result in disinhibition of sensory inputs to the dorsal horn, thus leading to increased activity in the somatosensory tracts of the spinal cord. As described in detail above, anodal tsDCS has already been shown to inhibit spinothalamic nociceptive pathways, as shown via reduced amplitudes of laser-evoked potentials [19] and dorsal column pathways, as demonstrated by reduced amplitudes of tibial nerve SEPs [20], in healthy subjects. Therefore, it may be speculated that in RLS patients anodal tsDCS likely inhibits spinal pathways in the dorsal columns and the spinothalamic tracts. Alternatively, anodal tsDCS might inhibit dorsal horn activity and consecutively reduce activity in both ascending sensory tracts. These neurophysiological mechanisms could ultimately result in an alleviation of sensory RLS symptoms induced by anodal tsDSC. In contrast, cathodal tsDCS did not lead to a significant modulation of SEPs and LEPs in healthy controls [19,20]. Corresponding with findings of previous studies, cathodal tsDCS was less efficient in alleviating RLS symptoms than anodal tsDCS. Nevertheless, it still significantly alleviated RLS symptoms. Similar findings have been reported in studies using transcranial DCS (tDCS) for specific conditions. The following three mechanisms discussed for tDCS might also hold true for spinal stimulation (tsDCS): 1. For the human motor cortex and animal preparations it could be shown that DC stimulation protocols of identical polarity can have antagonistic effects on cortical excitability, according to stimulation duration, and area of a given neuron. Anodal transcranial DCS usually has excitatory effects in the brain at rest [24], but can also show inhibitory effects on long axons according to Rahman et al. [27], and for extended stimulation protocols [28]. For spinal DCS, previous studies in healthy subjects showed that anodal stimulation had mainly inhibitory effects at rest [18e20]. It might be speculated that cathodal spinal DCS, due to the above-mentioned mechanism, had not the usually accomplished antagonistic effects, as compared to anodal tDCS, but shifted excitability in the same direction. 2. Further studies of transcranial DCS of the motor cortex show that the effects of stimulation highly depend on the state of activation [29]: During performance of a motor exercise, both anodal and cathodal tDCS significantly reduced motor cortex excitability. In contrast, at rest only cathodal tDCS had inhibitory effects [29,30]. Respectively, the symptomatic state of RLS patients with a higher spinal cord activity might represent a state of enhanced activity and thus explain why not only

A.C. Heide et al. / Brain Stimulation 7 (2014) 636e642

641

anodal, but also cathodal tsDCS alleviated RLS symptoms via excitability reduction. 3. Medium doses of L-dopa change tDCS-induced enhancement of motor cortex excitability into diminution, and enhance the excitability-diminishing effects of cathodal tDCS [31]. Accordingly, the effects of long-term dopaminergic treatment in our RLS patients might cause a similar diminution of spinal excitability in response to spinal stimulation, irrespective of its polarity. TsDCS is a relatively new technique, and this is the first study to apply this approach in RLS patients. Therefore, we can only speculate that cathodal tsDCS in comparison to anodal tsDCS might not primarily inhibit the somatosensory tracts (SEPs and LEPs in healthy controls who were not affected in other studies by cathodal tsDCS), but instead activate the descending pain modulatory system. This system projects from the brainstem to the dorsal horns of the spinal cord and can powerfully inhibit somatosensory inputs [32]. An activation of this system through cathodal stimulation might then alleviate RLS symptoms. However, this explanation remains highly speculative. A similarly directed but minor effect of cathodal stimulation on the same pathways in RLS patients might also be possible. Furthermore, it has to be discussed that cathodal tsDCS significantly reduced RLS symptoms, but did not significantly (P ¼ 0.194) reduce H2/H1-ratios. It is important to note that in 14 patients VASscores and H-reflexes were assessed. An additional six patients only received VAS-ratings because they could not tolerate the H-reflex procedure. Therefore, the relationship between clinics and neurophysiology can only be assessed in the smaller group of 14 patients who received both procedures. Here we found that both, VAS-score and H2/H1-ratios, were significantly decreased after anodal tsDCS, but remained both unchanged through cathodal tsDCS. Thus, in this subgroup, clinical findings were in accordance with neurophysiological findings. However, in the whole group of 20 patients we additionally obtained a significant effect of cathodal tsDCS on the VAS score only. Further studies with additional H-reflex-measurements after cathodal stimulation and larger sample sizes are needed to explore the relationship between clinical effects and neurophysiology more deeply and to corroborate our findings. Future studies should also explore whether the clinical effects of anodal tsDCS can be enhanced, for example, by repeated stimulation [28,33] similar to repetitive anodal tDCS for the treatment of chronic pain [14,16]. Furthermore, the pathophysiology of RLS might influence the response to spinal stimulation. According to Allen and co-workers there are two classes of RLS patients: Those with a predominant spinal pathophysiology should respond better to spinal stimulation than those with a predominant cortical glutamatergic dysfunction [34]. This should be investigated in further studies. General remarks As the placebo response is high in RLS patients [35], we only included patients who were highly symptomatic prior to the intervention, with an average VAS-score of 63.8  11.9 for sham condition. Furthermore, the withdrawal of dopaminergic medication must still be considered as a potentially disturbing factor, but a longer off-medication period was not tolerable for the patients. The VAS used to assess the clinical effects has not been formally validated for RLS. Nevertheless, it is the most adequate measure for short-term assessment of subjective RLS symptom severity which was needed to quantify the temporal alleviation of RLS symptoms in our study [36]. The VAS is also a part of the suggested immobilization test (SIT) [37] and has been applied in several RLS studies

Figure 5. We defined responders to anodal tsDCS when showing a symptom amelioration of at least 50% on the VAS for t1, directly after stimulation (VAS t1/VAS t0  0.5). This definition included patients P2, P3, P4, P6, P7, P25, P27, P33, P34, P30 from Table 1 (red color) as responders, the rest of the patients were non-responders according to our definition (blue color). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

[38,39]. All specific RLS questionnaires are designed for longer time periods (e.g. IRLSS for one week, RLS-6 Scale still in the validating process). In this pilot study we used the IRLSS to assess general symptom severity only at the beginning of the study, but did not reassess it one week after stimulation, because all patients under RLS medication (18 of 20 RLS patients) had already restarted their medication at the day following tsDCS. Patients in the present study reported that restart of the medication was necessary, because the tsDCS-induced symptom alleviation lasted only a few hours. Thus, the present tsDCS protocol induced probably a short-term effect. The precise duration of tsDCS effects should be analyzed in future studies, as this assessment was beyond the scope of the present pilot study. The absence of data regarding the monitoring of the exact duration of the tsDCS effect remains a shortcoming of our study. Further studies might also assess the effect of tsDCS on sensory symptoms by using the quantitative sensory testing (QST) method described above [2], which might provide further detailed insight into the spinal pathophysiology of RLS. In conclusion, this study is the first to apply tsDCS in RLS. Our results support the pathophysiological concept of spinal cord hyperexcitability in idiopathic RLS. Especially the application of anodal tsDCS induced a decrease of elevated spinal cord activity and resulted in a short-lasting clinical improvement. It may provide the basis for a new non-pharmacological treatment tool. Acknowledgments We especially thank our participants in the study for their consent and cooperation and Svenja Happe, Andrea Antal and Alan Oberlin for discussion. We acknowledge Lilo Habersack, Hans Rhese and the German Restless Legs Syndrome patients’ organization (RLS e.V.) for supporting this study. All authors had full access to all of study data and take responsibility for the integrity of the data and the accuracy of the data analysis. Annex Subgroup analysis e responders to anodal tsDCS We observed a subgroup of primary RLS patients responding particularly well to treatment with anodal tsDCS. We defined

642

A.C. Heide et al. / Brain Stimulation 7 (2014) 636e642

responders to anodal tsDCS when showing a symptom amelioration of at least 50% on the VAS directly after stimulation (VAS t1/VAS t0  0.5). This definition included patients P2, P3, P4, P6, P7, P25, P27, P33, P34, P30 (Table 1, red color in Fig. 5), the rest of the patients were non-responders according to our definition (blue color in Fig. 5). According to our strict definition none of the patients responded to sham stimulation (VAS t1/VAS t0 > 0.5 after sham stimulation in all patients, the lowest score with VAS t1/VAS t0 ¼ 0.6 for P7). As this is a very strict criterion, we additionally performed additional correlation statistics between anodal and sham condition in the patient group: The changes of VAS during time course from t0 to t1 for anodal and sham tsDCS did not show a significant correlation for the whole patient group (P ¼ 0.75) or for the subgroup of patient “responders” (P ¼ 0.84). In particular, the last finding shows that the group of responders to anodal tsDCS did not respond to sham tsDCS. The demographic data of our RLS patients (Table 1) did not reveal any specific characteristics of patients who responded particularly well to treatment with tsDCS. Nevertheless the pathophysiology of RLS might influence the response to spinal stimulation. According to Allen and co-workers there are two classes of RLS patients: Those with a predominant spinal pathophysiology should respond better to spinal stimulation than those with a predominant cortical glutamatergic dysfunction [34]. This should be investigated in further studies.

References [1] Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 2010;6:337e46. [2] Bachmann CG, Rolke R, Scheidt U, et al. Thermal hypoaesthesia differentiates secondary restless legs syndrome associated with small fibre neuropathy from primary restless legs syndrome. Brain 2010;133:762e70. [3] Clemens S, Rye D, Hochman S. Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 2006;67: 125e30. [4] Högl B, Frauscher B, Seppi K, Ulmer H, Poewe W. Transient restless legs syndrome after spinal anesthesia: a prospective study. Neurology 2002;59: 1705e7. [5] Stiasny-Kolster K, Magerl W, Oertel WH, Möller JC, Treede RD. Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome. Brain 2004;127:773e82. [6] Bara-Jimenez W, Aksu M, Graham B, Sato S, Hallett M. Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex. Neurology 2000;54:1609e16. [7] Rijsman RM, Stam CJ, de Weerd AW. Abnormal H-reflexes in periodic limb movement disorder; impact on understanding the pathophysiology of the disorder. Clin Neurophysiol 2005;116:204e10. [8] Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996;19:205e13. [9] Allen RP, Ondo WG, Ball E, et al. Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample. Sleep Med 2011;12:431e9. [10] Paulus W, Trenkwalder C. Less is more: pathophysiology of dopaminergictherapy-related augmentation in restless legs syndrome. Lancet Neurol 2006;5:878e86. [11] Garcia-Borreguero D, Williams AM. Dopaminergic augmentation of restless legs syndrome: the scope of the problem. Sleep Med 2011;12:425e6. [12] Earley CJ, Silber MH. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med 2010;11:807e15. [13] Provini F, Antelmi E, Vignatelli L, et al. Association of restless legs syndrome with nocturnal eating: a case-control study. Mov Disord 2009;24:871e87. [14] Antal A, Terney D, Kühnl S, Paulus W. Anodal transcranial direct current stimulation of the motor cortex ameliorates chronic pain and reduces short intracortical inhibition. J Pain Symptom Manage 2010;39:890e903.

[15] Lefaucheur JP, Antal A, Ahdab R, et al. The use of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to relieve pain. Brain Stimul 2008;1:337e44. [16] Fregni F, Boggio PS, Lima MC, et al. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain 2006;122:197e209. [17] Fregni F, Gimenes R, Valle AC, et al. A randomized, sham-controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheum 2006;54:3988e98. [18] Cogiamanian F, Vergari M, Schiaffi E, et al. Transcutaneous spinal cord direct current stimulation inhibits the lower limb nociceptive flexion reflex in human beings. Pain 2011;152:370e5. [19] Truini A, Vergari M, Biasiotta A, et al. Transcutaneous spinal direct current stimulation inhibits nociceptive spinal pathway conduction and increases pain tolerance in humans. Eur J Pain 2011;15:1023e7. [20] Cogiamanian F, Vergari M, Pulecchi F, Marceglia S, Priori A. Effect of spinal transcutaneous direct current stimulation on somatosensory evoked potentials in humans. Clin Neurophysiol 2008;119:2636e40. [21] Winkler T, Hering P, Straube A. Spinal DC stimulation in humans modulates post-activation depression of the H-reflex depending on current polarity. Clin Neurophysiol 2010;121:957e61. [22] Walters AS. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord 1995;10:634e42. [23] Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of health. Sleep Med 2003;4:101e19. [24] Nitsche MA, Cohen LG, Wassermann EM, et al. Transcranial direct current stimulation: state of the art 2008. Brain Stimul 2008;1:206e23. [25] Kagamihara Y, Hayashi A, Okuma Y, Nagaoka M, Nakajima Y, Tanaka R. Reassessment of H-reflex recovery curve using the double stimulation procedure. Muscle Nerve 1998;21:352e60. [26] Sabbahi M, Etnyre B, Al-Jawayed I, Jankovic J. H-reflex recovery curves differentiate essential tremor, Parkinson’s disease, and the combination of essential tremor and Parkinson’s disease. J Clin Neurophysiol 2002;19: 245e51. [27] Rahman A, Reato D, Arlotti M, et al. Cellular effects of acute direct current stimulation: somatic and synaptic terminal effects. J Physiol 2013;591: 2563e78. [28] Monte-Silva K, Kuo MF, Hessenthaler S, et al. Induction of late LTP-like plasticity in the human motor cortex by repeated non-invasive brain stimulation. Brain Stimul 2013;6:424e32. [29] Antal A, Terney D, Poreisz C, Paulus W. Towards unravelling task-related modulations of neuroplastic changes induced in the human motor cortex. Eur J Neurosci 2007;26:2687e91. [30] Batsikadze G, Moliadze V, Paulus W, Kuo MF, Nitsche MA. Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans. J Physiol 2013;591:1987e2000. [31] Monte-Silva K, Liebetanz D, Grundey J, Paulus W, Nitsche MA. Dosagedependent non-linear effect of L-dopa on human motor cortex plasticity. J Physiol 2010;588:3415e24. [32] Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest 2010;120:3779e87. [33] Reis J, Schambra HM, Cohen LG, et al. Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation. Proc Natl Acad Sci U S A 2009;106:1590e5. [34] Allen RP, Barker PB, Horska A, Earley CJ. Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep. Neurology 2013;28:2028e34. [35] Fulda S, Wetter TC. Where dopamine meets opioids: a meta-analysis of the placebo effect in restless legs syndrome treatment studies. Brain 2008;131:902e17. [36] Lamy JC, Ho C, Badel A, Arrigo RT, Boakye M. Modulation of soleus H reflex by spinal DC stimulation in humans. J Neurophysiol 2012;108:906e14. [37] Tribl GG, Sycha T, Kotzailias N, Zeitlhofer J, Auff E. Apomorphine in idiopathic restless legs syndrome: an exploratory study. J Neurol Neurosurg Psychiatry 2005;76:181e5. [38] Hornyak M, Sohr M, Busse M, 604 and 615 Study Groups. Evaluation of painful sensory symptoms in restless legs syndrome: experience from two clinical trials. Sleep Med 2011;12:186e9. [39] Manconi M, Ferri R, Zucconi M, et al. First night efficacy of pramipexole in restless legs syndrome and periodic limb movements. Sleep Med 2007;8:491e7.