J Neurol DOI 10.1007/s00415-015-7789-1
ORIGINAL COMMUNICATION
Normalization of sensorimotor integration by repetitive transcranial magnetic stimulation in cervical dystonia S. Zittel1,2 • R. C. Helmich3 • C. Demiralay4 • A. Mu¨nchau1,2 • T. Ba¨umer1,2
Received: 2 April 2015 / Revised: 15 May 2015 / Accepted: 16 May 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Previous studies indicated that sensorimotor integration and plasticity of the sensorimotor system are impaired in dystonia patients. We investigated motor evoked potential amplitudes and short latency afferent inhibition to examine corticospinal excitability and cortical sensorimotor integration, before and after inhibitory 1 Hz repetitive transcranial magnetic stimulation over primary sensory and primary motor cortex in patients with cervical dystonia (n = 12). Motor evoked potentials were recorded from the right first dorsal interosseous muscle after application of unconditioned transcranial magnetic test stimuli and after previous conditioning electrical stimulation of the right index finger at short interstimulus intervals of 25, 30 and 40 ms. Results were compared to a group of healthy age-matched controls. At baseline, motor evoked potential amplitudes did not differ between groups. Short latency afferent inhibition was reduced in cervical dystonia patients compared to healthy controls. Inhibitory 1 Hz sensory cortex repetitive transcranial magnetic stimulation but not motor cortex repetitive transcranial magnetic stimulation increased motor evoked potential amplitudes in cervical dystonia patients. Additionally, both 1 Hz repetitive
& S. Zittel [email protected] 1
Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lu¨beck, Maria-Goeppert-Str. 1, 23562 Lu¨beck, Germany
2
Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3
Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands
4
Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
transcranial magnetic stimulation over primary sensory and primary motor cortex normalized short latency afferent inhibition in these patients. In healthy subjects, sensory repetitive transcranial magnetic stimulation had no influence on motor evoked potential amplitudes and short latency afferent inhibition. Plasticity of sensorimotor circuits is altered in cervical dystonia patients. Keywords Cervical dystonia Repetitive transcranial magnetic stimulation Plasticity Short latency afferent inhibition Sensorimotor integration
Introduction Dystonia is defined as a syndrome of sustained or intermittent muscle contractions leading to abnormal posture or movements [1]. Cervical dystonia (CD) is a focal dystonia affecting head and neck muscles. Previous studies indicated overactivity of the primary motor cortex (M1) in dystonia with reduced intracortical inhibition [2, 3] suggesting that a primary loss of cortical inhibition plays a major role in the pathophysiology of dystonia. Also, surround inhibition is impaired in dystonia leading to an overflow of muscle activity to adjacent muscles not involved in the movement [4]. In previous studies, inhibitory cathodal transcranial direct current stimulation (TDCS) over the affected (contralateral) M1 failed to improve fine motor control or focal hand dystonia in patients with musician’s dystonia and writer’s cramp (WC) [5, 6]. In contrast, the combination of cathodal TDCS over the affected, anodal TDCS over the unaffected cortex and behavioral training was beneficial in patients with musician’s dystonia [7]. Many CD patients report benefits from sensory ‘‘tricks’’, e.g., touching the chin with the hand. Thus, altered
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processing of sensory input seems to contribute to the development of dystonia. In line with these clinical findings, application of a sensory alleviating maneuver in CD patients significantly reduced increased intracortical M1 facilitation [8]. Additionally, several studies indicated abnormal processing of somatosensory stimuli in dystonia leading to alterations of sensorimotor integration [9, 10]. Previous studies also suggest that somatotopical organization and plasticity of the sensorimotor system are impaired in dystonia [2, 3, 11, 12]. Here, we investigated whether altered short latency afferent inhibition (SAI) in CD can be normalized by inhibiting the sensorimotor cortex using repetitive transcranial magnetic stimulation (rTMS). In a previous study, we evaluated the influence of inhibitory rTMS conditioning over primary sensory cortex (S1) and M1 on SAI in patients with WC [13]. In WC baseline SAI was normal. S1 but not M1 rTMS reduced SAI in these patients. WC is a task-specific dystonia without symptoms at rest. CD is a focal dystonia typically present in the upright position with patients at rest. Given different states of dystonia during measurements (WC asymptomatic, CD symptomatic), and against the light of previous work on homeostatic plasticity in humans [14, 15] we postulated that CD and WC patients would show differences in baseline SAI and different responsiveness to rTMS.
Methods Subject characteristics and clinical assessment 12 patients with isolated CD (6 men; aged 50 ± 11 years, mean ± SD) were compared to 8 healthy controls (4 men; aged 57 ± 9 years, mean ± SD). For comparison seven WC patients (2 men; mean age 57 ± 10 SD) previously reported were included in the statistical analysis [13]. All subjects were right handed according to the Edinburgh Handedness Inventory [16]. Diagnosis of dystonia was made based upon established clinical diagnostic criteria [17]. CD symptom severity was assessed using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) [18]. All CD patients were regularly treated with botulinum toxin injections. Experiments were performed before injections at least 3 months after the last treatment. None of the patients was taking any centrally acting medication. Study design Patients received two sessions of 1 Hz rTMS, one over left S1 (considered the active condition), and another over left M1 (control condition). Sessions were carried out in a counterbalanced pseudorandomized order at least 1 week
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apart to avoid carryover effects [19]. Healthy controls received one rTMS session over S1 since we hypothesized that in CD patients rTMS conditioning over this region, but not M1, would influence corticospinal excitability and SAI. Baseline examination (MEP amplitudes, SAI) was followed by 1 Hz rTMS of M1 or S1. Subsequently, MEP amplitudes and SAI were measured again to evaluate the rTMS influence. Effects of S1 rTMS in CD patients were compared to healthy subjects and previously described WC patients [13]. The TWSTRS was assessed at baseline and after rTMS application. Transcranial magnetic stimulation Subjects were seated in a comfortable reclining chair with their arms resting on a pillow. They were asked to keep their eyes open and to relax. Surface electromyographic (EMG) recordings were performed with two silver/silverchloride surface electrodes from the right first dorsal interosseus muscle (FDI) in a belly-tendon montage. EMG signals were amplified (D 360, Digitimer Limited, UK), filtered (high-pass filter 5 Hz, low-pass filter 1 kHz) and recorded at a sampling rate of 5 kHz using an analog– digital converter (1401 Micro, Cambridge electronic design, Cambridge, UK). EMG signals were monitored acoustically with a loudspeaker during the experiment. Trials without muscle relaxation were excluded from further analyses. For single pulse TMS application we used a Magstim 200 magnetic stimulator (Magstim Company, Dyfed, UK) connected to a figure-of-eight coil (outer diameter of 90 mm). The coil was placed tangentially on the scalp at a 45° angle away from the midline with the handle pointing backwards inducing a posterior-anterior current flow in the brain. The ‘‘motor hot spot’’ was defined as the place where slightly suprathreshold stimulus intensities induced the largest peak-to-peak MEP amplitude. Resting motor threshold (RMT) was defined as the lowest stimulus intensity that induced an MEP of 50 lV in five out of ten consecutive trials. For the test stimulus (TS) an intensity of 120 % RMT was used that evoked an MEP of 0.5–1.5 mV. Short latency afferent inhibition (SAI) For SAI measurements, a pair of ring electrodes was placed over the right index finger with the cathode positioned proximal and the anode distal. For electrical stimulation, the sensory perception threshold (SPT) was determined. Brief electrical conditioning stimuli (CS) (constant square wave current, 0.1 ms duration, 400 V) were delivered with stimulus intensities of three times SPT. Afferent conditioning was followed by a TS over the contralateral M1 at interstimulus intervals (ISI) of 25, 30 and 40 ms. Ten
J Neurol
conditioned stimuli and 20 unconditioned TS (for each ISI) were assessed before and after rTMS. rTMS conditioning Focal 1 Hz rTMS was applied using a figure-of-eight coil connected to a Magstim Rapid stimulator. The magnetic stimulus had a biphasic waveform with a pulse width of about 300 ls. For application of M1 rTMS the coil was held in an identical way as described above. The S1 stimulation site was localized 2 cm posterior and 1 cm lateral to M1 according to anatomical landmarks [13]. Although a current spread from the defined S1 stimulation site to the M1 region cannot be excluded due to the close anatomical proximity, it is referred to S1 rTMS application. The intensity of rTMS was referenced to the individual RMT at the rTMS stimulation site (i.e., RMTM1 and RMTS1) using Magstim Rapid stimulator pulses (Table 1). Given that RMTS1 was higher than RMTM1, S1 rTMS intensities were also considerably higher than M1 rTMS intensities. A single rTMS session consisted of a 20-min train of 1 Hz rTMS (1200 stimuli). The intensity was set at 90 % RMT. The rTMS protocol was in accordance with published safety recommendations [20].
one-way repeated measures analysis of variance (ANOVA) in CD and controls before and after rTMS. To compare relative conditioned MEP amplitudes at baseline between CD and controls repeated measures ANOVA with the factors GROUP (CD, controls) and ISI (three levels: 25, 30, 40 ms) was performed. In CD patients, we investigated whether there was a differential effect of M1 and S1 rTMS on SAI using a three-way repeated measures ANOVA with the factors SITE (M1, S1), TIME (pre, post rTMS) and ISI (three levels: 25, 30, 40 ms). Since there was a significant effect of rTMS on SAI in CD, we compared the effect of S1 rTMS on SAI in CD and controls with a three-way repeated measures ANOVA with the factors GROUP (CD patients, controls), TIME (pre, post rTMS) and ISI (three levels: 25, 30, 40 ms). Also, we tested whether the response to S1 rTMS differed between CD and WC. Again, we used a three-way repeated measures ANOVA with the factors GROUP (CD, WC), TIME (pre, and post rTMS) and ISI (three levels: 25, 30 and 40 ms). The Greenhouse-Geisser method was used to correct for non-sphericity. Conditional on a significant p value, post hoc tests were employed. A p value \0.05 was considered significant.
Data and statistical analysis
Results
MEP amplitudes were measured semi-automatically from peak to peak using a custom-made Signal software script (version 2.15; Cambridge Electronic Design). Mean values of conditioned and unconditioned MEP amplitudes were calculated. MEPs of conditioned trials were expressed as percentage of unconditioned TS amplitudes. To evaluate rTMS effects on unconditioned MEP amplitudes and TWSTRS and to compare RMTM1 and RMTS1 in different groups (CD, controls), we used paired sampled t tests. To compare RMTM1 and MEP amplitudes between groups before rTMS, we performed Student’s t tests. Influence of conditioning sensory stimuli on absolute MEP amplitudes in SAI measurements was assessed in
Clinical rating
Table 1 Resting motor threshold (RMT) over primary motor cortex (M1) and primary sensory cortex (S1) before rTMS at these sites in cervical dystonia (CD) patients
rTMS was well tolerated in all subjects without any side effects. S1 and M1 rTMS had no influence on symptom severity (Table 2). Also, baseline symptom severity did not differ between conditions. Thresholds and MEP amplitudes RMT over M1 and S1 as well as MEP amplitudes did not differ between groups before rTMS. RMT over S1 was significantly higher than over M1 in patients (p = 0.01) and controls (p \ 0.01). MEP amplitudes increased after
Before S1 1 Hz rTMS
Before M1 1 Hz rTMS
CD patients
CD patients
Control subjects
M1 RMT (Magstim 200 HP)
39.2 ± 7.4
41.3 ± 6.9
37.9 ± 8.2
RMT (Magstim rapid)
54.8 ± 6.3
52.0 ± 6.3
57.5 ± 6.8
67.6 ± 13.6
60.0 ± 7.3
–
S1 RMT (Magstim rapid)
For control subjects RMT before S1 rTMS is shown. Values are given as maximum stimulator output ± standard deviation
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J Neurol Table 2 Mean values (±standard error of mean) of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) before and after 1 Hz rTMS over primary sensory cortex (S1) and primary motor cortex (M1) After S1 1 Hz rTMS
Before M1 1 Hz rTMS
After M1 1 Hz rTMS
15 ± 6
14 ± 7
16 ± 6
16 ± 6
Fig. 1 Mean MEP amplitudes of CD patients are shown before and after 1 Hz rTMS over S1 and M1. MEP amplitudes of controls are displayed before and after 1 Hz rTMS over S1. S1 rTMS significantly increased MEP amplitudes in CD patients only. Values are given as mean ? standard error of mean (SEM). *p value \0.05
1,40
*
1,20 1,00 0,80
Control
mV
TWSTRS
Before S1 1 Hz rTMS
CD
0,60 0,40 0,20 0,00
baseline
post rTMS S1-rTMS
rTMS over S1, but not M1, in CD patients (S1 rTMS p = 0.01; Fig. 1). MEP amplitudes before and after S1 rTMS did not differ in controls. Baseline SAI Prior to rTMS, healthy subjects had clear SAI (main effect of ISI: F(3, 21) = 8.60; p \ 0.01). Post-hoc t test confirmed inhibition at ISIs of 25 (p \ 0.01), 30 (p \ 0.01) and 40 ms (p = 0.03). In contrast, CD patients did not have significant SAI prior to rTMS over S1 (main effect of ISI: F(3, 33) = 2.02; p = 0.13) or M1 (main effect of ISI: F(3, 24) = 1.94; p = 0.15). Accordingly, conditioned MEP amplitudes were overall smaller for controls than for CD patients (main effect of GROUP: F(1, 18) = 6.01; p = 0.02). There was no main effect of ISI and no interaction between factors (Fig. 2).
baseline
post rTMS M1-rTMS
p \ 0.01). In contrast, there was no effect of rTMS on SAI in controls. ANOVA comparing S1 rTMS effects on relative MEP amplitudes between CD and controls confirmed this group difference (F(1, 18) = 4.36; p = 0.05). Comparison of S1 rTMS effects in CD with previously reported data of WC We have previously demonstrated normal SAI at baseline and reduced SAI following S1 but not M1 1 Hz rTMS in WC patients [13]. Data of these patients were available for group comparison. ANOVA revealed a significant interaction of TIME 9 GROUP (F(1, 17) = 10.40, p \ 0.01) confirming a specific effect of S1 rTMS conditioning on SAI in both groups with 1 Hz S1 rTMS causing a reduction of SAI in WC and an increase in CD patients. There were no effects of single factors and no further interactions.
M1 and S1 rTMS conditioning effects on SAI in CD
Discussion In CD patients, SAI was normalized after both S1 and M1 rTMS (main effect of TIME: F(1, 8) = 7.63; p = 0.03) (Fig. 2). There were no effects of the factors SITE or ISI and no interaction. Analysis of absolute MEP amplitudes after rTMS in CD patients revealed that peripheral electrical stimulation caused significant inhibition of MEP amplitudes at ISIs of 25, 30 and 40 ms (post S1 rTMS: F(3, 33) = 10.17; p \ 0.01; post M1 rTMS: F(3, 24) = 6.67;
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Corticospinal excitability increased after inhibitory S1 rTMS in CD, but not in healthy controls. Reduced SAI at baseline was normalized following both S1 and M1 rTMS in CD, while S1 rTMS conditioning had no influence on SAI in healthy controls. The increase (or normalization) of SAI in CD was distinct from previously published findings in WC, where inhibitory S1 rTMS reduced SAI.
cervical dystonia control subjects
% of mean test pulse amplitude
% of mean test pulse amplitude
J Neurol 160%
S1 rTMS
M1 rTMS
140% 120% 100% 80% 60% 40%
pre rTMS
20%
post rTMS
160%
25
140%
30
40
ms (ISI)
120% 100% 80% 60% 40% 20% 25
30
40
ms (ISI)
Fig. 2 SAI before and after 1 Hz rTMS over S1 and M1 is demonstrated for CD patients. Also, SAI of controls before and after S1 rTMS is shown. Reduced SAI at baseline in CD patients was
normalized after inhibitory rTMS over S1 and M1. Mean values ± standard error of mean (SEM) are presented
Corticospinal excitability
By means of PAS it is possible to induce long-term potentiation (LTP) and long-term depression (LTD)-like effects in synaptic networks. In WC and CD patients, LTP and LTD-like effects after PAS are increased and input– output selectivity is reduced, i.e., cortical excitability changes following PAS are not only present in target but also adjacent muscles [24, 25]. Therefore, our finding of increased MEP amplitudes in CD after S1 rTMS may also be explained by aberrant S1 plasticity in the dystonic state. Different responses to S1 rTMS in CD and WC might be related to the activity state (metaplasticity) of the targeted area during stimulation. WC patients received S1 rTMS in a non-dystonic state whereas CD patients were stimulated with dystonic symptoms being present. Metaplasticity refers to the fact that depending on the previous level of neuronal activation the same stimulation protocol may induce LTP or LTD-like effects. For instance, animal experiments demonstrated that depending on the degree of neuronal depolarization the same tetanic stimulation protocol induced either LTP or LTD [26]. In healthy subjects, it has been shown that metaplasticity operates not only in M1 but also in S1 and that it influences corticospinal excitability as well as somatosensory skills [27]. Our finding
MEP amplitudes increased after inhibitory S1 rTMS in CD patients. Previously, inhibitory S1 rTMS did not alter MEP amplitudes in WC or healthy subjects [13]. Changes in corticospinal excitability after 1 Hz M1 rTMS have been reported before, typically with decreased MEP amplitudes in healthy subjects [21]. In contrast, 1 Hz rTMS over M1 increased mean MEP area in WC suggesting altered plasticity of M1 in these patients [22]. Functional imaging studies in focal dystonia patients demonstrated intrinsic sensory abnormalities with overactivity not only of M1 but also S1. We hypothesize that our findings may be based on S1 overactivity leading to increased inhibition from S1 to M1 in CD. Accordingly, the removal of S1 overactivity by 1 Hz rTMS may lead to increased corticospinal excitability. Another hypothesis is that altered plasticity in sensorimotor loops may play a role in increased corticospinal excitability after S1 rTMS. Maladaptive plasticity has been suggested to be one of the pathophysiological mechanisms in dystonia [13, 23]. This is corroborated by responses to paired associative stimulation (PAS) in dystonia patients.
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of increased MEP amplitudes after inhibitory S1 rTMS conditioning suggest that metaplasticity in cervical dystonia is altered in S1. Sensorimotor integration SAI originates at the cortical level and is mediated by cholinergic and GABA(A) receptors [28, 29]. Reduced SAI in CD at baseline suggests reduced capability of peripheral sensory stimuli to modulate M1 excitability possibly due to aberrant processing within the somatosensory cortex. Sensory abnormalities in dystonia are characterized by intrinsic sensory abnormalities and altered effects of external sensory input on the motor system [30]. In line with this, dystonia patients showed abnormal somatotopical organization of the sensorimotor system where not only peripheral electrical stimulation of a contiguous finger led to inhibition of MEP amplitudes but also stimulation of a non-contiguous finger [12] suggesting deficient gating of somatosensory input. Previous reports on neurophysiological measures of sensorimotor integration in CD are conflicting. Whereas some groups [12, 31] reported normal SAI, others described impaired sensorimotor integration [32]. These divergent findings may either be due to methodological differences, small sample size or different clinical characteristics. Impaired SAI in CD is in contrast to WC patients in whom SAI has been shown to be normal [10, 12, 13]. Apart from obvious clinical differences between CD and WC in terms of dystonia distribution, onset age and gender [33] one principal group difference relates to the fact that neurophysiological measurements were carried out in a non-dystonic state with the arms at rest in WC but with neck dystonia being present in CD. Abnormal SAI in the latter may thus reflect dystonia related altered processing of sensory information. Normalization of SAI after S1 and M1 1 Hz rTMS in CD may be explained by inhibition of these overactive cortical areas, which has repeatedly been demonstrated before [2, 3]. Due to the close anatomical proximity of S1 and M1, it cannot be excluded completely that there was a current spread to interconnected sites during rTMS. Since our previous investigation in WC with the same protocol revealed differential effects according to the stimulation site [13] it is unlikely that the results in CD are solely based on current spread. For the same reason, unspecific effects on SAI based on noise during rTMS application or relaxation of patients over time seem unlikely. It might be argued that the normalization of SAI after rTMS was driven by increased corticospinal excitability following rTMS during unconditioned trials (see Fig. 1), rather than by normalized sensorimotor interactions. However, in CD we observed the same change of SAI after
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M1 rTMS, which did not increase corticospinal excitability. Therefore, this possibility seems unlikely. S1 rTMS differentially affected SAI in CD and WC. Whereas S1 rTMS increased and normalized SAI in CD, it reduced normal baseline SAI in WC at an ISI 25 ms [13]. The reason why S1 rTMS has different effects on SAI in both patient groups remains speculative. We hypothesize that opposite effects of S1 conditioning are caused by different neuronal activity states in CD and WC patients during the experiment. Similar to the divergent influence of S1 rTMS on corticospinal excitability in CD and WC, the findings of differential modifiability of SAI may be explained by altered S1 plasticity based on specific changes in homeostatic metaplasticity in the symptomatic, dystonic state in CD and in the asymptomatic, non-dystonic condition in WC. There are several limitations of the study. M1 rTMS was not applied in controls precluding direct comparison between controls and CD. Also, we did not assess symptom severity in CD during TMS measurements. Therefore, our hypothesis that differences of rTMS effects in WC and CD are based on the fact that one group is investigated in the non-dystonic state whereas the other is in the dystonic state is speculative. Another weakness is that TMS targeted intrinsic hand muscles, which are affected by dystonia in WC but are distant from the symptomatic body region in CD. Also, anatomical organization of cortical projections to contralateral hand muscles differs from that to cervical muscles. We conclude that cervical dystonia is associated with impaired sensorimotor integration, which can be normalized by inhibition of S1 and M1. This suggests that abnormal sensorimotor cortical inhibition plays an important role in the pathophysiology of cervical dystonia. Acknowledgments Simone Zittel is supported by an intramural grant of the University of Luebeck (E36-2014). She received commercial research support from Merz Pharmaceuticals and St. Jude Medical. Rick Helmich is supported by the Dutch Brain Foundation. Cu¨neyt Demiralay has no financial disclosures. Alexander Mu¨nchau received grants by Pharm Allergan, Ipsen, Merz Pharmaceuticals and honoraria for lectures from Pharm Allergan, Ipsen, Merz Pharmaceuticals, Actelion, GlaxoSmithKline and Desitin. He is supported by the Possehl-Stiftung Lu¨beck, Dystonia Coalition (USA), Tourette Syndrome Association (Germany), European Huntington Disease Network and N.E.MO. (charity supporting the research of pediatric movement disorders). He receives academic research support by the Deutsche Forschungsgemeinschaft (SFB 936; DFG MU 1692/4-1) and the Bundesministerium fu¨r Bildung und Forschung (DysTract network). Tobias Ba¨umer received honaria for lectures from Pharm Allergan, Ipsen, Merz Pharmaceuticals. Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical standard We obtained written informed consent of all participants. Experiments were performed according to the
J Neurol Declaration of Helsinki with approval of the local ethics committee of Hamburg.
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ORIGINAL COMMUNICATION
Normalization of sensorimotor integration by repetitive transcranial magnetic stimulation in cervical dystonia S. Zittel1,2 • R. C. Helmich3 • C. Demiralay4 • A. Mu¨nchau1,2 • T. Ba¨umer1,2
Received: 2 April 2015 / Revised: 15 May 2015 / Accepted: 16 May 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Previous studies indicated that sensorimotor integration and plasticity of the sensorimotor system are impaired in dystonia patients. We investigated motor evoked potential amplitudes and short latency afferent inhibition to examine corticospinal excitability and cortical sensorimotor integration, before and after inhibitory 1 Hz repetitive transcranial magnetic stimulation over primary sensory and primary motor cortex in patients with cervical dystonia (n = 12). Motor evoked potentials were recorded from the right first dorsal interosseous muscle after application of unconditioned transcranial magnetic test stimuli and after previous conditioning electrical stimulation of the right index finger at short interstimulus intervals of 25, 30 and 40 ms. Results were compared to a group of healthy age-matched controls. At baseline, motor evoked potential amplitudes did not differ between groups. Short latency afferent inhibition was reduced in cervical dystonia patients compared to healthy controls. Inhibitory 1 Hz sensory cortex repetitive transcranial magnetic stimulation but not motor cortex repetitive transcranial magnetic stimulation increased motor evoked potential amplitudes in cervical dystonia patients. Additionally, both 1 Hz repetitive
& S. Zittel [email protected] 1
Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lu¨beck, Maria-Goeppert-Str. 1, 23562 Lu¨beck, Germany
2
Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3
Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands
4
Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
transcranial magnetic stimulation over primary sensory and primary motor cortex normalized short latency afferent inhibition in these patients. In healthy subjects, sensory repetitive transcranial magnetic stimulation had no influence on motor evoked potential amplitudes and short latency afferent inhibition. Plasticity of sensorimotor circuits is altered in cervical dystonia patients. Keywords Cervical dystonia Repetitive transcranial magnetic stimulation Plasticity Short latency afferent inhibition Sensorimotor integration
Introduction Dystonia is defined as a syndrome of sustained or intermittent muscle contractions leading to abnormal posture or movements [1]. Cervical dystonia (CD) is a focal dystonia affecting head and neck muscles. Previous studies indicated overactivity of the primary motor cortex (M1) in dystonia with reduced intracortical inhibition [2, 3] suggesting that a primary loss of cortical inhibition plays a major role in the pathophysiology of dystonia. Also, surround inhibition is impaired in dystonia leading to an overflow of muscle activity to adjacent muscles not involved in the movement [4]. In previous studies, inhibitory cathodal transcranial direct current stimulation (TDCS) over the affected (contralateral) M1 failed to improve fine motor control or focal hand dystonia in patients with musician’s dystonia and writer’s cramp (WC) [5, 6]. In contrast, the combination of cathodal TDCS over the affected, anodal TDCS over the unaffected cortex and behavioral training was beneficial in patients with musician’s dystonia [7]. Many CD patients report benefits from sensory ‘‘tricks’’, e.g., touching the chin with the hand. Thus, altered
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processing of sensory input seems to contribute to the development of dystonia. In line with these clinical findings, application of a sensory alleviating maneuver in CD patients significantly reduced increased intracortical M1 facilitation [8]. Additionally, several studies indicated abnormal processing of somatosensory stimuli in dystonia leading to alterations of sensorimotor integration [9, 10]. Previous studies also suggest that somatotopical organization and plasticity of the sensorimotor system are impaired in dystonia [2, 3, 11, 12]. Here, we investigated whether altered short latency afferent inhibition (SAI) in CD can be normalized by inhibiting the sensorimotor cortex using repetitive transcranial magnetic stimulation (rTMS). In a previous study, we evaluated the influence of inhibitory rTMS conditioning over primary sensory cortex (S1) and M1 on SAI in patients with WC [13]. In WC baseline SAI was normal. S1 but not M1 rTMS reduced SAI in these patients. WC is a task-specific dystonia without symptoms at rest. CD is a focal dystonia typically present in the upright position with patients at rest. Given different states of dystonia during measurements (WC asymptomatic, CD symptomatic), and against the light of previous work on homeostatic plasticity in humans [14, 15] we postulated that CD and WC patients would show differences in baseline SAI and different responsiveness to rTMS.
Methods Subject characteristics and clinical assessment 12 patients with isolated CD (6 men; aged 50 ± 11 years, mean ± SD) were compared to 8 healthy controls (4 men; aged 57 ± 9 years, mean ± SD). For comparison seven WC patients (2 men; mean age 57 ± 10 SD) previously reported were included in the statistical analysis [13]. All subjects were right handed according to the Edinburgh Handedness Inventory [16]. Diagnosis of dystonia was made based upon established clinical diagnostic criteria [17]. CD symptom severity was assessed using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) [18]. All CD patients were regularly treated with botulinum toxin injections. Experiments were performed before injections at least 3 months after the last treatment. None of the patients was taking any centrally acting medication. Study design Patients received two sessions of 1 Hz rTMS, one over left S1 (considered the active condition), and another over left M1 (control condition). Sessions were carried out in a counterbalanced pseudorandomized order at least 1 week
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apart to avoid carryover effects [19]. Healthy controls received one rTMS session over S1 since we hypothesized that in CD patients rTMS conditioning over this region, but not M1, would influence corticospinal excitability and SAI. Baseline examination (MEP amplitudes, SAI) was followed by 1 Hz rTMS of M1 or S1. Subsequently, MEP amplitudes and SAI were measured again to evaluate the rTMS influence. Effects of S1 rTMS in CD patients were compared to healthy subjects and previously described WC patients [13]. The TWSTRS was assessed at baseline and after rTMS application. Transcranial magnetic stimulation Subjects were seated in a comfortable reclining chair with their arms resting on a pillow. They were asked to keep their eyes open and to relax. Surface electromyographic (EMG) recordings were performed with two silver/silverchloride surface electrodes from the right first dorsal interosseus muscle (FDI) in a belly-tendon montage. EMG signals were amplified (D 360, Digitimer Limited, UK), filtered (high-pass filter 5 Hz, low-pass filter 1 kHz) and recorded at a sampling rate of 5 kHz using an analog– digital converter (1401 Micro, Cambridge electronic design, Cambridge, UK). EMG signals were monitored acoustically with a loudspeaker during the experiment. Trials without muscle relaxation were excluded from further analyses. For single pulse TMS application we used a Magstim 200 magnetic stimulator (Magstim Company, Dyfed, UK) connected to a figure-of-eight coil (outer diameter of 90 mm). The coil was placed tangentially on the scalp at a 45° angle away from the midline with the handle pointing backwards inducing a posterior-anterior current flow in the brain. The ‘‘motor hot spot’’ was defined as the place where slightly suprathreshold stimulus intensities induced the largest peak-to-peak MEP amplitude. Resting motor threshold (RMT) was defined as the lowest stimulus intensity that induced an MEP of 50 lV in five out of ten consecutive trials. For the test stimulus (TS) an intensity of 120 % RMT was used that evoked an MEP of 0.5–1.5 mV. Short latency afferent inhibition (SAI) For SAI measurements, a pair of ring electrodes was placed over the right index finger with the cathode positioned proximal and the anode distal. For electrical stimulation, the sensory perception threshold (SPT) was determined. Brief electrical conditioning stimuli (CS) (constant square wave current, 0.1 ms duration, 400 V) were delivered with stimulus intensities of three times SPT. Afferent conditioning was followed by a TS over the contralateral M1 at interstimulus intervals (ISI) of 25, 30 and 40 ms. Ten
J Neurol
conditioned stimuli and 20 unconditioned TS (for each ISI) were assessed before and after rTMS. rTMS conditioning Focal 1 Hz rTMS was applied using a figure-of-eight coil connected to a Magstim Rapid stimulator. The magnetic stimulus had a biphasic waveform with a pulse width of about 300 ls. For application of M1 rTMS the coil was held in an identical way as described above. The S1 stimulation site was localized 2 cm posterior and 1 cm lateral to M1 according to anatomical landmarks [13]. Although a current spread from the defined S1 stimulation site to the M1 region cannot be excluded due to the close anatomical proximity, it is referred to S1 rTMS application. The intensity of rTMS was referenced to the individual RMT at the rTMS stimulation site (i.e., RMTM1 and RMTS1) using Magstim Rapid stimulator pulses (Table 1). Given that RMTS1 was higher than RMTM1, S1 rTMS intensities were also considerably higher than M1 rTMS intensities. A single rTMS session consisted of a 20-min train of 1 Hz rTMS (1200 stimuli). The intensity was set at 90 % RMT. The rTMS protocol was in accordance with published safety recommendations [20].
one-way repeated measures analysis of variance (ANOVA) in CD and controls before and after rTMS. To compare relative conditioned MEP amplitudes at baseline between CD and controls repeated measures ANOVA with the factors GROUP (CD, controls) and ISI (three levels: 25, 30, 40 ms) was performed. In CD patients, we investigated whether there was a differential effect of M1 and S1 rTMS on SAI using a three-way repeated measures ANOVA with the factors SITE (M1, S1), TIME (pre, post rTMS) and ISI (three levels: 25, 30, 40 ms). Since there was a significant effect of rTMS on SAI in CD, we compared the effect of S1 rTMS on SAI in CD and controls with a three-way repeated measures ANOVA with the factors GROUP (CD patients, controls), TIME (pre, post rTMS) and ISI (three levels: 25, 30, 40 ms). Also, we tested whether the response to S1 rTMS differed between CD and WC. Again, we used a three-way repeated measures ANOVA with the factors GROUP (CD, WC), TIME (pre, and post rTMS) and ISI (three levels: 25, 30 and 40 ms). The Greenhouse-Geisser method was used to correct for non-sphericity. Conditional on a significant p value, post hoc tests were employed. A p value \0.05 was considered significant.
Data and statistical analysis
Results
MEP amplitudes were measured semi-automatically from peak to peak using a custom-made Signal software script (version 2.15; Cambridge Electronic Design). Mean values of conditioned and unconditioned MEP amplitudes were calculated. MEPs of conditioned trials were expressed as percentage of unconditioned TS amplitudes. To evaluate rTMS effects on unconditioned MEP amplitudes and TWSTRS and to compare RMTM1 and RMTS1 in different groups (CD, controls), we used paired sampled t tests. To compare RMTM1 and MEP amplitudes between groups before rTMS, we performed Student’s t tests. Influence of conditioning sensory stimuli on absolute MEP amplitudes in SAI measurements was assessed in
Clinical rating
Table 1 Resting motor threshold (RMT) over primary motor cortex (M1) and primary sensory cortex (S1) before rTMS at these sites in cervical dystonia (CD) patients
rTMS was well tolerated in all subjects without any side effects. S1 and M1 rTMS had no influence on symptom severity (Table 2). Also, baseline symptom severity did not differ between conditions. Thresholds and MEP amplitudes RMT over M1 and S1 as well as MEP amplitudes did not differ between groups before rTMS. RMT over S1 was significantly higher than over M1 in patients (p = 0.01) and controls (p \ 0.01). MEP amplitudes increased after
Before S1 1 Hz rTMS
Before M1 1 Hz rTMS
CD patients
CD patients
Control subjects
M1 RMT (Magstim 200 HP)
39.2 ± 7.4
41.3 ± 6.9
37.9 ± 8.2
RMT (Magstim rapid)
54.8 ± 6.3
52.0 ± 6.3
57.5 ± 6.8
67.6 ± 13.6
60.0 ± 7.3
–
S1 RMT (Magstim rapid)
For control subjects RMT before S1 rTMS is shown. Values are given as maximum stimulator output ± standard deviation
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J Neurol Table 2 Mean values (±standard error of mean) of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) before and after 1 Hz rTMS over primary sensory cortex (S1) and primary motor cortex (M1) After S1 1 Hz rTMS
Before M1 1 Hz rTMS
After M1 1 Hz rTMS
15 ± 6
14 ± 7
16 ± 6
16 ± 6
Fig. 1 Mean MEP amplitudes of CD patients are shown before and after 1 Hz rTMS over S1 and M1. MEP amplitudes of controls are displayed before and after 1 Hz rTMS over S1. S1 rTMS significantly increased MEP amplitudes in CD patients only. Values are given as mean ? standard error of mean (SEM). *p value \0.05
1,40
*
1,20 1,00 0,80
Control
mV
TWSTRS
Before S1 1 Hz rTMS
CD
0,60 0,40 0,20 0,00
baseline
post rTMS S1-rTMS
rTMS over S1, but not M1, in CD patients (S1 rTMS p = 0.01; Fig. 1). MEP amplitudes before and after S1 rTMS did not differ in controls. Baseline SAI Prior to rTMS, healthy subjects had clear SAI (main effect of ISI: F(3, 21) = 8.60; p \ 0.01). Post-hoc t test confirmed inhibition at ISIs of 25 (p \ 0.01), 30 (p \ 0.01) and 40 ms (p = 0.03). In contrast, CD patients did not have significant SAI prior to rTMS over S1 (main effect of ISI: F(3, 33) = 2.02; p = 0.13) or M1 (main effect of ISI: F(3, 24) = 1.94; p = 0.15). Accordingly, conditioned MEP amplitudes were overall smaller for controls than for CD patients (main effect of GROUP: F(1, 18) = 6.01; p = 0.02). There was no main effect of ISI and no interaction between factors (Fig. 2).
baseline
post rTMS M1-rTMS
p \ 0.01). In contrast, there was no effect of rTMS on SAI in controls. ANOVA comparing S1 rTMS effects on relative MEP amplitudes between CD and controls confirmed this group difference (F(1, 18) = 4.36; p = 0.05). Comparison of S1 rTMS effects in CD with previously reported data of WC We have previously demonstrated normal SAI at baseline and reduced SAI following S1 but not M1 1 Hz rTMS in WC patients [13]. Data of these patients were available for group comparison. ANOVA revealed a significant interaction of TIME 9 GROUP (F(1, 17) = 10.40, p \ 0.01) confirming a specific effect of S1 rTMS conditioning on SAI in both groups with 1 Hz S1 rTMS causing a reduction of SAI in WC and an increase in CD patients. There were no effects of single factors and no further interactions.
M1 and S1 rTMS conditioning effects on SAI in CD
Discussion In CD patients, SAI was normalized after both S1 and M1 rTMS (main effect of TIME: F(1, 8) = 7.63; p = 0.03) (Fig. 2). There were no effects of the factors SITE or ISI and no interaction. Analysis of absolute MEP amplitudes after rTMS in CD patients revealed that peripheral electrical stimulation caused significant inhibition of MEP amplitudes at ISIs of 25, 30 and 40 ms (post S1 rTMS: F(3, 33) = 10.17; p \ 0.01; post M1 rTMS: F(3, 24) = 6.67;
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Corticospinal excitability increased after inhibitory S1 rTMS in CD, but not in healthy controls. Reduced SAI at baseline was normalized following both S1 and M1 rTMS in CD, while S1 rTMS conditioning had no influence on SAI in healthy controls. The increase (or normalization) of SAI in CD was distinct from previously published findings in WC, where inhibitory S1 rTMS reduced SAI.
cervical dystonia control subjects
% of mean test pulse amplitude
% of mean test pulse amplitude
J Neurol 160%
S1 rTMS
M1 rTMS
140% 120% 100% 80% 60% 40%
pre rTMS
20%
post rTMS
160%
25
140%
30
40
ms (ISI)
120% 100% 80% 60% 40% 20% 25
30
40
ms (ISI)
Fig. 2 SAI before and after 1 Hz rTMS over S1 and M1 is demonstrated for CD patients. Also, SAI of controls before and after S1 rTMS is shown. Reduced SAI at baseline in CD patients was
normalized after inhibitory rTMS over S1 and M1. Mean values ± standard error of mean (SEM) are presented
Corticospinal excitability
By means of PAS it is possible to induce long-term potentiation (LTP) and long-term depression (LTD)-like effects in synaptic networks. In WC and CD patients, LTP and LTD-like effects after PAS are increased and input– output selectivity is reduced, i.e., cortical excitability changes following PAS are not only present in target but also adjacent muscles [24, 25]. Therefore, our finding of increased MEP amplitudes in CD after S1 rTMS may also be explained by aberrant S1 plasticity in the dystonic state. Different responses to S1 rTMS in CD and WC might be related to the activity state (metaplasticity) of the targeted area during stimulation. WC patients received S1 rTMS in a non-dystonic state whereas CD patients were stimulated with dystonic symptoms being present. Metaplasticity refers to the fact that depending on the previous level of neuronal activation the same stimulation protocol may induce LTP or LTD-like effects. For instance, animal experiments demonstrated that depending on the degree of neuronal depolarization the same tetanic stimulation protocol induced either LTP or LTD [26]. In healthy subjects, it has been shown that metaplasticity operates not only in M1 but also in S1 and that it influences corticospinal excitability as well as somatosensory skills [27]. Our finding
MEP amplitudes increased after inhibitory S1 rTMS in CD patients. Previously, inhibitory S1 rTMS did not alter MEP amplitudes in WC or healthy subjects [13]. Changes in corticospinal excitability after 1 Hz M1 rTMS have been reported before, typically with decreased MEP amplitudes in healthy subjects [21]. In contrast, 1 Hz rTMS over M1 increased mean MEP area in WC suggesting altered plasticity of M1 in these patients [22]. Functional imaging studies in focal dystonia patients demonstrated intrinsic sensory abnormalities with overactivity not only of M1 but also S1. We hypothesize that our findings may be based on S1 overactivity leading to increased inhibition from S1 to M1 in CD. Accordingly, the removal of S1 overactivity by 1 Hz rTMS may lead to increased corticospinal excitability. Another hypothesis is that altered plasticity in sensorimotor loops may play a role in increased corticospinal excitability after S1 rTMS. Maladaptive plasticity has been suggested to be one of the pathophysiological mechanisms in dystonia [13, 23]. This is corroborated by responses to paired associative stimulation (PAS) in dystonia patients.
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of increased MEP amplitudes after inhibitory S1 rTMS conditioning suggest that metaplasticity in cervical dystonia is altered in S1. Sensorimotor integration SAI originates at the cortical level and is mediated by cholinergic and GABA(A) receptors [28, 29]. Reduced SAI in CD at baseline suggests reduced capability of peripheral sensory stimuli to modulate M1 excitability possibly due to aberrant processing within the somatosensory cortex. Sensory abnormalities in dystonia are characterized by intrinsic sensory abnormalities and altered effects of external sensory input on the motor system [30]. In line with this, dystonia patients showed abnormal somatotopical organization of the sensorimotor system where not only peripheral electrical stimulation of a contiguous finger led to inhibition of MEP amplitudes but also stimulation of a non-contiguous finger [12] suggesting deficient gating of somatosensory input. Previous reports on neurophysiological measures of sensorimotor integration in CD are conflicting. Whereas some groups [12, 31] reported normal SAI, others described impaired sensorimotor integration [32]. These divergent findings may either be due to methodological differences, small sample size or different clinical characteristics. Impaired SAI in CD is in contrast to WC patients in whom SAI has been shown to be normal [10, 12, 13]. Apart from obvious clinical differences between CD and WC in terms of dystonia distribution, onset age and gender [33] one principal group difference relates to the fact that neurophysiological measurements were carried out in a non-dystonic state with the arms at rest in WC but with neck dystonia being present in CD. Abnormal SAI in the latter may thus reflect dystonia related altered processing of sensory information. Normalization of SAI after S1 and M1 1 Hz rTMS in CD may be explained by inhibition of these overactive cortical areas, which has repeatedly been demonstrated before [2, 3]. Due to the close anatomical proximity of S1 and M1, it cannot be excluded completely that there was a current spread to interconnected sites during rTMS. Since our previous investigation in WC with the same protocol revealed differential effects according to the stimulation site [13] it is unlikely that the results in CD are solely based on current spread. For the same reason, unspecific effects on SAI based on noise during rTMS application or relaxation of patients over time seem unlikely. It might be argued that the normalization of SAI after rTMS was driven by increased corticospinal excitability following rTMS during unconditioned trials (see Fig. 1), rather than by normalized sensorimotor interactions. However, in CD we observed the same change of SAI after
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M1 rTMS, which did not increase corticospinal excitability. Therefore, this possibility seems unlikely. S1 rTMS differentially affected SAI in CD and WC. Whereas S1 rTMS increased and normalized SAI in CD, it reduced normal baseline SAI in WC at an ISI 25 ms [13]. The reason why S1 rTMS has different effects on SAI in both patient groups remains speculative. We hypothesize that opposite effects of S1 conditioning are caused by different neuronal activity states in CD and WC patients during the experiment. Similar to the divergent influence of S1 rTMS on corticospinal excitability in CD and WC, the findings of differential modifiability of SAI may be explained by altered S1 plasticity based on specific changes in homeostatic metaplasticity in the symptomatic, dystonic state in CD and in the asymptomatic, non-dystonic condition in WC. There are several limitations of the study. M1 rTMS was not applied in controls precluding direct comparison between controls and CD. Also, we did not assess symptom severity in CD during TMS measurements. Therefore, our hypothesis that differences of rTMS effects in WC and CD are based on the fact that one group is investigated in the non-dystonic state whereas the other is in the dystonic state is speculative. Another weakness is that TMS targeted intrinsic hand muscles, which are affected by dystonia in WC but are distant from the symptomatic body region in CD. Also, anatomical organization of cortical projections to contralateral hand muscles differs from that to cervical muscles. We conclude that cervical dystonia is associated with impaired sensorimotor integration, which can be normalized by inhibition of S1 and M1. This suggests that abnormal sensorimotor cortical inhibition plays an important role in the pathophysiology of cervical dystonia. Acknowledgments Simone Zittel is supported by an intramural grant of the University of Luebeck (E36-2014). She received commercial research support from Merz Pharmaceuticals and St. Jude Medical. Rick Helmich is supported by the Dutch Brain Foundation. Cu¨neyt Demiralay has no financial disclosures. Alexander Mu¨nchau received grants by Pharm Allergan, Ipsen, Merz Pharmaceuticals and honoraria for lectures from Pharm Allergan, Ipsen, Merz Pharmaceuticals, Actelion, GlaxoSmithKline and Desitin. He is supported by the Possehl-Stiftung Lu¨beck, Dystonia Coalition (USA), Tourette Syndrome Association (Germany), European Huntington Disease Network and N.E.MO. (charity supporting the research of pediatric movement disorders). He receives academic research support by the Deutsche Forschungsgemeinschaft (SFB 936; DFG MU 1692/4-1) and the Bundesministerium fu¨r Bildung und Forschung (DysTract network). Tobias Ba¨umer received honaria for lectures from Pharm Allergan, Ipsen, Merz Pharmaceuticals. Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical standard We obtained written informed consent of all participants. Experiments were performed according to the
J Neurol Declaration of Helsinki with approval of the local ethics committee of Hamburg.
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