RESEARCH

ARTICLE

Does Abnormal Interhemispheric Inhibition Play a Role in Mirror Dystonia? Virginie Sattler, MD,1,2 Maya Dickler,3 Martin Michaud,1,3 Sabine Meunier, MD, PHD,4,5,6,7 and Marion Simonetta-Moreau, MD, PHD1,2,3* 1

^le Neurosciences, CHU Purpan, Place du Dr Baylac, F-31059 Toulouse Cedex 9, France Centre Hospitalier Universitaire de Toulouse, Po 2 re brale et handicaps neurologiques, UMR 825, CHU Purpan, Pavillon Baudot, Toulouse, France Inserm; Imagerie ce 3  de Toulouse, UPS, Imagerie ce re brale et handicaps neurologiques, UMR 825, CHU Purpan, Toulouse, France Universite 4  Pierre et Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle e pinie`re, UMR S975, Paris, France Universite 5 CNRS, UMR 7225, Paris, France 6 Inserm, U975, Paris, France 7 pinie`re, Paris, France ICM—Institut du Cerveau et de la Moelle e

ABSTRACT:

The presence of mirror dystonia (dystonic movement induced by a specific task performed by the unaffected hand) in the dominant hand of writer’s cramp patients when the nondominant hand is moved suggests an abnormal interaction between the 2 hemispheres. In this study we compare the level of interhemispheric inhibition (IHI) in 2 groups of patients with writer’s cramp, one with the presence of a mirror dystonia and the other without as well as a control group. The level of bidirectional IHI was measured in wrist muscles with dual-site transcranial magnetic stimulation with a 10-millisecond (short IHI) and a 40millisecond (long IHI) interstimulus interval during rest and while holding a pen in 9 patients with mirror dystonia 7 without mirror dystonia, and 13 controls. The group of patients without mirror dystonia did not differ from the controls in their IHI level. In contrast, IHI was significantly decreased in the group of patients with mir-

A unique clinical phenomenon in patients with writer’s cramp is mirror dystonia. It is defined as dystonic movement or posture triggered in the affected homolo-

-----------------------------------------------------------Additional Supporting Information may be found in the online version of this article.

*Correspondence to: Dr. Marion Simonetta-Moreau, Service de Neurologie, CHU Purpan, place du Dr Baylac, 31059 Toulouse cedex TSA40031, France; Email: [email protected] Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 23 May 2013; Revised: 6 November 2013; Accepted: 6 November 2013 Published online 18 December 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25768

ror dystonia in comparison with the group without mirror dystonia and the controls in both wrist muscles of both the dystonic and unaffected hand whatever the resting or active condition (P 5 0.001). The decrease of IHI level in the group of patients with mirror dystonia was negatively correlated with the severity and the duration of the disease: the weaker the level of IHI, the more severe was the disease and the longer its duration. Interhemispheric inhibition disturbances are most likely involved in the occurrence of mirror dystonia. This bilateral deficient inhibition further suggests the involvement of the unaffected hemisphere in the pathophysiolC ogy of unilateral dystonia. V 2013 International Parkinson and Movement Disorder Society

K e y W o r d s : interhemispheric inhibition; motor control; motor cortex; TMS; focal hand dystonia

gous muscles by a specific task (eg, writing) performed by the contralateral apparently normal hand.1 Mirror dystonia is seen in about 50% of writer’s cramp (WC) patients2 and can be very useful clinically as guidance for injection of botulinum toxin to distinguish the dystonia from compensatory movements.3 The mirror dystonic posture or movement may involve digit as well as wrist muscles, and its presence in the dominant hand when the nondominant hand is moved suggests an abnormal interaction between the 2 hemispheres. In humans, interhemispheric interactions between homologous muscle representations in primary motor cortices (M1) may be assessed using dual-site transcranial magnetic stimulation (TMS) protocol.4,5 A single

Movement Disorders, Vol. 29, No. 6, 2014

787

S A T T L E R

E T

A L

TABLE 1. Patients’ clinical findings Patient

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Age (y)

Sex

Mirror dystonia

Writer’s Cramp Rating Scale

Symptom duration (y)

Diagnosis

68 67 73 47 50 18 60 27 65 62 50 25 28 20 73 29

F M F M F M M F M M F F M F F M

1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2

4 9 18 14 12 17 16 22 11 5 5 8 4 3 10 9

31 41 51 3 6 10 20 19 46 13 13 7 1 3 13 10

Dystonic cramp Dystonic cramp Dystonic cramp Simple writer’s cramp Simple writer’s cramp Dystonic cramp Simple writer’s cramp Dystonic cramp Simple writer’s cramp Simple writer’s cramp Dystonic cramp Dystonic cramp Simple writer’s cramp Simple writer’s cramp Simple writer’s cramp Simple writer’s cramp

Simple writer’s cramp refers to dystonic symptoms occurring only during writing. Dystonic cramp indicates that dystonia also occurred with writing and other tasks.

TMS conditioning stimulus (CS) is applied to one motor cortex and followed by a test stimulus (TS) applied to the homologous area of the contralateral motor cortex. When preceded by the CS, the motor evoked potential (MEP) evoked by the TS is smaller than when it is evoked by the TS alone for a conditioning-test interval (ISI) between 6 and 50 ms.4,5 Further studies have reported that interhemispheric inhibition (IHI) between homologous M1s at ISIs of 10 ms (short-latency IHI [SIHI]) and 40 ms (long-latency IHI [LIHI]) may have different physiological origins.6-8 Data about mirror dystonia in writer’s cramp are scarce. It has been suggested that deficient interhemispheric inhibition/facilitation from the unaffected to the affected homologous M1 may play a role in its pathophysiology. This hypothesis was only partially confirmed by Beck et al in experiments using a dualsite TMS protocol in a subgroup of patients with a mirror dystonia compared with patients without mirror dystonia.9 The normal IHI reported in this study in the group of patients without mirror dystonia is in contrast with the reduced levels found by Nelson et al in another group of WC patients without mirror dystonia.10 In both studies, IHI was tested during the movement of the dystonic hand (and not during the movement of the unaffected hand) and in digit muscles, whereas the clinical observation of the patients with writer’s cramp showed that wrist muscles are often also involved in the dystonic mirror posture or movement. Using dual-site TMS protocol, we have recently reported that a bidirectional powerful IHI can be elicited at the short and long IHI phases in wrist exten-

788

Movement Disorders, Vol. 29, No. 6, 2014

sor and flexor muscles in healthy right-handed subjects at rest.11 The purpose of the current study was to compare the level of bidirectional SIHI and LIHI in wrist flexor and extensor muscles at rest and during the task of holding a pen performed by the hand contralateral to the conditioning stimulation in a group of writer’s cramp patients with a mirror dystonia (PATMIR1), a group of writer’s cramp patients without mirror dystonia (PATMIR2), and a group of healthy subjects. Our hypothesis was (1) that IHI level at rest in wrist muscles would be lower in patients with mirror dystonia than in patients without mirror dystonia and healthy subjects and (2) that patients with mirror dystonia would have deficient IHI modulation (in wrist muscles) from the unaffected right hemisphere to the affected left one during the postural task performed by the nondominant hand, which would contrast with normal modulation of IHI in the patients without mirror dystonia. This would support the idea that a deficient interhemispheric connection from the unaffected to the affected homologous primary motor cortex plays a role in the pathophysiology of mirror dystonia.

Patients and Methods Subjects Sixteen patients with WC (mean age, 46 years; range, 20-73 years; 9 women; mean duration of symptoms, 18 6 16 years; range, 1-51 years; Table 1) and 13 healthy controls (mean age, 47 years; range, 22-67 years; 8 women) were studied. All subjects were

I H I

I N

W R I T E R ’ S

C R A M P

FIG. 1. Experimental conditions. Experimental setup for studying IHI with dual-site TMS in left and right ECR/FCR muscles in the rest and active conditions (holding a pen with the CS contralateral to the active hand).

right-handed. Handedness (laterality quotient) was confirmed for all participants (0.85 6 0.16) using the Oldfield Handedness Inventory.12 Most patients included had a predominant dystonic posture of the wrist and/or the digits in flexion, (simple cramp, 9 patients; more complex dystonic cramp, 7 patients; Table 1). Nine patients showed mirror dystonia (PATMIR1 group: mean age, 51 years; range, 27-68 years; 4 women), whereas 7 patients did not (PATMIR2 group: mean age, 41 years; range, 20-73 years; 5 women). None of the patients had received botulinum toxin injections for at least 6 months prior to the study. The Writer’s Cramp Rating Scale (WCRS) was used to assess symptom severity13 (mean, 10.4 6 5.7; Table 1). All subjects gave written informed consent for the study. The experimental procedures used were approved by the local ethics committee and were carried out in accordance with the Declaration of Helsinki.

Recordings Surface electromyograms (EMGs) were simultaneously recorded from the left and right extensor carpi radialis (ECR) and flexor carpi radialis (FCR) muscles with Ag-AgCl surface electrodes. EMG signals were amplified (DIGITIMER D360), filtered (20 Hz to 2 KHz), digitized, and fed through a CED (Cambridge Electronic Design, Cambridge, UK) laboratory interface (sampling frequency, 5 kHz) to a PC for display, storage, and off-line analysis. The EMG signal of the four channels was also displayed on an oscilloscope (Textronix, Beaverton, OR) in order to monitor the resting and active conditions (see below).

Transcranial Magnetic Stimulation TMS was delivered to the motor cortex bilaterally using 2 Magstim 200 stimulators (The Magstim Co., Dyfed, UK) and through 2 figure-of-eight coils (outside diameter of each wing, 9 cm), with the handle of the coils pointed backward at approximately 45 from the midsagittal line.

Interhemispheric Inhibition The protocol used to test IHI has been described in a previous article.11 A conditioning stimulus (CS) to the optimal site on the scalp (hot spot) for wrist muscles (either ECR or FCR) of one hemisphere was followed by a test stimulus applied to the homologous hot spot in the opposite hemisphere. Two CS-TS ISIs were studied: 10 ms for SIHI and 40 ms for LIHI.14 Each block of stimulation consisted of 30 stimulations delivered every 5 seconds (10 TS alone, 10 CS-TS ISI 10 and 10 CS-TS ISI 40 randomly alternated). Two conditions were tested (Fig. 1): (1) rest, with both hands completely relaxed as confirmed by online EMG recordings, and (2) pen holding in the right or left hand, with the contralateral hand at rest.

Experimental Protocol For each participant, IHI was first tested at rest in both directions with IHI directions randomized across participants. Two other blocks were recorded during isometric left or right wrist contraction. In each of them, CS was applied contralateral to the hand holding the pen and TS contralateral to the resting hand (active condition); see Figure 1. The intensities of both

Movement Disorders, Vol. 29, No. 6, 2014

789

S A T T L E R

E T

A L

the conditioning and test stimuli were adjusted to elicit an MEP of 1 mV in the contralateral ECR and FCR muscles, irrespective of whether the muscle was at rest or active. This was done to normalize IHI to the increase in corticospinal excitability caused by voluntary contraction.10,11,14,15

during isometric contraction, TMS intensities to evoke MEPs of 1 mV were significantly lower than at rest (CONDITION, F1,26 5 25.5, P 5 0.0003; no significant interaction GROUP 3 CONDITION, F2,26 5 1.94, P 5 0.7); see Table 3.

Data Analyses

MEP size was often larger in the ECR than in the FCR and larger in the active condition yet did not differ between patients and controls (MUSCLE, F1,26 5 6.33, P 5 0.01; CONDITION, F1,26 5 8.6, P 5 0.007; GROUP, F2,26 5 1.45, P 5 0.2; SIDE, F1,26 5 1.84, P 5 0.1; CONDITION 3 GROUP, F2,26 5 2.89, P 5 0.07); see Table 3.

MEP Test Responses were rectified off-line to measure the areas of the ECR and FCR MEPs, using Signal V4 software. The MEP area window of analysis was set by vertical cursors at the duration of the biggest rectified MEP. The paired-pulse MEP area was expressed as a ratio of the mean conditioned MEP area (CS 1 TS) to the mean unconditioned MEP area (TS alone) for each subject and each condition. The mean area of the prestimulus EMG was calculated for a 30-ms window prior to the first TMS pulse for each trial in each condition in order to analyze the background EMG in ECR and FCR wrist muscles during the postural task and to compare it with the background EMG at rest. The prestimulus background EMG levels and the test MEP size were compared between rest and contraction (CONDITION), the right and left sides (SIDE), and the ECR and FCR muscles using a 3-level repeated analysis of variance (ANOVA) with GROUP as the between-subject variable. TMS intensities used were similarly tested with HEMISPHERE STIMULATED (2 levels, left M1 and right M1), CONDITION (rest/active), STIM (stimulus type; 2 levels, TS and CS). Repeated-measures ANOVA was used on normalized MEPs (MEP CS/MEP TS) to test the effect of IHI DIRECTION (2 levels, right M1 to left M1 and left M1 to right M1), CONDITION (2 levels, rest and active), CS-TS interval ISI (2 levels, 10 ms [SIHI] and 40 ms [LIHI]) as within-subject factors and GROUP as the between-subject variable (3 levels, PATMIR1, PATMIR2, and controls). Post hoc tests were performed using the Bonferroni corrected Student t test. The score on the WCRS and duration of symptoms were compared between the PATMIR1 and PATMIR2 groups with unpaired t tests. Correlations between clinical (WCRS, symptom duration, age) and electrophysiological (SIHI, LIHI) data were investigated using a Spearman test. The level of significance was set at P < 0.05. All data are presented as mean 6 standard deviation.

Results TMS Intensities TMS intensities used to obtain an MEP of 1 mV in ECR and FCR muscles did not significantly differ between the groups (GROUP, F2,26 5 1.38, P 5 0.2) or between left and right hemisphere (HEMISPHERE STIMULATED, F1,26 5 3.37, P 5 0.07). As expected,

790

Movement Disorders, Vol. 29, No. 6, 2014

Prestimulus EMG For the ECR, EMG level was significantly greater for the hand performing the task compared with rest and was similar across groups during all conditions (CONDITION, F1,26 5 89.7, P 5 0.0001; GROUP, F2,26 5 0.82, P 5 0.4; SIDE, F1,26 5 0.17, P 5 0.67; no interaction CONDITION 3 GROUP, F1,26 5 0.33, P 5 0.7, or SIDE 3 GROUP, F2,26 5 0.88, P 5 042). For the FCR, EMG level was significantly greater for the hand performing the task compared with rest but was not similar in the 3 groups (GROUP, F2,26 5 11.08, P 5 0.003; CONDITION, F1,26 5 13.53, P 5 0.001; SIDE, F1,26 5 1.21, P 5 0.28), with a significant interaction CONDITION 3 SIDE 3 GROUP (F2,26 5 4.94, P 5 0.01). Post hoc analysis showed a difference in the FCR EMG level between the PATMIR1 group and the controls (P 5 0.0003), the PATMIR2 group and the controls (P 5 0.01) and no differences between the 2 groups of patients (P 5 0.8). The significant interaction was explained by the FCR EMG level of both patient groups in the active condition being different (greater) compared with controls only when the task was performed with the right (dystonic) hand (PATMIR1/controls, P 5 0.001; PATMIR2/controls, P 5 0.05; PATMIR1/PATMIR2, P 5 1) and not when it was performed with the left (unaffected) hand (Fig. 4, Supporting Data).

Interhemispheric Inhibition The levels of SIHI and LIHI did not differ between the PATMIR2 group and the controls but were lower for the PATMIR1 group compared with the controls or the PATMIR2 group. These results were similarly observed in both muscles, for either direction of the IHI, and at rest as well as during pen holding (Fig. 2 and Table 2).

ECR Muscle At rest the PATMIR1 group showed a bilateral decrease in both SIHI and LIHI compared with the

I H I

I N

W R I T E R ’ S

C R A M P

FIG. 2. IHI in ECR and FCR muscles. Comparison of the mean MEP cond/MEP test ratio 6 SD at short (SIHI) and long (LIHI) delays in ECR and FCR muscles during rest and isometric contraction of the hand contralateral to CS among the control group (white bars), the PATMIR1 group (black bars), and the PATMIR2 group (gray bars).

controls or with the PATMIR2 group. During contralateral wrist muscle contraction, a bidirectional reduction in IHI compared with at rest was observed in the control group and to the same extent in both patient subgroups. Three-way repeated-measures ANOVA revealed main effects of GROUP (F2,26 5 8.08, P 5 0.002) and CONDITION (F1,26 5 11.02 P 5 0.003) without interaction between these 2 factors (F2,26 5 0.72, P 5 0.49) and no effect of IHI direction (F1,26 5 0.0004, P 5 0.9) or ISI (F1,26 5 0.26, P 5 0.6) but an interaction of ISI 3 GROUP (F2,26 5 3.57, P 5 0.04). Both SIHI and LIHI were reduced in the PATMIR1 group compared with the controls and the PATMIR2 group for both the dystonic and unaffected hands and for both IHI directions; post hoc tests reached significance only for LIHI (PATMIR1/con-

trols, P 5 0.001, PATMIR1/PATMIR2, P 5 0.002). The levels of SIHI and LIHI did not differ between the PATMIR2 group and the controls (P 5 1) for all conditions. Contralateral wrist muscle contraction evoked a global, bidirectional SIHI and LIHI reduction that did not differ across the 3 groups (P 5 0.001, no interaction of GROUP 3 CONDITION (F2,26 5 0.72, P 5 0.49).

FCR Muscle For the FCR muscle, we also found a main effect of GROUP (F2,26 5 5.71, P 5 0.009) but no effect of CONDITION (F1,26 5 0.009, P 5 0 .92) nor an interaction between these 2 factors, which means that IHI was not different during the motor task compared with rest across the 3 groups. There were no main

TABLE 2. Mean ratio of MEP cond/MEP test 6 SD for ECR and FCR in rest and active conditions at both short (10-ms) and long (40-ms) ISIs for each group

Controls PATMIR1 PATMIR2

Controls PATMIR1 PATMIR2

R ECR10, rest

L ECR10, rest

R ECR10, lph

L ECR10, rph

R ECR40, rest

L ECR40, rest

R ECR40, lph

L ECR40, rph

0.55 6 0.21 0.70 6 0.38 0.64 6 0.29

0.53 6 0.37 0.94 6 0.10 0.51 6 0.32

0.81 6 0.26 0.88 6 0.28 0.70 6 0.37

0.66 6 0.19 0.88 6 0.28 0.62 6 0.31

0.58 6 0.22 0.68 6 0.21 0.62 6 0.27

0.56 6 0.23 0.81 6 0.13 0.58 6 0.21

0.76 6 0.39 0.86 6 0.21 0.67 6 0.27

0.71 6 0.19 0.97 6 0.27 0.59 6 0.27

R FCR10, rest

L FCR10, rest

R FCR10, lph

L FCR10, rph

R FCR40, rest

L FCR40, rest

R FCR40, lph

L FCR40, rph

0.57 6 0.22 1.04 6 0.31 0.75 6 0.40

0.61 6 0.23 0.89 6 0.36 0.57 6 0.29

0.77 6 0.28 0.95 6 0.19 0.63 6 0.33

0.65 6 0.22 0.86 6 0.43 0.61 6 0.21

0.61 6 20 0.93 6 0.34 0.63 6 0.22

0.66 6 0.23 0.75 6 0.31 0.69 6 0.29

0.75 6 0.26 0.90 6 0.36 0.57 6 0.29

0.74 6 0.28 0.74 6 0.15 0.60 6 0.20

lph, left pen hold; rph, right pen hold.

Movement Disorders, Vol. 29, No. 6, 2014

791

S A T T L E R

E T

A L

TABLE 3. Mean TMS intensities (test and conditioning in percentage of maximum stimulus input) and mean MEP test areas (mV/ms2) 6 SD in the 4 conditions (left MEP rest, rph [right pen hold]; right MEP rest, lph [left pen hold] and in the 3 groups TS intensity

Right M1stim rest Controls PATMIR1 PATMIR2 Right M1stim rph Controls PATMIR1 PATMIR2 Left M1 stim rest Controls PATMIR1 MIR2 Left M1stim lph Controls PATMIR1 PATMIR2

CS intensity

ECR MP area

FCR MEP area

58.8 6 7.8 57.1 6 8.8 56.6 6 7.9

58.6 6 7.2 56 6 8.3 52.4 6 5.7

0.27 6 0.1 0.37 6 0.1 0.43 6 02

0.30 6 0.1 0.35 6 0.1 0.41 6 0.3

57.3 6 7.6 56 6 9.9 52.2 6 5.7

54.6 6 7.6 50.7 6 9.3 49.2 6 5

0.36 6 0.1 0.63 6 0.3 0.50 6 0.2

0.36 6 0.3 0.61 6 0.4 0.71 6 0.7

60 6 7.8 57.6 6 9.3 54.4 6 7 .4

59.7 6 6.3 56.8 6 8.5 54.8 6 8.2

0.50 6 0.3 0.47 6 0.2 0.58 6 0.3

0.33 6 0.1 0.31 6 0.2 0.38 6 0.4

59.3 6 7.3 55.4 6 8.1 54.4 6 8.5

56.6 6 7.1 52.2 6 7.2 53.5 6 6.2

0.49 6 0.3 0.76 6 0.6 0.71 6 0.6

0.41 6 0.3 0.34 6 0.2 0.35 6 0.2

effects of IHI direction (F1,26 5 0.89, P 5 0.35) or ISI (F1,26 5 2.24, P 5 0.14) and no interaction between these factors and group (F2,26 5 0.15, P 5 0.8; F2,26 5 3.57, respectively; P 5 0.4). Post hoc analysis showed that both SIHI and LIHI were significantly reduced in the PATMIR1 group in comparison with the controls (SIHI, P 5 0.03; LIHI, P 5 0.02) and the PATMIR2 group (SIHI, P 5 0.05; LIHI, P 5 0.02) for both the dystonic and unaffected hand and for both IHI directions. As for the ECR, the PATMIR2 group of patients did not differ from the controls (P 5 1).

Correlations With Clinical Data The mean severity score was higher in the PATMIR1 group than in the PATMIR2 group (13.6 6 5.3 vs. 6.2 6 2.6, respectively; P 5 0.005). There was also a longer duration of symptoms for the PATMIR1 group than for the PATMIR2 group (25.2 6 17.8 vs. 9.2 6 6, respectively; P 5 0.05) but no difference in age between the 2 groups (PATMIR1, 51.4 6 18.7; PATMIR2, 41 6 21.1; P 5 0.4). In the PATMIR2 group IHI levels did not correlate with severity score or duration of disease. In contrast, the amount of SIHI in the ECR muscle was negatively correlated with the severity score in the PATMIR1 group at rest (PATMIR1, r 5 0.83, P 5 0.005; all patients, r 5 0.50, P 5 0.04; Fig. 3A): the higher the score, the lower was the level of IHI from the right unaffected M1 to the left affected M1. Similar correlation was found for FCR muscle (Fig. 3B). The amount of SIHI and LIHI at rest in the right FCR muscle was also inversely correlated with the duration of symptoms

792

Movement Disorders, Vol. 29, No. 6, 2014

in the PATMIR1 group (SIHI, r 5 0.85, P 5 0.003; LIHI, r 5 0.83, P 5 0.005; Fig. 3C): the longer the duration of symptoms, the weaker was the level of IHI.

Discussion There were two main findings in the present study. First, although at rest, IHI was normal in writer’s cramp patients without mirror dystonia, it was bilaterally decreased in the patients who had mirror dystonia. The larger the decrease in IHI in these patients, the higher was the severity score, and the longer was the duration of symptoms. Second, during pen holding, modulation of IHI was similar in writer’s cramp patients and healthy subjects irrespective of the presence of mirror dystonia or of the tested side being affected or unaffected. These results only partly support our hypothesis and may appear contradictory. On the one hand, decreased IHI at rest and correlations with severity score and duration of disease were only observed in the group of patients with mirror dystonia, suggesting that impaired IHI may be a hallmark of mirror dystonia. On the other hand, movement-induced modulation of IHI was normal in patients irrespective of the side of the hand holding the pen and of the presence of mirror dystonia, suggesting that dynamic changes in IHI do not matter in mirror dystonia. We will focus on this discrepancy in the following discussion.

Can IHI Changes in Patients With Mirror Dystonia Be Explained by Methodological Factors? Differences in IHI level cannot be influenced by methodological factors such as TMS intensity or MEP size4 because there were no differences in MEP test sizes or TMS intensities used among the 3 groups or between hemispheres. There was no difference between the background EMG level across the 3 groups in the 4 conditions tested, except for background EMG of the right FCR, which was higher in both WC patient groups compared with controls. A possible explanation is the predominant involvement of flexor muscles in the dystonic hand of most of our patients and also a possible decrease in reciprocal inhibition.16,17 The physiologically weaker FCR contraction compared with ECR contraction observed in normal subjects when holding a pen may have also amplified these differences.11 However, although IHI disturbances were observed bilaterally in both muscles and only in patients with mirror dystonia, background FCR EMG differences were strictly unilateral and observed in both patient groups, and so their impact was likely minor.

I H I

I N

W R I T E R ’ S

C R A M P

FIG. 3. Correlations between IHI level and clinical findings. Correlations between the MEP cond/MEP test ratio (IHI level) and clinical findings (A, B: severity score; C: duration of symptoms) found in right ECR and right and left FCR at rest (black symbols, PATMIR1; gray symbols, PATMIR2). The amount of SIHI in the ECR muscle of the right dystonic hand was negatively correlated with the severity score in the PATMIR1 group at rest (A: PATMIR1, r 5 0.83, P 5 0.005; all patients, r 5 0.50, P 5 0.04). A negative correlation was also found between the severity score and the amount of SIHI in the left FCR muscle (B: all patients, r 5 0.60, P 5 0.01; PATMIR1, r 5 0.45, P 5 0.2). The amount of SIHI at rest for the right FCR muscle was also inversely correlated with the duration of symptoms in the PATMIR1 group (C: r 5 0.85, P 5 0.003).

Does Normal Modulation of IHI During the Simple Task of Holding a Pen in Dystonic Patients Exclude the Hypothesis That IHI May Play a Role in Mirror Dystonia? In healthy adults overt mirror movements are typically absent. Mirror EMG activity can be seen occasionally if the task is demanding, if fatigue occurs, or if the attentional capacities decrease with aging.18 Several studies19-21 support the notion that transcallosally mediated IHI from the voluntary active to the contralateral M1 plays a functionally relevant role in suppressing unwanted mirror activity during intentional unilateral movements. To reach such a concept, IHI from the active to the mirror contralateral M1 was altered by means of rTMS applied to the active M1. IHI changes were associated with changes in mirror activity: an increase in IHI going with a decrease in mirror activity and vice versa.20 So a functional role of IHI from the active to the contralateral M1 in nor-

mal subjects performing unilateral intentional movements was clearly established. This was shown mainly for finger muscles, which can be engaged in highly selective and complex motor activities. In normal subjects we had previously shown that SIHI was more bidirectionally reduced than LIHI in wrist muscles in comparison with rest during a postural task (holding a pen as in the present study) involving the hand contralateral to the CS stimulation. This was more pronounced for the ECR than for the FCR muscle.11 These results fit those of Nelson et al,14 who described a bidirectional decrease of IHI for flexor digitorum indicis (FDI) muscles when the subjects performed isometric contraction of the FDI muscle in the context of holding a pen. Results from other studies are less consistent, as IHI is found to be either increased or decreased in comparison with rest depending on the methodology used and on the type of movement (adjustment or no adjustment of the

Movement Disorders, Vol. 29, No. 6, 2014

793

S A T T L E R

E T

A L

intensity of conditioning magnetic stimulation between active and rest conditions).4,8,15,22,23 Here, we confirm our previous results in healthy subjects, and we add that unexpectedly in dystonic patients, SIHI and LIHI were reduced during holding the pen as they were in healthy subjects. Even in patients with mirror dystonia who had reduced IHI, a small IHI was still measurable, and it did decrease during pen holding. This negative result raises the issue of whether the normal modulation of IHI from the active to the contralateral M1 that we observed during the holding of a pen faithfully reflects what happens during mirror dystonia. In other words, does this negative result rule out the idea that impaired IHI is involved in mirror dystonia? Probably not. Mirror dystonia represents an involuntary movement of the dystonic hand caused by the intended recall of a given motor program executed by the unaffected hand (most often the left one). In the present experiments the subjects did not exactly “recall” an overlearned motor program; they performed intentional postural contractions. The neural circuits engaged in the two situations are different, and this probably results in different modulations of IHI. Also, although writing is supported by a complex pattern of bursts of alternating activities in numerous forearm and finger muscles,24 holding a pen induces a tonic muscle activity. It is known that mechanisms controlling the corticospinal output to the resting hand during unimanual movement differ in an activity-dependent manner,15 and this is verified for IHI, SICI, and their interaction. So modulation of IHI from the active to the contralateral M1 can be influenced differently during a tonic activity like holding a pen and a phasic complex activity such as writing.

Does Decreased IHI at Rest Play a Role in Mirror Dystonia? SIHI and LIHI were lower in both hemispheres of patients with mirror dystonia compared with patients without mirror dystonia. As the PATMIR1 group had more severe disease than the PATMIR2 group (longer duration of illness, higher severity score), it is possible that impaired IHI reflects the severity of the illness more rather than being related to the presence of mirror dystonia. From this point of view, patients without mirror dystonia should later develop progressive loss of IHI and mirror dystonia correlated with worsening of the dystonia. Although not ruling it out, the history of the illness in our patients does not favor this view. Four of the 7 patients in the PATMIR2 group had a follow-up of 10 years or more and mirror dystonia did not occur in any of them. In contrast, 3 patients in the PATMIR1 group in whom the diagnosis of focal hand dystonia was made soon after the first symptoms occurred showed a mirror dystonia at the

794

Movement Disorders, Vol. 29, No. 6, 2014

first visit. So decreased IHI seems to be related more to the presence of mirror dystonia than to the severity or duration of the disease. It fits with recent results obtained in healthy subjects. The baseline level of SIHI, which varies from person to person, was highly predictive of how well individuals would improve performance of a motor task, whereas there was no change in IHI from the trained to the contralateral hemisphere for after training versus before training. Individual changes in EMG mirroring did correlate with the baseline level of SIHI: the greater the baseline level of SIHI, the greater was the reduction in EMG mirroring.25 The authors conclude that individuals with greater SIHI at rest have a greater potential for controlling mirror activity during training in intentional movement, as more “resource” is available. If we consider that dystonic patients, like healthy subjects, have different baseline levels of IHI, that is, different “resource” in the use of IHI for controlling mirror activity, it could be that those patients with low baseline levels of SIHI are more prompt to develop mirror dystonia than those with high levels of baseline SIHI. Both groups have similar impairment of GABAergic circuits, but an additional factor, that is, limited “resource” of IHI, is necessary for mirror dystonia to develop. As IHI levels are found to be decreased in both hemispheres of patients with mirror dystonia, we can wonder whether a low level of SIHI constitutes a more general predictive factor for mirroring activities, be they mirror dystonia or mirror movements, than a specific predictor of mirror dystonia. That occurrence of mirror dystonia does not parallel occurrence of mirror movements may be linked with the dystonic features of the affected hemisphere being superimposed on additional phenomena secondary to the occurrence of the dystonic movements/contractures.

Motor Drive in the Mirror Affected Hemisphere? There is a large body of evidence supporting the view that physiological “mirroring” activity exists in healthy adults.26-28 Overt mirror activity can develop if the task is demanding, if there is concomitant fatigue or cognitive distractions, and if there is decreased attention. Such mirroring activity was probed by asking the subjects to maintain a background isometric muscle contraction with the mirror hand while they were performing a voluntary movement with the other hand29-31 or by measuring the duration of the silent period after ipsilateral TMS activation.4,32,33 Neurophysiological data from these studies suggest that “physiological” mirroring depends on activation of the crossed corticospinal tract originating from the mirror M1 and results from the transfer of activation from the task-M1 to the mirror-M1 through

I H I

excitatory transcallosal pathways.34 Strictly unimanual voluntary movements involve a neural so-called nonmirror transformation network35,36 that transforms bilateral to lateralized neural activity.35,36 Activation of this network occurs late during preparation of intentional unilateral movements. Data from lesioned monkeys, humans patients, and healthy subjects undergoing rTMS suggest that the supplementary motor area (SMA), dorsal premotor cortex (PMd), cingulate gyrus, and interhemispheric pathways are involved in restricting the production of motor output to the task hemisphere.30,35,37 Inhibition of motor output in the mirror M1 through an active inhibition process mediated by inhibitory transcallosal inputs from the task to the mirror M1 may also be involved.4 During voluntary activation of the unaffected M1 in patients with mirror dystonia, there is an excitatory drive to the neurons of the affected mirror M1 that is strong enough to make them discharge. A simple explanation is a failure of the “nonmirror transformation” network with abnormal motor programming in the secondary motor areas, leading to the inability to restrict the motor output to the task M1. Accordingly, using fMRI, abnormal activity of the PMd was observed in patients with writer’s cramp who imagined grasping a pencil to write compared with grasping a pencil to sharpen it.38 Another explanation would be enhancement of the physiological mirroring system with enhanced transfer from the “unaffected” overactivated hemisphere to the affected mirror hemisphere through excitatory transcallosal pathways. Transcallosal pathways consist of excitatory glutamatergic neurons39 that synapse on inhibitory cells as well as on excitatory ones in the receiving M1. In the case of a hyperactive unaffected M1, MEPs evoked from the unaffected M1 were expected to be larger in the mirror group than in the nonmirror group. That was not the case. Whatever the origin of the excitatory drive to the motor neurons in the affected hemisphere during mirror dystonia, decreased local GABAergic inhibition in the affected mirror cortex,40-44 and low levels of baseline interhemispheric inhibition (our results) both favor the building up of motor output from the affected M1. GABAergic inhibition is also decreased in the unaffected motor cortex, and this favors an enhanced drive from the unaffected to the affected one. As GABAergic inhibition is decreased in both M1s irrespective of the presence of mirror dystonia,40-44 it probably does not participate in mirror dystonia production. In contrast, low baseline levels of IHI, which is specifically decreased in patients with mirror dystonia, may constitute a factor of susceptibility to mirror dystonia development. In conclusion, we have provided further evidence for altered interhemispheric communication between M1s in patients with writer’s cramp and mirror dystonia

I N

W R I T E R ’ S

C R A M P

compared with patients without mirror dystonia or healthy controls. In addition to bilateral deficient intrinsic M1 inhibition, IHI disturbances are likely involved in the occurrence of mirror dystonia and might be associated with the expression of a more severe focal hand dystonia, as supported by the correlations found between clinical findings and amount of IHI decrease. This bilateral deficient IHI fits well into the global failure of cortical inhibitory mechanisms in dystonia and further suggests that the contralateral, clinically unaffected hemisphere is also involved in the pathophysiology of task-specific focal hand dystonia.

References 1.

Sitburana O, Jankovic J. Focal hand dystonia, mirror dystonia and motor overflow. J Neurol Sci 2008;266:31-33.

2.

Jedynak PC, Tranchant C, de Beyl DZ. Prospective clinical study of writer’s cramp. Mov Disord 2001;16:494-499.

3.

Singer C, Papapetropoulos S, Vela L. Use of mirror dystonia as guidance for injection of botulinum toxin in writing dysfunction. J Neurol Neurosurg Psychiatry 2005;76:1608-1609.

4.

Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, Marsden CD. Interhemispheric inhibition of the human motor cortex. J Physiol 1992;453:525-546.

5.

Gerloff C, Cohen LG, Floeter MK, Chen R, Corwell B, Hallett M. Inhibitory influence of the ipsilateral motor cortex on responses to stimulation of the human cortex and pyramidal tract. J Physiol 1998;510:249-259.

6.

Chen R, Yung D, Li JY. Organization of ipsilateral excitatory and inhibitory pathways in the human motor cortex. J Neurophysiol 2003;89:1256-1264.

7.

Kukaswadia S, Wagle-Shukla A, Morgante F, Gunraj C, Chen R. Interactions between long latency afferent inhibition and interhemispheric inhibitions in the human motor cortex. J Physiol 2005;563: 915-924.

8.

Talelli P, Waddingham W, Ewas A, Rothwell JC, Ward NS. The effect of age on task-related modulation of interhemispheric balance. Exp Brain Res 2008;186:59-66.

9.

Beck S, Shamim EA, Richardson SP, Schubert M, Hallett M. Interhemispheric inhibition is impaired in mirror dystonia. Eur J Neurosci 2009;29:1634-1640.

10.

Nelson AJ, Hoque T, Gunraj C, Ni Z, Chen R. Impaired interhemispheric inhibition in writer’s cramp. Neurology 2010;75:441-447.

11.

Sattler V, Dickler M, Michaud M, Simonetta-Moreau M. Interhemispheric inhibition in human wrist muscles. Exp Brain Res 2012; 221:449-458.

12.

Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9:97-113.

13.

Wissel J, Kabus C, Wenzel R, et al. Botulinum toxin in writer’s cramp: objective response evaluation in 31 patients. J Neurol Neurosurg Psychiatry 1996;61:172-175.

14.

Nelson AJ, Hoque T, Gunraj C, Ni Z, Chen R. Bi-directional interhemispheric inhibition during unimanual sustained contractions. BMC Neurosci 2009;10:31.

15.

Perez MA, Cohen LG. Mechanisms underlying functional changes in the primary motor cortex ipsilateral to an active hand. J Neurosci 2008;28:5631-5640.

16.

Chen RS, Tsai CH, Lu CS. Reciprocal inhibition in writer’s cramp. Mov Disord 1995;10:556-561.

17.

Panizza ME, Hallett M, Nilsson J. Reciprocal inhibition in patients with hand cramps. Neurology 1989;39:85-89.

18.

Beaule V, Tremblay S, Theoret H. Interhemispheric control of unilateral movement. Neural Plast 2012;2012:627816.

19.

Gilio F, Rizzo V, Siebner HR, Rothwell JC. Effects on the right motor hand-area excitability produced by low-frequency rTMS

Movement Disorders, Vol. 29, No. 6, 2014

795

S A T T L E R

E T

A L

motor cortical areas in normal humans and patients with abnormalities of the corpus callosum. Brain 1995;118:429-440.

over human contralateral homologous cortex. J Physiol 2003;551: 563-573. 20.

Hubers A, Orekhov Y, Ziemann U. Interhemispheric motor inhibition: its role in controlling electromyographic mirror activity. Eur J Neurosci 2008;28:364-371.

21.

22.

23.

33.

Pal PK, Hanajima R, Gunraj CA, et al. Effect of low-frequency repetitive transcranial magnetic stimulation on interhemispheric inhibition. J Neurophysiol 2005;94:1668-1675.

Zijdewind I, Butler JE, Gandevia SC, Taylor JL. The origin of activity in the biceps brachii muscle during voluntary contractions of the contralateral elbow flexor muscles. Exp Brain Res 2006; 175:526-535.

34.

Duque J, Mazzocchio R, Dambrosia J, Murase N, Olivier E, Cohen LG. Kinematically specific interhemispheric inhibition operating in the process of generation of a voluntary movement. Cereb Cortex 2005;15:588-593.

Cincotta M, Borgheresi A, Balestrieri F, et al. Mechanisms underlying mirror movements in Parkinson’s disease: a transcranial magnetic stimulation study. Mov Disord 2006;21:1019-1025.

35.

Hinder MR, Schmidt MW, Garry MI, Summers JJ. Unilateral contractions modulate interhemispheric inhibition most strongly and most adaptively in the homologous muscle of the contralateral limb. Exp Brain Res 2010;205:423-433.

Chan JL, Ross ED. Left-handed mirror writing following right anterior cerebral artery infarction: evidence for nonmirror transformation of motor programs by right supplementary motor area. Neurology. 1988;38:59-63.

36.

Cincotta M, Ziemann U. Neurophysiology of unimanual motor control and mirror movements. Clin Neurophysiol 2008;119:744762.

24.

Linderman M, Lebedev MA, Erlichman JS. Recognition of handwriting from electromyography. PLoS One 2009;4:e6791.

37.

25.

Bologna M, Caronni A, Berardelli A, Rothwell JC. Practice-related reduction of electromyographic mirroring activity depends on basal levels of interhemispheric inhibition. Eur J Neurosci 2012;36: 3749-3757.

Cincotta M, Borgheresi A, Balestrieri F, et al. Involvement of the human dorsal premotor cortex in unimanual motor control: an interference approach using transcranial magnetic stimulation. Neurosci Lett 2004;367:189-193.

38.

26.

Addamo PK, Farrow M, Hoy KE, Bradshaw JL, GeorgiouKaristianis N. The effects of age and attention on motor overflow production—a review. Brain Res Rev 2007;54:189-204.

Delnooz CC, Helmich RC, Medendorp WP, Van de Warrenburg BP, Toni I. Writer’s cramp: increased dorsal premotor activity during intended writing. Hum Brain Mapp 2013;34:613-625.

39.

27.

Aranyi Z, Rosler KM. Effort-induced mirror movements. A study of transcallosal inhibition in humans. Exp Brain Res 2002;145:7682.

Geffen GM, Jones DL, Geffen LB. Interhemispheric control of manual motor activity. Behav Brain Res 1994;64:131-140.

40.

Beck S, Richardson SP, Shamim EA, Dang N, Schubert M, Hallett M. Short intracortical and surround inhibition are selectively reduced during movement initiation in focal hand dystonia. J Neurosci 2008;28:10363-10369.

41.

Chen R, Wassermann EM, Canos M, Hallett M. Impaired inhibition in writer’s cramp during voluntary muscle activation. Neurology 1997;49:1054-1059.

42.

Ikoma K, Samii A, Mercuri B, Wassermann EM, Hallett M. Abnormal cortical motor excitability in dystonia. Neurology 1996; 46:1371-1376.

43.

Ridding MC, Sheean G, Rothwell JC, Inzelberg R, Kujirai T. Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia. J Neurol Neurosurg Psychiatry 1995;59:493-498.

44.

Stinear CM, Byblow WD. Impaired modulation of intracortical inhibition in focal hand dystonia. Cereb Cortex 2004;14:555-561.

28.

Baliz Y, Armatas C, Farrow M, et al. The influence of attention and age on the occurrence of mirror movements. J Int Neuropsychol Soc 2005;11:855-862.

29.

Cincotta M, Giovannelli F, Borgheresi A, et al. Surface electromyography shows increased mirroring in Parkinson’s disease patients without overt mirror movements. Mov Disord 2006;21:14611465.

30.

Giovannelli F, Borgheresi A, Balestrieri F, et al. Role of the right dorsal premotor cortex in “physiological” mirror EMG activity. Exp Brain Res 2006;175:633-640.

31.

Mayston MJ, Harrison LM, Stephens JA. A neurophysiological study of mirror movements in adults and children. Ann Neurol 1999;45:583-594.

32.

Meyer BU, Roricht S, Grafin von Einsiedel H, Kruggel F, Weindl A. Inhibitory and excitatory interhemispheric transfers between

796

Movement Disorders, Vol. 29, No. 6, 2014