BRAINA JOURNAL OF NEUROLOGY

Defective cerebellar control of cortical plasticityin writer’s crampCecile Hubsch,1,2 Emmanuel Roze,1,2,3,4,5 Traian Popa,2,3,4,5 Margherita Russo,6

Ammu Balachandran,7 Salini Pradeep,7 Florian Mueller,8 Vanessa Brochard,9 Angelo Quartarone,6

Bertrand Degos,1 Marie Vidailhet,1,2,3,4,5 Asha Kishore7,* and Sabine Meunier2,3,4,5,*

1 Department of Neurology, Groupe Hospitalier Pitie-Salpetriere, Paris, France

2 ICM – Institut du Cerveau et de la Moelle epiniere, Paris, France

3 Universite Pierre et Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle epiniere, UMR-S975, Paris, France

4 CNRS, UMR 7225, Paris, France

5 Inserm, U975, Paris, France

6 Department of Neurosciences, University of Messina, Messina, Italy

7 Comprehensive Care Centre for Movement Disorders, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology,

Kerala, India

8 Institut Pasteur, Unite Imagerie et Modelisation CNRS, URA 2582, F-75015, Paris, France

9 Centre for Clinical Investigations Pitie-Salpetriere CIC No 9503, Paris, France

*These authors contributed equally to this work.

Correspondence to: Sabine Meunier MD, PhD,

CRICM INSERM UMRS_975 CNRS UMR 7225,

‘Movement disorders and basal ganglia: pathophysiology and experimental therapeutics’,

ICM building, room 1040, GH Pitie Salpetriere, 75651 Paris cedex 13 France.

E-mail: sabine.meunier@upmc.fr

A large body of evidence points to a role of basal ganglia dysfunction in the pathophysiology of dystonia, but recent studies indicate

that cerebellar dysfunction may also be involved. The cerebellum influences sensorimotor adaptation by modulating sensorimotor

plasticity of the primary motor cortex. Motor cortex sensorimotor plasticity is maladaptive in patients with writer’s cramp. Here we

examined whether putative cerebellar dysfunction in dystonia is linked to these patients’ maladaptive plasticity. To that end we

compared the performances of patients and healthy control subjects in a reaching task involving a visuomotor conflict generated by

imposing a random deviation (�40� to 40�) on the direction of movement of the mouse/cursor. Such a task is known to involve the

cerebellum. We also compared, between patients and healthy control subjects, how the cerebellum modulates the extent and

duration of an ongoing sensorimotor plasticity in the motor cortex. The cerebellar cortex was excited or inhibited by means of

repeated transcranial magnetic stimulation before artificial sensorimotor plasticity was induced in the motor cortex by paired asso-

ciative stimulation. Patients with writer’s cramp were slower than the healthy control subjects to reach the target and, after having

repeatedly adapted their trajectories to the deviations, they were less efficient than the healthy control subjects to perform reaching

movement without imposed deviation. It was interpreted as impaired washing-out abilities. In healthy subjects, cerebellar cortex

excitation prevented the paired associative stimulation to induce a sensorimotor plasticity in the primary motor cortex, whereas

cerebellar cortex inhibition led the paired associative stimulation to be more efficient in inducing the plasticity. In patients with

writer’s cramp, cerebellar cortex excitation and inhibition were both ineffective in modulating sensorimotor plasticity. In patients

with writer’s cramp, but not in healthy subjects, behavioural parameters reflecting their capacity for adapting to the rotation and for

washing-out of an earlier adaptation predicted the efficacy of inhibitory cerebellar conditioning to influence sensorimotor plasticity:

the better the online adaptation, the smaller the influence of cerebellar inhibitory stimulation on motor cortex plasticity. Altered

cerebellar encoding of incoming afferent volleys may result in decoupling the motor component from the afferent information flow,

doi:10.1093/brain/awt147 Brain 2013: 136; 2050–2062 | 2050

Received February 4, 2013. Revised March 30, 2013. Accepted April 18, 2013

� The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

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and also in maladjusted sensorimotor calibration. The loss of cerebellar control over sensorimotor plasticity might also lead to

building up an incorrect motor program to specific adaptation tasks such as writing.

Keywords: cerebellum; dystonia; plasticity; transcranial magnetic stimulation; sensorimotor adaptation

Abbreviations: AN = angle of the trajectory 250 ms after movement onset; PAS = paired-associative stimulation; MEP = motorevoked potential; RT = reaction time; TC = time to curvature; TMS = transcranial magnetic stimulation; TT = target time;WCIS = Writer’s Cramp Impairment Scale

IntroductionThe classical view that basal ganglia dysfunction is responsible for

the abnormal sensory processing (Tinazzi et al., 2009) and dis-

turbed sensorimotor integration associated with dystonia

(Abbruzzese et al., 2001; Tamburin et al., 2002; Tecchio et al.,

2008) has been challenged by new evidence of cerebellar dysfunc-

tion in both focal and generalized dystonia (Sadnicka et al., 2011;

Raike et al., 2012). Like the lemniscal pathway, the cerebellum

relays sensory afferent inputs to the motor cortex (M1) (Butler

et al., 1992) and processes proprioceptive information for both

temporal and spatial discrimination of sensory signals (Restuccia

et al., 2001; Pastor et al., 2004). Cerebellar dysfunction might

therefore affect sensory processing in patients with dystonia.

Numerous studies have demonstrated that the cerebellum is

involved in sensorimotor adaptation (Wolpert and Miall, 1996;

Wolpert and Kawato, 1998; Doya, 1999; Paulin, 2005;

Shadmehr and Krakauer, 2008; Izawa and Shadmehr, 2011;

Izawa et al., 2012), and cerebellar dysfunction in dystonia might

therefore affect sensorimotor adaptation. Indeed, eye blink condi-

tioning is altered in patients with various forms of focal dystonia

(Teo et al., 2009), and saccadic adaptation is impaired in patients

with myoclonus-dystonia (Hubsch et al., 2011).

The cerebellum is defective in dystonia associated with structural

(Delmaire et al., 2007) and functional abnormalities: abnormally

increased cerebellar activity is consistently observed in neuroima-

ging studies of dystonias, including focal dystonia (Galardi et al.,

1996; Odergren et al., 1998; Hutchinson et al., 2000; Preibisch

et al., 2001; Hu et al., 2006). Altered functional connectivity be-

tween the cerebellum and thalamus has been shown in DYT1

dystonia (Argyelan et al., 2009) but not yet in focal dystonia.

However, in patients with occupational dystonia, transcranial mag-

netic stimulation (TMS) experiments point to defective connectiv-

ity between the cerebellum and motor cortex both ipsilateral and

contralateral to the dystonic upper limb (Brighina et al., 2009).

The pathophysiology of dystonia also involves maladaptive

sensorimotor plasticity (Hallett, 2006; Breakefield et al., 2008).

Aberrant plasticity in patients with focal dystonia, shown by the

enhanced response of their motor cortex to plasticity-inducing

TMS interventions such as paired-associative stimulation (PAS)

(Quartarone et al., 2003), is more likely to be directly related to

the cause of dystonic movements than to be a simple conse-

quence (Tisch et al., 2007). Indeed, intensive repetition of highly

trained activity is a risk factor for developing writer’s cramp or

other task-specific dystonia of the upper limb (Roze et al., 2009;

Le Floch et al., 2010), and this could be mediated through

aberrant M1 plasticity, although it is unclear which defect leads

to this aberrant plasticity. Excitation or inhibition of the cerebellar

cortex exerts a powerful priming effect on the development and

extent of M1 sensorimotor plasticity by processing the sensory

afferent volley at a subcortical level, either in the cerebellum

itself or upstream of the cerebellum in the olivary nucleus (Popa

et al., 2013). This is compatible with the role of the cerebellum in

filtering or encoding sensory inputs (Dean and Porrill, 2010).

In patients with writer’s cramp, defective sensory encoding by

the cerebellum could affect sensorimotor plasticity in M1, possibly

leading to abnormal sensorimotor adaptation.

To test for abnormal sensorimotor adaptation in writer’s cramp,

we compared the performance of patients with writer’s cramp and

healthy control subjects in a reaching task that included a visuo-

motor conflict. To test the effect of putative, abnormal cerebellar

sensory encoding on M1 plasticity development, we modulated

the excitability of the cerebellar cortex and examined how this

influenced the M1 plasticity induced by PAS.

Materials and methods

SubjectsTwenty-one patients with writer’s cramp (mean age 42.9 � 14.3 years;

seven from France, 12 from India, two from Italy) participated in the

study (Table 1). They were recruited through the Movement Disorders

clinics of the three participating centres (Table 1), namely Pitie-

Salpetriere Hospital (Paris, France), Sree Chitra Tirunal Institute for

Medical Sciences and Technology (Trivandrum, India), and Clinica

Neurologica II of Policlinico Universitario (Messina, Italy). They

were compared with 25 age-matched healthy volunteers (mean age:

41.7 � 16.6 years; nine from France, 13 from India, three from Italy;

15 females, 10 males). The patients experienced dystonia only when

writing, with the exception of two patients, one of whom also had dys-

tonia of the right hand when playing drums, and one who also had

laryngeal dystonia. None of the participants had a history of neurological

disorders (other than dystonia in the patients) or psychiatric illness, or

were taking drugs acting on the CNS at the time of the study. Medical

treatment (Table 1) was stopped at least 3 weeks before the study and

was withheld until study completion. Twelve patients had never received

botulinum toxin injections, and the remaining nine patients had not

received botulinum toxin injections for at least 3 months before the

study (Table 1). All the subjects were right-handed.

The experimental procedures were approved by the local ethics

committees of the participating centres and conformed to the

Declaration of Helsinki. All the subjects gave their written informed

consent before participating in the experiments.

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Video recordingDystonia severity in the affected limb was assessed from videos recorded

at the beginning of the first session. The video protocol was designed to

score the Writer’s Cramp Impairment Scale (WCIS) and was used by all

three centres. The WCIS scale, developed at HMCS, NINDS, NIH

(Bethesda, USA), is awaiting validation. The WCIS scale assesses the

speed of writing, the number of breaks during writing, the occurrence

and intensity of involuntary (pathological) postures/abnormal move-

ments (while writing, while performing repetitive wrist movements),

the degree of tremor that occurs while performing repetitive spiral move-

ments, and the presence of mirror movements. All videos from the three

centres were rated offline by the same movement disorders specialist

(R.E.), who was blinded to the electrophysiological data.

Experiment 1All the subjects (healthy volunteers = 25, writer’s cramp = 21) were

invited to attend three sessions. In all three sessions, 5 Hz PAS

(Quartarone et al., 2006) was used to induce plasticity in the dominant

(left) M1. PAS was preceded by right cerebellar stimulation consisting of

the following three randomized interventions: cortical cerebellar cortex

excitation [cerebellar-intermittent theta burst stimulation (CB-iTBS)],

cerebellar cortex inhibition [cerebellar-continuous theta burst stimulation

(CB-cTBS)], or sham stimulation of the cerebellum (CB-sham). The three

sessions were separated by intervals of at least 1 week. PAS (5 Hz) was

applied 5 min after the end of cerebellar conditioning.

Electromyography recordings

The subjects were seated comfortably in an armchair, with the two

hands resting symmetrically on a pillow placed on their lap. They were

asked to fix their vision on a point 1 m in front of them during the

procedure. Motor evoked potentials (MEPs) were recorded from the

right Abductor pollicis brevis (the target muscle) and Abductor digiti

minimi (the control surround muscle) through disposable Ag/AgCl sur-

face electrodes in a muscle belly–tendon montage. The cortical repre-

sentations of the Abductor pollicis brevis and Abductor digiti minimi

are close enough for consistent measurable MEPs to be evoked sim-

ultaneously in the two muscles (Weise et al., 2006, 2011; Quartarone

et al., 2008).

Responses were amplified (�1000) and filtered (100–3000 Hz) with

a Digitimer D360 amplifier (Digitimer Ltd), then digitally transformed

at a sampling rate of 10 000 Hz (CED Power 1401 MkII, CED Ltd), and

stored offline for analysis (Signal 4.02, CED Ltd).

Transcranial magnetic stimulation sessions

Evaluation of cortico-spinal excitability

TMS pulses were applied over the left M1 by using a 70-mm figure-

of-eight coil connected to two MAGSTIM 200 stimulators via a Bistim

unit (The Magstim Company). The coil was held at �45� from the

midline for optimal trans-synaptic activation of the motor cortex

(Werhahn et al., 1994; Kaneko et al., 1996). The direction of the

induced current was posterior to anterior.

The motor ‘hot spot’ of the right Abductor pollicis brevis was first

marked on a default image in a MRI-based neuronavigation system

(eXimia 2.2.0, Nextim Ltd in the Paris and Messina labs; Brainsight 2,

Rogue Resolutions in the Indian lab). This allowed the same position to

be maintained over the ‘hot spot’ across the different sessions. The

resting motor threshold (RMTbistim) was then calculated for Abductor

pollicis brevis by using the standard procedure (Rossini et al., 1994;

Rothwell, 1997).

Repetitive transcranial magnetic stimulation

Repetitive TMS stimulation was delivered through a 70-mm figure-of-

eight cooled coil connected to a SuperRapid2 magnetic stimulator

(Magstim Company). The magnetic stimulus had a biphasic waveform

Table 1 Clinical features of the patients

Centre Gender Age (years) Disorder Symptomsduration (years)

Total WCISscore

Treatment Time from the lastinjection (months)

1 F 23 WC 3 46

1 M 54 WC 11 41 Propranolol

1 F 40 WC 17 66

1 F 68 WC 16 16 BT 4

1 F 68 WC 7 19

1 M 58 WC 11 39

1 F 44 WC, LD 31 31 BT (vocal cords) 3.5

2 F 18 WC 2 26

2 M 52 WC 7 11

2 F 38 WC 5 25 BT 3.5

2 M 37 WC 3 9 BT 13

2 F 39 WC 3 9

2 M 38 WC 7 8 BT 18

2 M 36 WC, MC 15 32 BT 24

2 M 36 WC 2 10

2 M 42 WC 2 46 BT 3.5

2 M 53 WC 5 15 Atenolol

2 F 41 WC 0.5 47

2 F 18 WC 3 54

3 M 63 WC 20 MD

3 M 35 WC 12 19

1 = Paris, France; 2 = Trivandrum, India; 3 = Messina, Italy.M = male; F = female; WC = writer’s cramp; MC = musician cramp; LD = laryngeal dystonia; BT = botulinum toxin.

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with a pulse width of 0.3 ms. The RMTrapidstim and active motor

threshold (AMTrapidstim) for the right Abductor pollicis brevis were

assessed first, using the standard procedure (Rossini et al., 1994;

Rothwell, 1997).

Paired associative stimulation of M1

The 5 Hz PAS protocol (Quartarone et al., 2006) was applied to the

left M1. Electric pulses (Digitimer D 180 stimulator Digitimer) were

delivered over the right median nerve at the wrist at 2.5 times the

perceptual threshold and always below the electromyographically

measured motor threshold. Each pulse was followed 25 ms later by a

magnetic pulse delivered over the ‘hot spot’ of the right Abductor

pollicis brevis at 90% AMTrapidstim. Six hundred pairs of stimuli were

delivered at 5 Hz.

Twenty MEPs were averaged just before the intervention (cerebellar

stimulation followed by PAS), and at 10 (T10), 20 (T20) and 30 (T30)

min after the end of the intervention, using the same intensity of

stimulation of 1.3 � RMTbistim. At this intensity the range of the test

MEPs in the Abductor pollicis brevis before the intervention was 0.5–

1 mV (Fig. 1).

Cerebellar cortex stimulation

The procedure for cerebellar cortex stimulation has been discussed in

detail in a previous publication (Popa et al., 2013) and will only be

summarized here. Stimulation was applied to the right cerebellum with

the coil handle pointing upwards so that the induced current had a

caudal to rostral orientation. The target was lobule VIII of the cere-

bellum (Popa et al., 2010, 2013). Indeed the posterior part of this

lobule is superficial and thus reachable by TMS and has been shown

to be activated during somatosensory and motor tasks (Stoodley and

Schmahmann, 2009). Classical theta-burst stimulation (TBS) protocols

(Huang et al., 2005) were used for cerebellar cortex excitation and

inhibition. Six hundred stimuli were delivered at 80% AMTrapidstim in

three-pulse bursts at 50 Hz, repeated every 200 ms either continuously

(cTBS) for 40 s, or intermittently (iTBS) in blocks of 2 s with 8 s gaps for

200 s. These patterns of stimulation can modulate cerebellar output for

at least 30 min (Popa et al., 2010). For sham stimulation (delivered

with a cTBS pattern), the coil was moved vertically 5 cm below the

cerebellar target and 600 stimuli were delivered at 80% AMTrapidstim.

The stimulation intensities used in this study are well below the max-

imum limit recommended by current repetitive TMS safety guidelines

(Rossi et al., 2009).

Evaluation of intracortical inhibition and facilitation

Short- and long-interval intracortical inhibitions, intracortical facilita-

tion, and short- and long-latency afferent inhibitions were measured

before and at 15 and 25 min after the intervention.

The pre-PAS test stimulation was set at 1.3 � RMTbistim, and was

then adjusted at the 15-min (T15) and 25-min (T25) test points to

maintain the test MEP amplitude at the same level as before the inter-

vention (Sanger et al., 2001). The conditioning TMS stimulus was set

at 0.7 � RMTbistim to measure short interval intracortical inhibition and

intracortical facilitation. The inter-stimulus interval was 2.5 ms for short

interval intracortical inhibition (Fisher et al., 2002) and 15 ms for intra-

cortical facilitation (Kujirai et al., 1993). The conditioning stimulus was

set at 1.2 � RMTbistim and the interstimulus interval at 100 ms when

measuring long-interval intracortical inhibitions. To measure short and

long-latency afferent inhibitions, an electrical conditioning stimulus

(200 ms pulse width) was delivered to the median nerve at an intensity

three times the perception threshold, using a Digitimer DS7A Constant

Current Stimulator. The interstimulus interval was 20 ms for short-

latency afferent inhibition and 200 ms for long-latency afferent

inhibition (Di Lazzaro et al., 2005). Fifteen trials of test stimulation

alone and 15 trials of conditioning plus test stimulation were delivered

in random order.

Short-interval intracortical inhibition, long-interval intracortical inhib-

ition, intracortical facilitation, short-latency afferent inhibition, long-

latency afferent inhibition, and intracortical facilitation were expressed

Figure 1 Design of Experiment 1. Before the intervention, at baseline, 20 MEPs were recorded and averaged, and physiological par-

ameters were measured. Twenty MEPs were recorded and averaged, 10 (T10), 20 (T20) and 30 (T30) min after the intervention (cortical

cerebellar conditioning and 5 Hz PAS to M1). The physiological parameters were measured 15 (T15) and 25 (T25) min after the inter-

vention. ICF = intracortical facilitation; SICI = short interval intracortical inhibition; SAI = short latency afferent inhibition; LAI = long la-

tency afferent inhibition; LICI = long interval intracortical inhibition; cTBS = continuous theta burst stimulation; iTBS = intermittent theta

burst stimulation.

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as the ratio (percentage) of the mean amplitude of the conditioned

MEP to the mean amplitude of the test MEPs.

Experiment 2Subjects who were willing to participate in a fourth session (writer’s

cramp = 16, healthy volunteers = 10) performed a visuomotor adapta-

tion task. This task derived from the task design used by Tseng et al.

(2007).

All subjects who participated in Experiment 2 had also participated

in Experiment 1. The subjects were instructed to move a computer

mouse with their right hand in order to make the cursor touch five

different targets on a computer screen. The mouse position was

sampled at 30 Hz by using a custom Matlab program that controlled

a black circular cursor on a white screen. The target was displayed in

one of five positions arrayed radially at �90�, �45�, 0�, 45� and 90�

in a half circle (Fig. 2). The subjects were asked to move the cursor

straight to the target and then to return it to the starting position. The

targets were randomly presented one by one. A visuomotor conflict

was generated during the task by imposing a random deviation

(�40�,�20�,�10�, 0�, 10�, 20�, 40�) on the direction of movement

of the mouse/cursor.

Data analysisDifferent strategies were used to evaluate data from different methods

used. The analytical method for each section will be described at the

beginning of the section.

Correlations

Correlations between the severity of dystonia (WCIS scale) and

baseline physiological parameters were sought, as well as correlations

between performance in the visuomotor task (reaction time, time

to curvature/ time to reach the target, and angle of the trajectory

250 ms after movement onset) and baseline physiological param-

eters, and correlations between task performance and the degree of

PAS-induced plasticity. Values were considered significant at P5 0.05.

Stat View software (SAS Institute Inc) was used for all statistical

analyses.

ResultsNone of the subjects reported any adverse effects. None of the

interventions resulted in a visible change in the severity of dystonia

or in the appearance of any sign of overt cerebellar dysfunction.

Clinical scoresThe patients’ mean score on the WCIS scale was 28.8 � 18.1

(range 0–180).

Physiological parametersPhysiological parameters (RMTbistim, AMTrapidstim, test MEP mean

amplitude, short-interval intracortical inhibition, intracortical facili-

tation, short-latency afferent inhibition, long-latency afferent in-

hibition, long-interval intracortical inhibition) were measured at

baseline in each of the three sessions. It was first verified that

all the parameters were stable across the three sessions by using

a repeated-measures ANOVA in which the three measures formed

the repeats. As the parameters were stable across time, their mean

value was used in subsequent analyses and compared between the

patients with writer’s cramp and healthy volunteers using unpaired

t-tests.

RMTbistim and AMTrapidstim were not different between the

healthy volunteers and patient groups (RMTbistim: healthy volun-

teers: 46.7 � 7.4%, writer’s cramp: 48.4 � 9.0%; P = 0.1;

AMTrapidstim: healthy volunteers: 39.8 � 6.3%, writer’s cramp:

40.6 � 8.3%; P = 0.3).

At baseline, long-latency afferent inhibition was significantly

lower in the patients than in the healthy volunteers (Table 2)

(healthy volunteers: �40.6 � 3.2%, writer’s cramp: �23.2 �

7.6%; P50.03). None of the other parameters measured for

Abductor pollicis brevis were different between the healthy volun-

teers and patients (Table 2).

None of the baseline parameters measured for Abductor digiti

minimi were different between the healthy volunteers and

patients.

Paired-associative stimulation-inducedplasticity in healthy subjects and inpatients with writer’s crampPAS-induced plasticity preceded by sham cerebellar stimulation

served as the control condition; it was compared between

the healthy volunteers and patients with writer’s cramp and

between the Abductor pollicis brevis and Abductor digiti minimi

muscles by using repeated-measures ANOVA, in which the

three values of the normalized MEPs (MEPT10/MEPT0, MEPT20/

MEPT0, MEPT30/MEPT0) formed the repeats.

PAS-induced plasticity differed according to the muscle tested

(muscle: Abductor pollicis brevis target muscle or Abductor

digiti minimi control surrounding muscle) and the group to

which the subjects belonged (group: healthy volunteers or

patients with writer’s cramp) [Group: F(1,86) = 0.9, P = 0.3;

Figure 2 Experimental setup for behavioural testing. The

hatched surface corresponds to the difference between the

actual (dashed line) and ideal (black line) trajectories.

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Time: F(1,86) = 2.9, P = 0.05; Muscle: F(1,86) = 3.7, P50.05;

Time � Group: F(2,172) = 8.9, P50.0002].

At T10 there was no effect of PAS in either group or muscle

[Group: F(1,86) = 0.5, P = 0.5; Muscle: F(1,86) = 0.04, P = 0.8]. At

T20, there was a bigger effect of PAS on Abductor pollicis brevis

than on Abductor digiti minimi in both groups [Group:

F(1,86) = 0.4, P = 0.6; Muscle: F(1,86) = 4.5, P50.03]. At T30,

the effect of PAS was no longer detected in the healthy sub-

jects, while in the patients, MEP was clearly facilitated in both

Abductor pollicis brevis and Abductor digiti minimi [Group:

F(1,86) = 9.5, P50.003; Muscle: F(1,86) = 3.5, P = 0.06] (Fig. 3).

Effect of cerebellar cortexconditioning on paired-associativestimulation-induced plasticityThe effects of cerebellar cortex conditioning on M1 plasticity were

compared between the healthy volunteers and patients with wri-

ter’s cramp (‘Group’ factor) and/or between the cerebellar cortex

excitation, cerebellar cortex inhibition and sham stimulation of the

cerebellum interventions (‘Intervention’ factor) by using repeated

ANOVA in which the nine normalized values of the MEPs formed

the repeats (MEPT10/MEPT0, MEPT20/MEPT0, MEPT30/MEPT0 after

cerebellar cortex excitation, cerebellar cortex inhibition and sham

stimulation of the cerebellum). Bonferoni’s post hoc test was used

to characterize the time course of the parameters after each type

of intervention.

Abductor pollicis brevis target muscle

Cerebellar stimulation had a different effect on PAS-induced M1

plasticity according to the type of cerebellar cortex conditioning

(sham, cerebellar cortex inhibition, cerebellar cortex excitation)

and according to the group (healthy volunteers and patients

with writer’s cramp) [Group: F(1,44) = 0.01, P = 0.9;

Intervention: F(2,88) = 4.6, P50.01; Time: F(2,88) = 11.5,

P50.0001; Group � Intervention � Time: F (4,176) = 11.5,

P50.0001].

In healthy volunteers, cerebellar cortex inhibition enhanced PAS-

induced M1 plasticity when compared to sham stimulation of the

cerebellum, confirming the results of our previous study of healthy

volunteers (Popa et al., 2013) (Fig. 3B) [CB-cTBS versus CB-sham:

F(1,24) = 6.1, P50.02, Time: F(2,48) = 11.8, P50.0001;

Intervention � Time: F(2,48) = 7.0, P50.002]. This was true at

T30 (t-test P5 0.0005), indicating that the duration of the PAS

effect increased more than the degree of the PAS effect. This was

at contrast to the patients with writer’s cramp, in whom cerebellar

cortex inhibition did not induce any enhancement of the PAS

Table 2 Physiological parameters at baseline and after cerebellar cortex conditioning

Healthy volunteers Writer’s cramp

APB ADM APB ADM

Mean SEM Mean SEM Mean SEM Mean SEM

TEST (mV) Pre 1.01 0.06 0.79 0.09 0.93 0.07 0.75 0.11Post sham 1.08 0.09 0.84 0.15 0.89 0.09 1.00 0.23

Post cTBS 1.04 0.06 0.67 0.11 0.9 0.08 0.8 0.2

Post iTBS 0.97 0.07 0.74 0.13 0.97 0.09 0.81 0.13

ICF (MEPc/MEPt) Pre 1.24 0.06 1.25 0.06 1.21 0.05 1.32 0.09Post sham 1.20 0.09 1.21 0,08 1.04 0.08 1.23 0.16

Post cTBS 1.12 0.11 1.12 0.09 1.27 0.15 1.32 0.17

Post iTBS 1.28 0.07 1.22 0.07 1.20 0.07 1.34 0.11

SICI (MEPc/MEPt) Pre 0.44 0.01 0.61 0.04 0.49 0.02 0.70 0,06Post sham 0.43 0.02 0.53 0.03 0.48 0.03 0.59 0.03

Post cTBS 0.46 0.04 0.48 0.03 0.49 0.02 0.94 0.18

Post iTBS 0.48 0.02 0.83 0,19 0.54 0.03 0.65 0.05

SAI (MEPc/MEPt) Pre 0.80 0,10 0.70 0.05 0.85 0.04 0.89 0.06Post sham 0.76 0.09 0.70 0.05 0.93 0.06 0.89 0.06

Post cTBS 1.12 0.14 0.81 0.07 0..84 0.07 0.88 0.06

Post iTBS 0.65 0.07 0.77 0.05 0.65 0.05 0.81 0.07

LAI (MEPc/MEPt) Pre 0.59 0.02 0.78 0.03 0.77 0.05 0.81 0.04Post sham 0.64 0.03 0.72 0.03 0.79 0.07 0.87 0.06

Post cTBS 0.62 0.04 0.81 0.04 0.71 0.03 0.91 0.12

Post iTBS 0.69 0.05 0.78 0.03 0.69 0.03 0.85 0.04

LICI (MEPc/MEPt) Pre 0.21 0.01 0.39 0.02 0.33 0.02 0.52 0.04Post sham 0.19 0.01 0.30 0.01 0.33 0.02 0.39 0.03

Post cTBS 0.17 0.01 0.47 0.04 0.21 0.01 0.37 0.02

Post iTBS 0.26 0.02 0.38 0.02 0.34 0.02 0.48 0.02

ADM = abductor digiti minimi; APB = abductor pollicis brevis; ICF = intracortical facilitation; SICI = short interval intracortical inhibition; SAI = short latency afferentinhibition; LAI = long latency afferent inhibition; LICI = long interval intracortical inhibition; MEPc = conditioned MEP; MEPt = test MEP; cTBS = continuous theta burst

stimulation; iTBS = intermittent theta burst stimulation; SEM = standard error of the mean.ICF, SICI, SAI, LAI, LICI are expressed as the size of the conditioned MEP normalized to the size of the test MEP. A value 51 indicates an inhibition and smaller the value,larger the inhibition; a value 41 indicates a facilitation and larger the value, larger the facilitation.

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effect when compared with sham stimulation of the cerebellum

and even, at T30, had a trend to reduce this effect [CB-cTBS

versus CB-sham: F(1,20) = 0.07, P = 0.8; Time: F(2,40) = 2.2,

P = 0.1; Intervention � Time: F(2,40) = 2.9, P = 0.06] (Fig. 3A).

In healthy volunteers, cerebellar cortex excitation blocked the

effect of PAS on M1 plasticity when compared with sham stimu-

lation of the cerebellum, again confirming our previous results

[CB-iTBS versus CB-sham: F(1,24) = 10.2, P50.004; Time:

F(2,48) = 6.9, P50.002; Intervention � Time: F(2,48) = 6.4,

P5 0.003]. This effect was seen at T10 (t-test: P50.01) and

T20 (P50.0007) but had disappeared at T30 (P = 0.4) (Fig. 3A).

The patients exhibited no such fall in the MEP amplitude, showing

that PAS-induced plasticity did not differ between cerebellar

cortex excitation and sham stimulation of the cerebellum.

However, the plastic response of M1 was longer-lasting in the pa-

tients than in the healthy volunteers, as it persisted at T30 [CB-iTBS

versus CB-sham: F(1,20) = 0.3, P = 0.6; Time: F(2,40) = 6.6,

P50.003; Intervention � Time: F(2,40) = 0.6, P = 0.5;

Bonferroni test: T10 versus T30 P5 0.001] (Fig. 3B).

Abductor digiti minimi (control) muscle

The effect of cerebellar stimulation on PAS-induced plasticity in

Abductor digiti minimi differed according to the type of stimulation

and the group of subjects [Group: F(1,42) = 0.5, P = 0.5;

Intervention: F(2,84) = 2.8, P = 0.7; Time: F(2,84) = 0.2, P = 0.8;

Group � Intervention: F(2,84) = 3.5, P50.03] (Fig. 3 D). In the pa-

tients, the effect did not differ across the interventions [Intervention:

F(2,38) = 0.7, P = 0.5; Time: F(2,38) = 0.08, P = 0.9]. In contrast,

in the healthy subjects, cerebellar cortex inhibition enhanced

PAS-induced plasticity more than sham stimulation of the cerebellum

or cerebellar cortex excitation [Intervention: F(2,46) = 4.6, P50.01;

Time: F(2,46) = 0.5, P = 0.6; Bonferroni test: CB-cTBS versus CB-

sham: P5 0.01; CB-cTBS versus CB-iTBS: P50.01; CB-iTBS

versus CB-sham: P = 0.8].

Effects of cerebellar cortex conditioningon intracortical inhibition andfacilitationThe effects of 5 Hz PAS on MEPs in the control condition (pre-

ceded by sham stimulation of the cerebellum) were compared

between the healthy volunteers and patients with writer’s cramp

by using repeated ANOVA, in which the three values of the nor-

malized MEPs (MEPT10/MEPT0, MEPT20/MEPT0, MEPT30/MEPT0)

formed the repeats.

The test MEPs were of similar sizes before each intervention

[Intervention: F(2,78) = 0.1, P = 0.8; Group: F(1,39) = 1.3,

P = 0.2; Group � Intervention: F(2,78) = 0.6, P = 0.6], suggesting

that any effect of the intervention on short-interval intracortical

inhibition, intracortical facilitation, short-latency afferent inhibition,

long latency afferent inhibition, long-interval intracortical inhib-

ition would not be due to a difference in test MEP sizes

[Intervention: F(2.76) = 0.4, P = 0.7; Group: F(1,38) = 1.6,

P = 0.2; Group � Intervention: F(2,76) = 0.7, P = 0.5].

Short-interval intracortical inhibition, intracortical facilitation,

long-interval intracortical inhibition, and short-latency afferent

inhibition were similar in the two groups at baseline and were

not modified by any of the interventions. Long-latency afferent

inhibition, which was smaller in the patients than in the healthy

volunteers at baseline, remained at the same level after each

intervention [long-latency afferent inhibition: Intervention

F(3,105) = 0.4, P = 0.7; Group F(1,35) = 4.1, P5 0.05; Group �

Intervention F(3,105) = 1.6, P = 0.2] (Fig. 4).

Correlations between the extent ofpaired-associative stimulation-inducedplasticity and physiological parametersor clinical scoresExtent of PAS-induced plasticity was assessed in two ways: (i) the

overall effect of PAS (mean MEP amplitude at T10, T20 and T30

normalized to MEP amplitude at T0 (MEPoverall)); and (ii) the peak

Figure 3 PAS-induced plasticity after cortical cerebellar

conditioning in patients with writer’s cramp and healthy

controls. Normalized MEPs from abductor pollicis brevis (A and

B) and abductor digiti minimi (C and D) are presented at 10, 20

and 30 min after 5 Hz PAS stimulation to the left M1 cortex in

healthy volunteers (dots) and patients with writer’s cramp

(squares). PAS was preceded by sham stimulation of the cere-

bellum (black dots and squares), continuous theta burst stimu-

lation of the cerebellum (A–C) (red dots and squares) or

intermittent theta burst stimulation of the cerebellum (B–D)

(blue dots and squares). PAS-induced plasticity of the abductor

pollicis brevis was longer-lasting in patients with writer’s cramp

than in healthy subjects, as it was still present 30 min after the

end of the intervention. Continuous theta burst stimulation to

the cerebellum enhanced the effect of PAS on both abductor

pollicis brevis and abductor digiti minimi in healthy subjects,

while it had no effect on either muscle in patients with writer’s

cramp. Intermittent theta burst stimulation to the cerebellum

decreased the effect of PAS on the abductor pollicis brevis

in healthy subjects but not in patients with writer’s cramp.

*Significant difference in the PAS effect when preceded by

sham or active stimulation of the cerebellum (*P50.05,

**0.055P5 0.01, ***P50.01).

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value of the MEP amplitude post-PAS (MEPpeak). Linear regression

was used to assess correlations.

WCIS scores did not correlate with physiological parameters

(RMTbistim, AMTrapidstim, short-latency afferent inhibition, long

latency afferent inhibition, short-interval intracortical inhibition,

intracortical facilitation, long-interval intracortical inhibition) or

with the degree of PAS-induced plasticity in the abductor pollicis

brevis, irrespective of the type of cerebellar cortex conditioning.

At baseline, short-interval intracortical inhibition, intracortical fa-

cilitation, long-interval intracortical inhibition, short-latency

afferent inhibition and long-latency afferent inhibition did not

correlate with the extent of PAS-induced plasticity, regardless of

the type of cerebellar conditioning.

Visuomotor adaptation taskTask performance was assessed in terms of (i) the reaction time,

i.e. the time between the ‘go’ signal and the onset of the move-

ment (RT); (ii) the total time taken to reach the target (TT); and

(iii) the time taken to correct the initial trajectory towards the

correct trajectory when an artificial error was introduced (TC).

The trajectories had a parabolic shape and were fitted by poly-

gons; the time corresponding to the maximum of the curve was

assumed to be the time taken by the subject to begin correcting

the trajectory. We also calculated TC/TT in order to compare the

time taken to adjust the trajectory to the ideal trajectory, inde-

pendently of the speed of movement; and (iv) the angle between

the actual trajectory and the ideal one (trajectory curve) measured

250 ms after the onset of movement (AN). These measures were

evaluated for each angle of imposed error (0�, 10�, 20�, 40�), and

for all the angles together. TC/TT and AN measured at imposed

error angles of 10�, 20�, and 40�, reflect the capacity for online

error correction, while those made at 0� reflect the capacity for

washing out previous correction strategies, as the 0� trials were

randomly interleaved with the other deviations (Fig. 2).

The performance of the patients and healthy volunteers was

compared by using the non-parametric Mann Whitney U test.

Comparative performance of healthyvolunteers and patients with writer’scrampThe patients reacted with the same speed as the healthy volun-

teers (reaction time was similar in the two groups for all angles)

but were slower than the healthy volunteers in reaching the target

(target time was longer in the patients), irrespective of the

imposed deviation (Mann Whitney U test: TT all angles: P50.03;

TT0�: P50.01; TT10�: P50.03; TT20�: P50.05; TT40�: P = 0.09).

As a group, the patients were able to adjust for the deviation

Figure 4 Long latency afferent inhibition (LAI) after cortical

cerebellar conditioning in healthy subjects (HV) and patients

with writer’s cramp (WC). The amount of long latency afferent

inhibition is presented at baseline (black bars), after sham

stimulation of the cerebellum (dark grey bars), after continuous

theta burst stimulation of the cerebellum (light grey bars) and

after intermittent theta burst stimulation of the cerebellum

(white bars). Long latency afferent inhibition was significantly

smaller in the patients than in the healthy volunteers in all

situations, except after intermittent theta burst stimulation of

the cerebellum. Cerebellar conditioning induced no significant

change in long latency afferent inhibition. *P5 0.05, patients

versus healthy controls.

Table 3 Behavioural parameters for the adaptation task

Healthy volunteers Writer’s cramp

Mean SEM Mean SEM

RT Tot 0.52 0.04 0.55 0.030� 0.59 0.06 0.54 0.04

10� 0.54 0.04 0.52 0.04

20� 0.56 0.05 0.52 0.03

40� 0.55 0.04 0.53 0.03

TT Tot 1 0.28 1.64 0.150� 0.81 0.22 1.31 0.14

10� 0.86 0.24 1.39 0.12

20� 0.96 0.27 1.49 0.14

40� 1.21 0.34 1.9 0.17

TC Tot 0.36 0.06 0.48 0.050� 0.37 0.04 0.45 0.04

10� 0.32 0.05 0.45 0.04

20� 0.35 0.06 0.45 0.05

40� 0.47 0.08 0.49 0.04

AN Tot 21.52 2.36 22.47 0.70� 7.03 3.58 10.07 1.35

10� 13.66 3.79 14.39 1.1

20� 19.7 1.98 20.39 0.69

40� 38.64 1.73 38.72 2.55

TC/TT Tot 0.24 0.04 0.27 0.060� 0.33 0.06 0.31 0.06

10� 0.27 0.04 0.30 0.07

20� 0.23 0.04 0.28 0.08

40� 0.21 0.06 0.24 0.06

RT = reaction time; TT = time to reach the target; TC = time to curvature;AN = angle of the trajectory 250 ms after movement onset; SEM = standard errorof the mean; Tot = total value for all angles confounded.

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(TC/TT and AN were not different between the healthy volunteers

and patients, irrespective of the angle) but were less efficient in

washing out previous adjustments (AN0�: P50.01).

Correlations between behaviouralparameters and the response tocerebellar stimulationIn the healthy volunteers, there was no correlation between the

behavioural parameters [reaction time (RT), target time (TT), time

to curvature (TC), time to curvature/target time (TT/TC), angle of

the trajectory 250 ms after movement onset (AN)] and the effects

of PAS (MEPoverall or MEPpeak) regardless of the type of cerebellar

conditioning.

In the patients, there was no correlation between the behavioural

parameters (RT, TT, TC, TT/TC, AN) and the effects of PAS after

sham stimulation. However, performance in the task was predictive

of the effect of cerebellar cortex inhibition on M1 plasticity but not of

the effect of cerebellar excitation: the poorer the task performance

(larger TC/TT values or higher AN), the larger the enhancement of

test MEP size after cerebellar inhibitory conditioning (Fig. 5) (MEPmax

after CB-cTBS-PAS versus TC/TTall angles: P5 0.002, R2 = 0.5; versus

TC/TT0�: P50.005, R2 = 0.5; versus TC/TT10�: P50.0004,

R2 = 0.6; versus TC/TT20�: P = 0.002, R2 = 0.5; versus TC/TT40�:

P = 0.01, R2 = 0.4) (MEPmax after CB-cTBS-PAS versus ANall angles:

P5 0.01, R2 = 0.4; versus AN0�: P50.03, R2 = 0.3; versus AN10�:

P5 0.01, R2 = 0.4; versus AN20�: P50.02, R2 = 0.3; versus AN40�:

P = 0.3). This correlation was also seen with the overall effect of PAS,

assessed in terms of MEPoverall (MEPoverall after CB-cTBS-PAS versus

TC/TTall angles: P50.001, R2 = 0.5; versus TC/TT0�: P50.01,

R2 = 0.4; versus TC/TT10�: P50.001, R2 = 0.5; versus TC20�:

P5 0.003, R2 = 0.5; versus TC/TT40�: P50.02, R2 = 0.3)

(MEPoverall after CB-cTBS-PAS versus ANall angles: P50.02,

R2 = 0.3; versus AN0�: P50.04, R2 = 0.3; versus AN10�: P50.02,

R2 = 0.35; versus AN20�: P50.05, R2 = 0.3, versus AN40�: P = 0.3).

Reaction time and target time did not correlate with PAS-induced

plasticity following cerebellar cortex inhibition.

Correlation between task performanceand baseline physiological measuresIn the healthy volunteers, the larger the baseline long-latency af-

ferent inhibition, the shorter the reaction time in the visuomotor

task, for all angles of deviation (healthy volunteers: RTall angles:

P5 0.02, R2 = 0.6; RT0�: P50.01, R2 = 0.6; RT10�: P50.007,

R2 = 0.75; RT20�: P50.02, R2 = 0.6; TR40�: P50.04, R2 = 0.5).

A similar but weaker correlation was found in the patients

(RTall angles: P = 0.3; RT0�: P = 0.4; RT10�: P50.02, R2 = 0.3;

RT20�: P50.05, R2 = 0.3; RT40�: P50.05, R2 = 0.3).

DiscussionWe report that patients with writer’s cramp exhibit a complete loss

of both inhibitory and excitatory cerebellar priming of cortical sen-

sorimotor plasticity. Online adaptive performance in a visuomotor

task predicted the effect of cerebellar cortex conditioning on M1

plasticity. Patients with writer’s cramp were also less efficient than

healthy subjects at washing out a previous adaptation strategy

during task performance. These findings point to a dysfunction

of cerebellar sensory adaptive encoding in patients with writer’s

cramp, and to maladjusted sensorimotor calibration. These alter-

ations might play a role in the pathophysiology of task-specific

dystonias such as writer’s cramp.

Cerebellar priming of paired-associativestimulation-induced plasticityEffects of cerebellar cortex conditioning on M1 plasticity are not

exerted directly through a change in M1 excitability but rather

upstream of M1, by processing the sensory afferent volley in

PAS. Indeed, cerebellar cortex conditioning has been found to

influence the subsequent M1 response to a 5 Hz PAS protocol

(involving a sensory component) but not its response to a theta-

burst protocol (not involving a sensory component) (Popa et al.,

2013). As cerebellar cortex conditioning did not influence

Figure 5 Correlation between task performance and PAS-

induced plasticity after inhibitory stimulation of the cerebellum

(CB-cTBS-PAS)in patients with writer’s cramp. The overall effect

of 5 Hz PAS preceded by inhibitory stimulation of the cerebellum

[(MEPT10 + MEPT20 + MEPT30)/3]/ MEPT0 is plotted against

baseline performance, in terms of TC/TT (time required to cor-

rect the initial trajectory to the ideal one, normalized to the time

to target). In A, TC/TT was measured when deviations of 10�

and 20� were imposed on the cursor movement; in B, no devi-

ation was imposed on the cursor. (A) The better the perform-

ance (i.e. the lower the TC/TT at 10� and 20�), the smaller the

PAS effect, indicating a smaller modulatory effect of cortical

cerebellar inhibition on PAS-induced plasticity. (B) The better the

forgetting (i.e. the TC/TT at 0� deviation), the smaller the PAS

effect, indicating a smaller modulatory effect of cortical cere-

bellar inhibition on PAS-induced plasticity.

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somatosensory evoked potentials that travel through the lemniscal

pathway via the thalamus to the somatosensory cortex, Popa

et al. (2013) concluded that these latter two structures were un-

likely to be the sites where the afferent volley was modified. Our

findings support this hypothesis, as 5 Hz PAS, whether preceded

by sham or real cerebellar cortex stimulation, did not modify the

short-latency afferent inhibition (SAI20ms). The short-latency affer-

ent inhibition has been suggested to reflect the modulation of M1

excitability by somatosensory afferent inputs (Classen et al., 2000;

Tokimura et al., 2000; Tamburin et al., 2001; Sailer et al., 2002;

Chen and Curra, 2004). With a 20 ms interval between median

nerve stimulation and the TMS pulse, short-latency afferent inhib-

ition can be mediated by direct projection of afferent inputs from

the thalamus to M1 or, after a short relay, through the primary

sensory cortex (Tokimura et al., 2000). The absence of change in

the SAI20ms after 5 Hz PAS or cerebellar cortex inhibition-PAS, as

observed here, confirms that the afferent volley was not modified

along the relay of the lemniscal pathway. In contrast, when a

25 ms interstimulus interval was used for short latency afferent

inhibition in a previous study (Quartarone et al., 2006), short-

latency afferent inhibition was decreased after 5 Hz PAS, suggest-

ing that short-latency afferent inhibition was modified by an

additional subcortical relay.

Here, cerebellar cortex output modulation in healthy subjects

influenced M1 sensorimotor plasticity. Cerebellar cortex inhibitory

stimulation led to an enhancement of PAS-induced plasticity that

involved both the target muscle and a control muscle with close

cortical representation. In contrast, cerebellar cortex excitation

prevented PAS-induced plasticity only in the target muscle.

Given the spatio-temporal filtering properties of the cerebellum

(Solinas et al., 2010), this spatially non-specific and prolonged

enhancement of plasticity after cerebellar cortex inhibition in

healthy subjects may be secondary to a lack of filtering and or

to prolonged relay of the sensory afferent volley to M1. In con-

trast, the spatially specific decrease in plasticity after cerebellar

excitation in healthy subjects may be secondary to exaggerated

filtering of the afferent volley. Depending on cerebellar cortex

excitability, the unexpected afferent input resulting from PAS

could be modified by the cerebellum through its sensory filtering

capability (Hamada et al., 2012; Popa et al., 2013). How non-in-

vasive stimulation techniques influence excitability of the cerebellar

cortex is not fully understood. According to their bidirectional

effects on cerebellar brain inhibition (Galea et al., 2009) and

on M1 plasticity (Popa et al., 2013) and the lack of concomitant

changes of M1 excitability it is commonly thought that stimula-

tions acts locally by changing the tonic excitability of Purkinje cells.

In this study, patients with writer’s cramp showed a complete

loss of both the inhibitory and the excitatory cerebellar cortex

conditioning effect on PAS-induced M1 plasticity in both the

target and control muscles. The observed correlation between

the effect of cerebellar inhibition and the impairment of behav-

ioural parameters in the visuomotor task suggests that this loss of

cerebellar priming of M1 plasticity may be due to: (i) a dysfunction

that makes the cerebellum unable to control sensorimotor encod-

ing or scaling; or (ii) a hyperactive cerebellum that is no longer

able to be modulated by inhibitory thetaburst stimulation, owing

to a ceiling effect. The latter hypothesis is supported by

neuroimaging studies of dystonic patients that have consistently

shown above-normal cerebellar activity (Neychev et al., 2011).

Cerebellar hyperactivity might serve to compensate for deficient

basal ganglia functioning (at a cost of some cerebellar functions)

or play a role in the primary dysfunction associated with dystonia.

The observed correlation between the effect of cerebellar inhib-

ition and the impairment of behavioural parameters (Fig. 5), sup-

ports direct involvement of the cerebellum in the impaired motor

function that results in writer’s cramp.

How might cerebellar dysfunction cause motor dysfunction in a

limited territory and only during writing? One possible explanation

comes from recent animal experiments in which the extent of

cerebellar dysfunction was found to determine the topographical

extent of abnormal movements (Raike et al., 2012). It is therefore

conceivable that limited cerebellar impairment might produce

abnormal movements only in an isolated anatomical region and/

or in a particular task.

Adaptation to a visuomotor perturbationin patients with writer’s crampImpaired sequence learning has been described in both non-mani-

festing (Ghilardi et al., 2003) and manifesting carriers of the DYT1

mutation, and was found to be associated with increased activa-

tion of the left lateral cerebellar cortex (Carbon et al., 2011).

Patients with writer’s cramp have not been explored during se-

quence learning and are reported to have normal (Meunier et al.,

2012) or impaired performance (Belvisi et al., 2013) when learning

a simple motor task. Here we sought behavioural disturbances

linked to a potential cerebellar dysfunction. We thus measured

performance during adaptation to a visuomotor conflict in a reach-

ing task. Indeed, the cerebellum is a key node of the neural net-

work involved in adapting goal-directed arm movements. We

chose a pointing task that allowed for online corrections and for

abrupt perturbation, as subjects with cerebellar dysfunction are

able to adapt to gradual but not to abrupt perturbation

(Criscimagna-Hemminger et al., 2010; Schlerf et al., 2012). The

different degrees of perturbation were introduced randomly, in

order to separate, as far as possible, online corrections from

motor learning. Trials with no perturbation were also randomly

introduced in order to test the subjects’ ability to wash out the

adaptation process (forgetting). The patients with writer’s cramp

showed longer movement times (increased target time) than the

healthy volunteers in all movement conditions. Slowness of simple

and sequential movements is a known characteristic of patients

with dystonia (Agostino et al., 1992; Curra et al., 2000) and

specifically of patients with writer’s cramp (Prodoehl et al.,

2008), but it remains to be shown whether this is related to cere-

bellar or basal ganglia dysfunction.

Patients with writer’s cramp were slower than healthy volun-

teers to wash out the previous adaptation. This is in agreement

with a previous report showing that patients with cerebellar dis-

orders exhibited slower wash-out than healthy volunteers

(Criscimagna-Hemminger et al., 2010). Slowness of the move-

ment per se could influence the adaptation capabilities. To disen-

tangle the effect of slowness from that of an impairment of the

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online adaptation process we only kept in the analysis of adapta-

tion, parameters that were hardly influenced by the distance cov-

ered, i.e. time to curvature/target time and angle of the trajectory

250 ms after movement onset. At the group level, no significant

differences were found in our study between patients with writer’s

cramp and healthy volunteers with respect to their capacity to

adapt to the visuomotor perturbation (no difference in time to

curvature/target time or angle of the trajectory 250 ms after

movement onset). Yet, in the group with writer’s cramp, the

parameters reflecting the capacity for online adjustment to the

perturbation and for washing out an earlier adaptation (reflected

in the trajectory curvature, AN, and the time to reverse the actual

trajectory to the ideal one, TC/TT) were good predictors of the

capacity of cerebellar inhibitory conditioning to influence sensori-

motor plasticity. The better the online adaptation, the smaller the

influence of cerebellar inhibitory stimulation on M1 plasticity (less

enhancement of the plastic response) (Fig. 5). Performance did not

correlate with sham stimulation of the cerebellum-PAS effects,

indicating that cerebellar inhibition rather than PAS determined

the correlation.

The lack of effect of cortical cerebellar conditioning in patients

with good performance may reflect their adaptive capabilities.

Two explanations may account for this observation: (i) the cere-

bellum may not be involved during the task; or (ii) the cerebellum

is so overactivated that it is no longer susceptible to inhibition

because of a ceiling effect. (i) Patients who adapt well would be

able to ‘silence’ their dysfunctioning cerebellum and to use alter-

native circuits (perhaps the basal ganglia) to perform the task.

When alternative compensatory circuits fail, the cerebellum returns

to the adaptive network and cerebellar inhibition becomes effi-

cient. (ii) A hyperactive cerebellum may compensate for the defi-

ciency of another circuit, such as the basal ganglia. When the

cerebellum is overactive, patients would perform as well as healthy

volunteers, but when the illness worsens, the cerebellum would

become less active and cerebellar inhibition would become

effective.

Paired-associative stimulation-inducedmotor cortex plasticity in patients withwriter’s cramp: the effect of 5 Hzpaired-associative stimulationIn the patients with writer’s cramp, the extent of M1 plasticity

induced by 5 Hz (‘high frequency, low intensity’) PAS differed

from that in healthy volunteers only by the longer duration of

the plastic response in the target muscle. Such a prolonged

effect of a plastic intervention has already been observed in pa-

tients with cervical dystonia and in DYT 1 patients after cTBS of

M1 (Edwards et al., 2006). In contrast, ‘low frequency/low-dose’

PAS does not induce exaggerated plasticity in patients with wri-

ter’s cramp (Kang et al., 2011; Meunier et al., 2012). A key fea-

ture of the enhanced effect of ‘low frequency/high-dose’ PAS

plasticity in dystonic patients is its spread to surrounding muscles

not receiving the sensory inputs of PAS, namely the first dorsal

interrosseous muscle (Quartarone et al., 2003) or the Abductor

digiti minimi (Weise et al., 2006) during PAS targeting the

Abductor pollicis brevis. This was also the case of the Abductor

pollicis brevis during PAS targeting the Abductor digiti minimi

(Weise et al., 2006, 2011). No such spread of the PAS effect

was found in our patients with writer’s cramp. The spatial select-

ivity of the ‘high frequency/low dose’ 5 Hz PAS effect was not

different between the healthy volunteers and patients with writer’s

cramp and was limited to weaker facilitation of the Abductor digiti

minimi MEP at T20 compared to the Abductor pollicis brevis MEP.

In the original description of 5 Hz PAS in healthy subjects

(Quartarone et al., 2006), the non-target muscle was not the

Abductor digiti minimi but the first dorsal interrosseous muscle,

which showed no facilitation. Such differences in the spatial diffu-

sion of PAS effects in dystonic patients according to the PAS tech-

nique used (‘high-frequency/low-dose’ versus ‘low-frequency/

high-dose’) may be due to qualitative differences in the re-organ-

ization of muscle representations in M1 when stimulated with dif-

ferent PAS techniques (Quartarone et al., 2006). Confirmation of

this explanation will require further experiments that are outside

the scope of the present study. Contrary to previous studies, the

‘control’ PAS intervention in this study was preceded by sham

stimulation of the cerebellum. The sham stimulation at the location

used in this study does not reproduce the effects of real cerebellar

stimulation (Popa et al., 2010). Nevertheless, in most of the sub-

jects, sham stimulation led to small head or shoulder movements

that might activate the afferents from neck and shoulder muscles.

By itself, stimulation of peripheral afferents from these muscles

could reorganize the cortical motor maps of hand muscles

(Thickbroom et al., 2003) and mask possible differences in the

spatial selectivity of PAS-induced effects in healthy volunteers

and patients.

ConclusionThis study shows that patients with writer’s cramp have lost the

normal bidirectional cerebellar priming effect on M1 sensorimotor

plasticity. We propose that this is due to defective cerebellar

adaptive filtering or encoding of incoming afferent volleys.

Impaired online adjustment to visuomotor conflict in this setting

might be due to deficient cerebellar sensory encoding, resulting in

a decoupling of the motor component from the afferent infor-

mation flow generated by changes in the environment. Such

maladjusted sensorimotor calibration and the resulting loss of

cerebellar control of sensorimotor plasticity could also lead to

the build-up and recall of an incorrect motor program during

specific adaptation tasks (such as writing) and thus participate

in dystonic movements.

AcknowledgementsWe thank the CIC (Centre for Clinical Investigations) Pitie-

Salpetriere N� 9503 and the platform ‘Gait, Equilibrium, Posture,

Movement, TMS and Navigated Brain Stimulation (NBS)’ of

CR-ICM for their invaluable support with the experiments.

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FundingThis work was supported by the Dystonia Coalition, part of the

NIH Rare Diseases Clinical Research Network. Funding and/or pro-

grammatic support for this project has been provided through

grant NS065701 from the NIH Office of Rare Diseases Research

and the National Institute of Neurological Disorders and Stroke.

The views expressed in written materials or publications do not

necessarily reflect the official policies of the Department of Health

and Human Services; nor does mention by trade names, commer-

cial practices, or organizations imply endorsement by the U.S.

Government. This research was conducted within the framework

of an INSERM–Indian Council of Medical Research (ICMR) collab-

orative project. INSERM supported the research through grant

#C10-01 and ICMR through ‘Indo-INSERm/Neurol/21/2010-

NCD-I’. T.P. was supported by Fondation Motrice and the

‘Investissements d’avenir’ program ANR-10-IAIHU-06. C.H. was

the recipient of a scholarship from Fondation Groupama pour la

Sante. S.M. and M.V. were the beneficiaries of an INSERM/APHP

Contrat d’interface. F.M. was supported by Region Ile-de-France

within the framework of C’Nano IdF, the Paris Region

Nanoscience Competence Center.

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