• motor cortex;
  • movement disorders;
  • surround inhibition;
  • transcranial magnetic stimulation;
  • ventral premotor cortex


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

A major feature of focal hand dystonia (FHD) pathophysiology is the loss of inhibition. One inhibitory process, surround inhibition, for which the cortical mechanisms are still unknown, is abnormal in FHD. As the ventral premotor cortex (PMv) plays a key role in the sensorimotor processing involved in shaping finger movements and has many projections onto the primary motor cortex (M1), we hypothesized that the PMv–M1 connections might play a role in surround inhibition. A paired-pulse transcranial magnetic stimulation paradigm was used in order to evaluate and compare the PMv–M1 interactions during different phases (rest, preparation and execution) of an index finger movement in patients with FHD and controls. A sub-threshold conditioning pulse (80% resting motor threshold) was applied to the PMv at 6 ms before M1 stimulation. The right abductor pollicis brevis, a surround muscle, was the target muscle. In healthy controls, the results showed that PMv stimulation induced an ipsilateral ventral premotor–motor inhibition at rest. This cortico-cortical interaction changed into an early facilitation (100 ms before movement onset) and turned back to inhibition 50 ms later. In patients with FHD, this PMv–M1 interaction and its modulation were absent. Our results show that, although the ipsilateral ventral premotor–motor inhibition does not play a key role in the genesis of surround inhibition, PMv has a dynamic influence on M1 excitability during the early steps of motor execution. The impaired cortico-cortical interactions observed in patients with FHD might contribute, at least in part, to the abnormal motor command.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

A major feature of the pathophysiology of focal hand dystonia (FHD) is the lack of inhibition at the cortical, sub-cortical, and spinal levels, which is probably due to GABAergic dysfunction (Hallett, 2011). Impairment of intracortical circuits has been demonstrated in FHD, and this may be either an intrinsic abnormality or secondary to striatal dysfunction (Peller et al., 2006). In particular, surround inhibition (SI), which represents the suppression of excitability in the area surrounding an activated neural network in order to focus and select neuronal responses (Sohn & Hallett, 2004b), is impaired in FHD (Sohn & Hallett, 2004a). The lack of SI might explain, at least in part, the excessive antagonist and accessory muscle activation in patients with FHD (van der Kamp et al., 1989).

The mechanisms responsible for SI are still unknown. No intracortical inhibitory circuit located in or projecting to the primary motor cortex (M1) has been identified as a source of SI (Beck & Hallett, 2011). As it starts during movement preparation, SI could result from connections between the M1 and premotor areas involved in hand motor control. Accordingly, Beck and colleagues investigated the potential role of the dorsal premotor cortex in the generation of SI. Indeed, the dorsal premotor cortex plays an important role in movement selection (Rushworth et al., 2003) and some imaging studies have shown an impairment of dorsal premotor cortex activation in right-sided FHD (Ceballos-Baumann et al., 1997; Ceballos-Baumann & Brooks, 1998; Ibanez et al., 1999). However, the results demonstrated that the ipsilateral dorsal premotor–motor inhibition was not involved in the genesis of SI (Beck et al., 2009a).

The ventral premotor cortex (PMv) plays a key role in fine finger and hand movements. PMv neurons specialize in sensorimotor transformations and are actively involved in hand posture during grasping. PMv is also responsible for fingertip positions and elaborates the appropriate pattern of activation of intrinsic hand muscles (Davare et al., 2006). Positron emission tomography studies have shown abnormal activation patterns in the PMv and dorsal premotor cortex (PMd) in FHD (Ceballos-Baumann et al., 1997; Ibanez et al., 1999). These studies showed a dysfunction of the premotor cortical network as well as a dysfunction of premotor cortex–basal ganglia circuits. Using transcranial magnetic stimulation (TMS), it has been demonstrated that the PMv has an inhibitory influence on the M1 at rest in healthy subjects (Davare et al., 2008). This PMv–M1 interaction is muscle specific and modulated during different phases of grasp preparation and execution (Davare et al., 2008).

The aims of this study were to evaluate the PMv–M1 interactions during different phases of an index finger movement using a paired-pulse TMS paradigm, and to compare these interactions between patients with FHD and healthy volunteers. We hypothesized that the ipsilateral ventral premotor–motor inhibition would be involved in the physiology of SI and impaired in FHD.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References


Eighteen patients with FHD (mean age 57.9 ± 6.4 years, 14 male) and 18 healthy volunteers (mean age 55.7 ± 11.4 years, 11 male) participated in the study (see Table 1). Patients with FHD had unilateral, right hand, symptoms. One patient was left-handed but had symptoms in his right hand (musician’s dystonia, guitar player). Participants had no history of psychiatric disorders, neurosurgery or metal or electronic implants. Most patients had been treated with local injections of botulinum toxin type A in the affected hand and forearm muscles. For each patient, the last injection had been given at least 3 months prior to the recordings (Table 1).

Table 1.   Patient demographics
GenderAge (years)Type of crampDuration (years)Botulinum toxin/last injection
  1. MC, musician cramp; WC, writer cramp.

M54MC5Yes/3 months
M62WC11Yes/18 months
M57MC4Yes/4 years
M59MC7Yes/6 months
M60WC19Yes/4 months
M57WC16Yes/3 years
M58MC14Yes/2 years
M56WC9Yes/3 months
M75WC18Yes/2 years
M47MC16Yes/3 months
M51WC15Yes/6 months

The study was approved by the Institutional Review Board of the National Institute of Neurological Disorders and Stroke. All participants gave their informed oral and written consent before the experiments in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and National Institute of Neurological Disorders and Stroke guidelines.

Experimental procedures

Participants were seated in a comfortable armchair with both arms resting on a pillow placed on their laps. Their right hand was supported on a small board, to which a force transducer was attached (model S215 load cell; Strain Measurement Devices, Inc., Meriden, CT, USA). They rested their palm on the board, with the tip of their index finger on the force transducer.


Electromyographic activity of the right first dorsal interosseus (FDI) and abductor pollicis brevis (APB) was recorded in a belly-tendon montage using Ag–AgCl surface electrodes. Impedances were kept below 5 kΩ. Electromyographic signals were collected using a Viking IV electromyography machine (Nicolet Biomedical, Madison, WI, USA), bandpass-filtered at 20–2000 Hz. The amplified analog outputs from the Viking were digitized at 5 kHz using labview software (National Instruments, Austin, TX, USA), and stored on a PC for offline analysis.

Motor task

The task, similar to one previously published (Beck et al., 2008, 2009a,b,c; Beck & Hallett, 2010), was a simple acoustic reaction time (RT) task. Subjects had to perform an index finger flexion in order to press on the force transducer in response to a tone. The acoustic signal lasted 200 ms. In this task, FDI participated as a synergist rather than as prime mover, but it has been shown that the modulation of the cortical excitability of synergists is similar to that of prime movers (Sohn & Hallett, 2004b).

In response to the tone, subjects had to press the transducer as fast as possible, using only 10% of their maximum voluntary contraction. The maximum voluntary contraction was defined as the averaged strength obtained after three trials during which subjects used their maximal strength to push on the transducer device. They were told to use only the strength of their index finger and not to contract other forearm and arm muscles. The force level was then individually adjusted to 10% of the maximum voluntary contraction and displayed online as a target line on an oscilloscope placed on a table in front of them. The output of the force transducer was also displayed on the oscilloscope as direct online feedback. During the task, subjects had to maintain their contraction for approximately 1 s. Subjects practiced the task at the beginning of the experiment to attain a consistent motor performance.

Once the subjects showed consistent motor performance, four different phases of the movement preparation were assessed: rest, 100 ms before electromyography onset in FDI (T100), 50 ms before electromyography onset (T50) and time of the first peak of electromyography in FDI (Tpeak). The electromyography onset and first peak were measured individually as an average of FDI electromyography in 10 consecutive trials (Fig. 1).


Figure 1.  Experimental set-up. (A) An example of localization of M1 and PMv in one participant. M1 was defined as the stimulating point over which the greatest MEPAPB could be evoked. PMv was defined using a neuronavigation system (Brainsight, Rogue Research, Inc., Rogue Resolutions Ltd), and placed over the caudal portion of the pars opercularis of the inferior frontal gyrus. (B) Acoustic, force and electromyographic signals are displayed. Single-pulse (part 1) or paired-pulse (part 2) TMS was applied at four different timings (rest, T100, T50 and Tpeak). Subjects had to respond as fast as possible to the tone by pressing the button, using 10% of their strength. APB muscle stayed at rest during the entire task. Subjects maintained the movement for approximately 1 s and then came back to a relaxed position.

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Transcranial magnetic stimulation

Magnetic stimulation was delivered using two custom-made figure-of-eight coils with an inner loop diameter of 35 mm connected to two high-power Magstim 200 stimulators (Magstim Company Ltd, Whitland, Dyfed, UK). Stimulations were applied over the point that evoked the largest motor evoked potential (MEP) in the contralateral APB (‘motor hotspot’). MEPs were measured over the APB and FDI, but only one motor hotspot was tested (APB hotspot). MEP size was determined by averaging peak-to-peak amplitudes. The coil used to stimulate the motor hotspot was held tangentially to the scalp, at a 45° angle from the anteroposterior axis and with the handle pointing posterolaterally (Fig. 1A1). The resting motor threshold (RMT) of the APB was measured for each subject and defined as the lowest intensity that induced a 50 μV peak-to-peak amplitude MEP in at least five out of 10 trials. The second coil was positioned over the left PMv, with the handle pointing forward to induce a current directed anterioposteriorly (Fig. 1A2). Neuronavigation (Brainsight, Rogue Research, Inc., Rogue Resolutions Ltd, Cardiff, UK) was used for precise positioning of the coil over the PMv. Magnetic resonance imaging data specific to each participant were used to ensure correct placement of the coil, which was placed over the caudal portion of the pars opercularis of the inferior frontal gyrus (Davare et al., 2006). Each individual magnetic resonance image was normalized, a posteriori, onto the Montreal Neurological Institute brain template using the same software. PMv stimulation coordinates were then expressed with respect to the Montreal Neurological Institute standard space. The mean normalized Montreal Neurological Institute coordinates of the PMv stimulation sites were (x, y, z; mean ± SD in mm): (−59.0 ± 2.5, −2.1 ± 9.8, 7.6 ± 4.9) in controls and (−60.4 ± 3.8, −1.5 ± 8.0, 9.5 ± 4.0) in FHD. These two mean coordinates belong to BA6 according to the Talairach atlas (see Fig. 1). This confirmed that the conditioning coil was targeting the PMv in both groups. The positions of the two coils were marked on a tight-fitting cap to ensure proper coil placement throughout the experiment.

The experiment was conducted in two parts (parts 1 and 2). Part 1 aimed at assessing SI. Single TMS pulses were delivered over the motor hotspot at an intensity of 140% RMTAPB in four different conditions, in a random order: at rest, T100, T50,Tpeak and a condition in which no stimulation was given. In order to be able to randomize the order of the different phases, rest stimulation was given 100 ms before the acoustic tone (Fig. 1B). Two blocks of 45 stimuli were recorded, resulting in 18 MEPs for each condition.

Part 2 consisted of a paired-pulse paradigm designed to assess the effect of a conditioning stimulation over the PMv on the excitability of the M1. The conditioning stimulus was applied at 80% RMTAPB at an interstimulus interval (ISI) of 6 ms (Davare et al., 2008). The test stimulus was applied over the motor hotspot at an intensity set to evoke an MEP of 1 mV over the APB, at rest. Due to spatial interference of the two coils, the conditioning coil was placed directly on the skull, whereas the test pulse coil over the motor hotspot was slightly elevated. Four separate paired-pulse blocks were conducted for each subject: at rest, with the test pulse stimulating the M1 at T100, with the test pulse at T50 and with the test pulse at Tpeak. Thirty stimuli were applied for each of the four blocks (15 conditioned and 15 unconditioned stimuli).

During TMS recording, electromyography from the ABP was monitored. The APB is not involved in the task and therefore remained relaxed throughout the entire experiment. Trials in which there was background electromyography > 0.02 mV in the APB, assessed as root mean square over 50 ms prior to MEP onset in each phase, were rejected.

Statistical analysis

The RMTAPB, RTs and MEP sizes at rest in the APB and FDI were compared between groups using an independent samples t-test. In each group, rest MEPAPB and rest MEPFDI were compared using an independent samples t-test. The x, y and z coordinates of the PMv location were compared, between groups, using a Mann–Whitney test.

Statistical analyses of MEP amplitudes obtained in parts 1 and 2 were performed using a repeated anova. As the data were not Gaussian, our analyses used Conover’s free distribution method, a non-parametric anova based on ranks (Conover & Iman, 1982). Two factors were used: GROUP (two levels: FHD and controls) and PHASE (four levels: rest, T100, T50, Tpeak). If a main effect was observed at the 0.05 level, contrasts were calculated. If a significant interaction was found between the two factors, Mann–Whitney tests were performed to compare, between groups, MEP sizes for each phase. In part 2, the interaction between the PMv and M1 during the different phases of motor preparation was expressed as a ratio between conditioned and test MEPs (unconditioned), in percent – MEPcond/MEPtest*100. This ratio was used in the Conover analysis. If a significant interaction was found between the two factors, a non-parametric one-way anova (Friedman test) was performed to attest for significant differences between phases, in each group. If a significant main effect was found, Mann–Whitney tests were performed to compare MEP sizes for each phase between the two groups.

Independently, and for each group, the effect of the premotor–motor interaction on MEPs was assessed using a non-parametric Wilcoxon test comparing test MEPs with conditioned MEPs, for each phase. This analysis was performed to assess whether premotor stimulation had an inhibitory or facilitatory influence on the MEPs, in each group and for each phase.

In order to define whether patients with musician cramp and writer cramp displayed the same results, we performed a sub-group analysis. First, Wilcoxon tests were used in each group to detect any significant effect of PMv stimulation on the test MEP amplitude, for each phase. Then, in order to determine whether those two sub-groups behaved differently, a Conover analysis was performed on the PMv–M1 interaction results. Our sub-groups were made of six patients with musician cramp and 12 patients with writer cramp. In order to balance the power of our test, we compared the six patients with musician cramp with six patients with writer cramp who were age- and gender-matched to the patients.

Lastly, and in order to test the relationship between SI and PMv–M1 interaction, we performed a non-parametric Spearman correlation analysis between the amount of SI and the PMv–M1 interactions at T1, T2 and T3, in our two populations. Statistical analyses were performed using pasw Statistics 18.0 (SPSS, Inc., Chicago, IL, USA).


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

All of the data are displayed in Tables 2 and 3. The RTs did not differ between groups (P = 0.535). RMTAPB (Table 2) was not significantly different (P = 0.31) between patients with FHD and controls (48.6 ± 7.6 and 51.4 ± 8.5% of stimulator output, respectively). Rest MEPs over the APB and FDI (Table 2) were not significantly different between groups (P = 0.5 for APB and P = 0.25 for FDI). However, in each group, MEPAPB was smaller than MEPFDI (P = 0.022 in controls and P = 0.002 in patients). The x, y and z coordinates did not differ between groups (P > 0.05).

Table 2.   RTs, RMTs and baseline MEPs amplitude
 RT (ms) (mean ± SD)RMT (mean ± SD)MEP rest (mean ± SD) (mV)
  1. RMT is expressed as a percentage of stimulator output. HV, healthy volunteer.

HV161 ± 3651.4 ± 8.52.5 ± 1.53.9 ± 2.1
FHD168 ± 3248.6 ± 7.62.2 ± 1.35.0 ± 3.3
Table 3.   SI and ventral premotor–motor interactions
 Single-pulse – MEP size (mV) [median (range)]Paired-pulse – percentage of test MEP [median (range)]
  1. MEPAPB and MEPFDI amplitudes during single-pulse and paired-pulse stimulations at the different timings (rest, T100, T50 and Tpeak). A significant decrease in MEPAPB amplitude in healthy volunteers (HVs) is observed, during single-pulse TMS, demonstrating a significant SI. A central excitation is demonstrated in both groups by a significant increase of MEPFDI amplitude. No SI is found in patients. Paired-pulse TMS induced a significant premotor–motor inhibition at rest and at T50 in HVs and a significant facilitation at T100. No such influence is observed in patients. *P < 0.05.

 HV1.88 (0.69–5.42)1.82 (0.69–5.07)1.78 (0.73–5.28)*1.59 (0.61–5.4)*89.8 (35.3–115.4)*112.6 (83.9–168.8)*91.7 (25.4–109.2)*97.7 (69.9–143.5)
 FHD1.66 (0.65–4.63)1.84 (0.58–4.86)1.88 (0.73–4.7)1.94 (0.55–6.1)92.8 (75.6–120.7)100.4 (72–117)96.6 (71.8–135.3)96.8 (88–139.9)
 HV3.47 (1.61–10.41)3.61 (1.57–9.98)3.82 (1.76–10.45)*4.65 (2.06–8.42)*99.47 (85.25–129.37)97.62 (77.66–123.96)98.93 (88.07–138.61)101.39 (84.99–120.62)
 FHD4.13 (0.38–10.79)3.91 (0.38–10.7)5.1 (0.33–13.61)*6.21 (0.56–14.11)*108.78 (77.47–132.45)97.56 (88.56–102.31)107.47 (88.55–118.94)99.05 (76.26–111.56)

The Conover analysis of single-pulse TMS on MEPAPB (part 1, Fig. 2A) showed a significant GROUP effect (P = 0.002), a significant GROUP × PHASE interaction (P = 0.003), and no significant PHASE effect (P = 0.974), probably due to the significant interaction. Mann–Whitney tests demonstrated significant group differences at T50 (P = 0.007) and Tpeak (P = 0.001). Indeed, Wilcoxon tests showed that MEPAPB was significantly inhibited at T50 (P = 0.035) and Tpeak (P = 0.006) in controls only, reflecting significant SI (Table 3).


Figure 2.  Effect of movement preparation and movement onset on the amplitude of MEPAPB and MEPFDI. MEPs are expressed as a percentage of rest MEPs in the four different conditions (rest, T100, T50, Tpeak), in controls (black) and patients (gray), during single-pulse TMS. (A) A significant decrease of MEPAPB was observed in controls at T50 and Tpeak (SI), whereas patients exhibited no significant SI. *P < 0.05. (B) Significant MEPFDI amplitude increase was found in both groups at T50 and Tpeak (central excitation).

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Regarding MEPFDI sizes (evoked by stimulation of the APB hotspot), the Conover analysis demonstrated a significant PHASE effect (P < 0.001) (Fig. 2B). There were no significant GROUP or GROUP × PHASE interactions (P = 0.427 and P = 0.888, respectively). Contrast analyses revealed that, in both groups, MEP amplitudes at T50 and Tpeak were significantly different from the other conditions (P < 0.001 in each case). Wilcoxon tests showed a significant increase in MEPFDI at T50 in controls (P = 0.003) and patients (P = 0.004). This increase of MEP size was maximal at movement onset (P = 0.001 in both groups) and reflected a process that could be qualified as central excitation.

Regarding the premotor–motor interactions (Fig. 3, Table 3), Conover’s analysis of MEPAPB indicated a significant PHASE effect (P = 0.006), a significant PHASE × GROUP interaction (P = 0.029) and no significant GROUP effect (P = 0.615). Friedman’s test indicated a significant main effect of PHASE in controls (P = 0.001) and no significant main effect in patients with FHD (P = 0.737). The Mann–Whitney tests showed significant differences between the two groups at T100 (P = 0.01) and T50 (P = 0.04). At T100, PMv stimulation significantly enhanced MEP sizes in controls (P = 0.025) but not in patients. At T50, a significant premotor–motor inhibition was observed in controls (P = 0.001) and not in patients. In the patient group, no significant influence of PMv stimulation on MEPAPB size was found either at rest, or during the different phases of motor execution. A significant premotor–motor inhibition was observed in controls at rest (P = 0.011). Although this inhibition was absent in patients, there was no significant difference between the two groups at rest (P = 0.48). Analyses of MEPFDI revealed an absence of modulation of MEPFDI amplitude following PMv stimulation, either at rest or during movement, in both groups. The Conover analyses showed no PHASE effect (P = 0.086), no GROUP effect (P = 0.853) and no GROUP × PHASE interaction (P = 0.645).


Figure 3.  Premotor–motor interactions are expressed as a percentage of MEPAPB test in controls (black) and patients (gray) during paired-pulse TMS. No influence of the PMv over the M1 was constantly found in patients. Controls showed a significant premotor–motor inhibition at rest and at T50, whereas a significant facilitation was observed at T100. *P < 0.05.

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The sub-group analyses showed that, for the two sub-groups, PMv exerted no significant influence over M1 (similar to the whole group analysis). The Conover test indicated that there was no significant difference between those two sub-groups of patients (P = 1.00). Correlation analyses did not show any signification association between the amount of SI and the PMv–M1 interactions, suggesting an independence of the two phenomena (Table 4).

Table 4.   Correlation coefficients between the amount of SI and PMv–M1 interactions
  1. Correlation data between SI and PMv–M1 interactions at T100, T50 and Tpeak, in healthy volunteers (HVs) and patients (FHD). Correlations were considered significant if P ≤ 0.05. No significant correlations were observed between the two phenomena, in both populations.

HV−0.098 (P = 0.699)−0.234 (P = 0.349)0.309 (P = 0.213)
FHD0.079 (P = 0.754)0.313 (P = 0.206)0.018 (P = 0.945)


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Our results showed that the PMv exerted a modulatory influence on the M1 at rest and during movement preparation, and that this influence was absent in patients. We confirmed that the PMv inhibited the M1 at rest in controls and that this inhibition was muscle specific. Moreover, contrary to our hypothesis, we showed that this inhibition was not enhanced during movement initiation, indicating that the ipsilateral ventral premotor–motor inhibition does not play a key role in SI in normal subjects.

Surround inhibition – central excitation

In accordance with the literature, we showed that healthy volunteers presented with SI (regarding the APB muscle) before and at movement onset and that this SI was absent in patients (Sohn & Hallett, 2004a,b; Beck et al., 2008, 2009a,b,c). In parallel with this inhibition, the excitability of the synergist muscle cortical representation was increased before and at movement onset in controls as well as in patients with FHD without significant differences between the two groups, as previously reported (Beck et al., 2008). Indeed, we showed that MEPFDI was significantly enhanced at T50 and Tpeak. This preserved central excitation, in line with the literature, shows that the cortico-spinal excitability of the synergist muscle is not impaired in patients with FHD. Together with this finding, we did not observe any differences in RTs between patients and controls (Stinear & Byblow, 2005; Beck et al., 2008, 2009a,b). Although RTs as well as the central excitation were not impaired in patients, it is noteworthy that some EEG studies have demonstrated an abnormal motor preparation in patients with FHD. Abnormally reduced event-related desynchronization or Bereitschaftspotential has been reported in patients with FHD, preceding voluntary, self-paced movements (Deuschl et al., 1995; Ikeda et al., 1996; Yazawa et al., 1999; Toro et al., 2000). Event-related desynchronization and Bereitschaftspotential reflect the activation of premotor and motor areas involved in movement preparation and execution. Abnormal event-related desynchronization or Bereitschaftspotential suggests an impairment of premotor and/or motor cortex activation during self-paced movement preparation. These complementary EEG–TMS data suggest that, although the excitability of the synergist muscle representation over the M1 is preserved in patients with FHD, the premotor–motor interactions preceding voluntary movement are impaired.

Impaired cortico-cortical interactions in focal hand dystonia

Our results showed a lack of RT, RMT and rest MEP differences between patients and controls. This implies that any group differences observed in this study could not be explained by a change of motor threshold or a different RT in patients with FHD. In the current study, we confirmed previous reports indicating that the PMv has an inhibitory influence on the M1 at rest in healthy subjects (Davare et al., 2008). This ipsilateral ventral premotor–motor inhibition might depend on GABA-a interneurons. Indeed, it has previously been shown in monkeys that injection of bicuculline (a GABA-a antagonist) in the premotor cortex (dorsal and ventral) provoked co-contractions of agonists and antagonists (Matsumura et al., 1991). The effects provoked by bicuculline injection in the premotor cortex were not as severe as those observed after M1 injection, but they shared the same time-course. Kurata & Hoffman (1994) confirmed the GABA-a dependency of PMv neurons by injecting muscimol (a GABA-a agonist) in the PMv. They observed a decrease of movement (wrist flexion or extension) amplitude and velocity. Although the PMv has some direct projections to the spinal cord (Dum & Strick, 1991, 2005; He et al., 1993; Luppino et al., 1999), it has strong output onto the hand representation of the M1 (Cerri et al., 2003; Shimazu et al., 2004). Shimazu et al. (2004) showed that, in monkeys, stimulation of F5 (the equivalent of the human PMv) can facilitate the cortico-spinal volley from the M1 and that this effect can be abolished by a reversible inactivation of M1. The ISI of 6 ms between the conditioning stimulus and test stimulus in our experiment suggests that the cortico-cortical pathway between the PMv and M1 might be a direct oligosynaptic connection (Shimazu et al., 2004).

The lack of ipsilateral ventral premotor–motor inhibition at rest in patients with FHD (Fig. 3) is coherent with the pathophysiology of the disease and more particularly with the hypothesis of a dysfunction in GABA-a transmission. Indeed, many studies conducted on dystonic animal models have demonstrated alterations in GABA levels (Messer & Gordon, 1979; Loscher & Horstermann, 1992) or in GABA receptor density and affinity in different brain regions (Beales et al., 1990; Nobrega et al., 1995; Pratt et al., 1995; Gilbert et al., 2006; Alterman & Snyder, 2007). In patients with FHD, a magnetic resonance spectroscopy study showed a decreased GABA level in the sensorimotor cortex and lentiform nuclei contralateral to the affected hand (Levy & Hallett, 2002). This result, however, could not be reproduced in a larger population (Herath et al., 2010). Recently, a positron emission tomography study conducted on patients presenting with primary dystonia showed a significant reduction in GABA-a receptor expression and affinity in the premotor and M1, primary and secondary somatosensory cortex and cingulate gyrus (Garibotto et al., 2011). The involvement of the PMv in FHD has also been suggested by several neuroimaging studies. Positron emission tomography studies have shown abnormal functioning of the PMv either toward an increase of activity (Ceballos-Baumann et al., 1997) or toward a decrease of activity (Ibanez et al., 1999). These two results probably differed because of the different patient selection and different tasks involved. Ibanez et al. (1999) studied cerebral activity during different tasks and showed a decreased activity in the left PMv during writing. This result and the impaired functional interaction between the PMv and M1 in our study suggest that the PMv plays an important role in the generation of the abnormal motor command in FHD.

Abnormal balance between excitation and inhibition

Our results show that the ipsilateral ventral premotor–motor inhibition was modulated during the different phases of motor execution in healthy subjects. During the early stages of movement preparation, the inhibition turned into facilitation. This result is concordant with previous studies showing that the premotor–motor interactions differ according to the movements and muscles involved (Ceballos-Baumann et al., 1997; Ibanez et al., 1999). One could hypothesize that this early premotor–motor facilitation reflects a general facilitatory influence of the PMv on the M1 during the early stages of motor execution. First, the excitability of the muscles located in the movement area would increase, then, along with the adjustment of the motor plan, the premotor–motor facilitation would turn into an inhibition if the muscles are not to be involved in the action. Indeed, the inhibition was restored at 50 ms prior to movement and was abolished at the onset of movement. These findings suggest that ipsilateral ventral premotor–motor inhibition may help to select the movement. In contrast, the absence of increased inhibition at movement onset, when SI is at its maximum (Sohn & Hallett, 2004a,b; Beck et al., 2008), indicates that this ipsilateral ventral premotor–motor inhibition is not the main generator of SI. We can thus hypothesize that the premotor–motor inhibition might be complementary and different from SI. This might constitute an early step in movement selection as it starts and evolves before movement onset and disappears before the start of the movement.

Our results show a lack of premotor–motor inhibition and premotor–motor facilitation in patients with FHD. In patients, PMv had no significant influence on the M1 either at rest or during the early steps of motor execution. This shows that excitatory cortico-cortical connections are also impaired in FHD, which is consistent with a previous finding showing an abnormal facilitation instead of long afferent inhibition in FHD following median nerve stimulation (Abbruzzese et al., 2001). Although the major cortical and sub-cortical neurotransmission deficiency in FHD involves the GABA network, these results illustrate that excitatory circuits might also be impaired in patients and that the balance between inhibition and excitation is abnormal. The lack of premotor–motor inhibition suggests that the abnormal cortical hyperexcitability observed in patients with FHD also affects the early steps of movement preparation, and not solely SI. It has also been demonstrated that the premotor–motor interactions are very sensitive to ISIs and stimulus intensity (Civardi et al., 2001; Davare et al., 2008, 2009). It is thus possible that the PMv–M1 interactions might be shifted towards different components (latencies, activation threshold) in patients with FHD. As our study focused on investigating the role of the premotor–motor interactions in SI at various phases of movement, the experiment even with one ISI took about 2 h. Hence, we could not test more ISIs. We decided to test the ISI that exerted the most efficient premotor–motor influence (6 ms), as shown by Davare et al. (2008). In order to fully define the importance of the impairment of the premotor–motor interactions in patients with FHD, more ISIs should be tested in future studies.

Looking at the synergistic muscle, the current study shows that MEP amplitudes in the FDI are not modulated by stimulation of the PMv. This is probably due to the fact that PMv–M1 interactions are muscle specific (Davare et al., 2009) and are extremely sensitive to the parameters of stimulation. Indeed, small variations of the conditioning stimulus intensity greatly influence the outcome (Civardi et al., 2001). As the stimulation intensities used in the current study were adjusted to RMTAPB, we cannot make clear conclusions about the effects of the paired stimulations over the FDI. Indeed, although the FDI and APB hotspots and RMT are very close to each other, we showed that, at rest, MEPFDI was higher than MEPAPB in both groups. This difference is probably explained by a difference in the input–output curve. Thus, a stimulation set at 80% RMTAPB might correspond to approximately 90% RMTFDI. It is then reasonable to expect significant differences in results between the FDI and APB, as it has been demonstrated that a stimulation at 90% AMTFDI over the dorsal premotor cortex could inhibit M1, whereas a stimulation set at 80 or 100% AMTFDI had no effect on the M1 (Civardi et al., 2001). As a consequence, we can only make conclusions about significant premotor–motor interactions regarding the APB muscle, a surrounding muscle, not involved in the task. Although the APB is not recruited during this task, it is probable that this latter muscle might be under the influence of the PMv. Indeed, it has been shown that the PMv exerts an important role in hand posture and fingertip position, and elaborates the appropriate pattern of activation of intrinsic hand muscles (Ceballos-Baumann et al., 1997; Ibanez et al., 1999; Davare et al., 2006). It has also been described that the PMv plays a relevant role in visually-cued finger movements (Pollok et al., 2009; Ruspantini et al., 2011). PMv might thus play a key role in finger positioning in our task. Patients with FHD suffer from an abnormal activation pattern of the hand muscles during writing or music playing, with abnormal overflow of agonist and antagonist muscles (van der Kamp et al., 1989). We can thus hypothesize that the muscular adjustment usually exerted by the PMv over the M1 before movement onset is impaired in patients with FHD, explaining the abnormal PMv–M1 interactions regarding the APB muscle.

It seems unlikely that the premotor–motor facilitation observed in controls at T100 is due to the tone processing. In this simple acoustic RT task, we were expecting a facilitation of the synergist muscle (FDI) starting at 100 ms after the tone presentation, as has been reported in previous studies (Starr et al., 1988; Pascual-Leone et al., 1992; Leocani et al., 2000). Our results confirmed this expectation. In the current experiment, RTs were approximately 160 ms, which indicates that T50 was approximately 110 ms after the tone presentation; during the single-pulse TMS paradigm, MEPFDI was significantly enhanced at T50 and Tpeak, in both groups. We did not observe an early facilitation of the synergist muscle (FDI) similar to that reported by Leocani et al. (2000). Moreover, many studies based on auditory evoked potential recordings identified cortical potentials over the fronto-central areas at 200–300 ms after the stimulus onset. In our study, T100 stimulation occurred on average at 60 ms after the tone presentation; it is very unlikely that the premotor–motor facilitation that we observed was due to the influence of the tone processing on the motor and premotor areas.

One limitation regarding the interpretation of our results could arise from the issue as to whether the involvement of the PMv might be expected in a simple RT task of index finger pressing. However, recent neuroimaging studies have demonstrated the activation of the PMv during unilateral hand or finger tapping tasks (Horenstein et al., 2009; Pollok et al., 2009), and thus corroborate previous data reported in monkeys (Matsumura et al., 1991; Kurata & Hoffman, 1994). As the PMv is highly involved in shaping hand movements (Davare et al., 2009) and constitutes a key component of visuomotor transformation for hand posture, it is reasonable to hypothesize that the PMv is involved in the finger-pressing RT task used in this study. The current results obtained using the paired-pulse paradigm indeed prove the involvement of the PMv.

In conclusion, this study highlights the importance of the PMv–M1 interactions in the generation of the hand motor command. PMv–M1 interactions are both excitatory and inhibitory in nature. The inhibitory effects do not seem to contribute to the genesis of SI. Further experimentation is needed in order to define clearly the nature of these cortico-cortical interactions as well as their exact role in the abnormal hand posture observed in patients with FHD.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. E.H. was funded by the Fyssen Foundation.


abductor pollicis brevis


first dorsal interosseus


focal hand dystonia


interstimulus interval


primary motor cortex


motor evoked potential


ventral premotor cortex


resting motor threshold


reaction time


surround inhibition


transcranial magnetic stimulation


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • Abbruzzese, G., Marchese, R., Buccolieri, A., Gasparetto, B. & Trompetto, C. (2001) Abnormalities of sensorimotor integration in focal dystonia: a transcranial magnetic stimulation study. Brain, 124, 537545.
  • Alterman, R.L. & Snyder, B.J. (2007) Deep brain stimulation for torsion dystonia. Acta Neurochir. Suppl., 97, 191199.
  • Beales, M., Lorden, J.F., Walz, E. & Oltmans, G.A. (1990) Quantitative autoradiography reveals selective changes in cerebellar GABA receptors of the rat mutant dystonic. J. Neurosci., 10, 18741885.
  • Beck, S. & Hallett, M. (2010) Surround inhibition is modulated by task difficulty. Clin. Neurophysiol., 121, 98103.
  • Beck, S. & Hallett, M. (2011) Surround inhibition in the motor system. Exp. Brain Res., 210, 165172.
  • Beck, S., Richardson, S.P., Shamim, E.A., Dang, N., Schubert, M. & Hallett, M. (2008) Short intracortical and surround inhibition are selectively reduced during movement initiation in focal hand dystonia. J. Neurosci., 28, 1036310369.
  • Beck, S., Houdayer, E., Richardson, S.P. & Hallett, M. (2009a) The role of inhibition from the left dorsal premotor cortex in right-sided focal hand dystonia. Brain Stimul., 2, 208214.
  • Beck, S., Schubert, M., Richardson, S.P. & Hallett, M. (2009b) Surround inhibition depends on the force exerted and is abnormal in focal hand dystonia. J. Appl. Physiol., 107, 15131518.
  • Beck, S., Shamim, E.A., Richardson, S.P., Schubert, M. & Hallett, M. (2009c) Inter-hemispheric inhibition is impaired in mirror dystonia. Eur. J. Neurosci., 29, 16341640.
  • Ceballos-Baumann, A.O. & Brooks, D.J. (1998) Activation positron emission tomography scanning in dystonia. Adv. Neurol., 78, 135152.
  • Ceballos-Baumann, A.O., Sheean, G., Passingham, R.E., Marsden, C.D. & Brooks, D.J. (1997) Botulinum toxin does not reverse the cortical dysfunction associated with writer’s cramp. A PET study. Brain, 120(Pt 4), 571582.
  • Cerri, G., Shimazu, H., Maier, M.A. & Lemon, R.N. (2003) Facilitation from ventral premotor cortex of primary motor cortex outputs to macaque hand muscles. J. Neurophysiol., 90, 832842.
  • Civardi, C., Cantello, R., Asselman, P. & Rothwell, J.C. (2001) Transcranial magnetic stimulation can be used to test connections to primary motor areas from frontal and medial cortex in humans. Neuroimage, 14, 14441453.
  • Conover, W.J. & Iman, R.L. (1982) Analysis of covariance using the rank transformation. Biometrics, 38, 715724.
  • Davare, M., Andres, M., Cosnard, G., Thonnard, J.L. & Olivier, E. (2006) Dissociating the role of ventral and dorsal premotor cortex in precision grasping. J. Neurosci., 26, 22602268.
  • Davare, M., Lemon, R. & Olivier, E. (2008) Selective modulation of interactions between ventral premotor cortex and primary motor cortex during precision grasping in humans. J. Physiol., 586, 27352742.
  • Davare, M., Montague, K., Olivier, E., Rothwell, J.C. & Lemon, R.N. (2009) Ventral premotor to primary motor cortical interactions during object-driven grasp in humans. Cortex, 45, 10501057.
  • Deuschl, G., Toro, C., Matsumoto, J. & Hallett, M. (1995) Movement-related cortical potentials in writer’s cramp. Ann. Neurol., 38, 862868.
  • Dum, R.P. & Strick, P.L. (1991) The origin of corticospinal projections from the premotor areas in the frontal lobe. J. Neurosci., 11, 667689.
  • Dum, R.P. & Strick, P.L. (2005) Frontal lobe inputs to the digit representations of the motor areas on the lateral surface of the hemisphere. J. Neurosci., 25, 13751386.
  • Garibotto, V., Romito, L.M., Elia, A.E., Soliveri, P., Panzacchi, A., Carpinelli, A., Tinazzi, M., Albanese, A. & Perani, D. (2011) In vivo evidence for GABA(A) receptor changes in the sensorimotor system in primary dystonia. Mov. Disord., 26, 852857.
  • Gilbert, S.L., Zhang, L., Forster, M.L., Anderson, J.R., Iwase, T., Soliven, B., Donahue, L.R., Sweet, H.O., Bronson, R.T., Davisson, M.T., Wollmann, R.L. & Lahn, B.T. (2006) Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice. Nat. Genet., 38, 245250.
  • Hallett, M. (2011) Neurophysiology of dystonia: The role of inhibition. Neurobiol. Dis., 42, 177184.
  • He, S.Q., Dum, R.P. & Strick, P.L. (1993) Topographic organization of corticospinal projections from the frontal lobe: motor areas on the lateral surface of the hemisphere. J. Neurosci., 13, 952980.
  • Herath, P., Gallea, C., Van der Veen, J.W., Horovitz, S.G. & Hallett, M. (2010) In vivo neurochemistry of primary focal hand dystonia: a magnetic resonance spectroscopic neurometabolite profiling study at 3T. Mov. Disord., 25, 28002808.
  • Horenstein, C., Lowe, M.J., Koenig, K.A. & Phillips, M.D. (2009) Comparison of unilateral and bilateral complex finger tapping-related activation in premotor and primary motor cortex. Hum. Brain Mapp., 30, 13971412.
  • Ibanez, V., Sadato, N., Karp, B., Deiber, M.P. & Hallett, M. (1999) Deficient activation of the motor cortical network in patients with writer’s cramp. Neurology, 53, 96105.
  • Ikeda, A., Shibasaki, H., Kaji, R., Terada, K., Nagamine, T., Honda, M., Hamano, T. & Kimura, J. (1996) Abnormal sensorimotor integration in writer’s cramp: study of contingent negative variation. Mov. Disord., 11, 683690.
  • van der Kamp, W., Berardelli, A., Rothwell, J.C., Thompson, P.D., Day, B.L. & Marsden, C.D. (1989) Rapid elbow movements in patients with torsion dystonia. J. Neurol. Neurosurg. Psychiatry, 52, 10431049.
  • Kurata, K. & Hoffman, D.S. (1994) Differential effects of muscimol microinjection into dorsal and ventral aspects of the premotor cortex of monkeys. J. Neurophysiol., 71, 11511164.
  • Leocani, L., Cohen, L.G., Wassermann, E.M., Ikoma, K. & Hallett, M. (2000) Human corticospinal excitability evaluated with transcranial magnetic stimulation during different reaction time paradigms. Brain, 123(Pt 6), 11611173.
  • Levy, L.M. & Hallett, M. (2002) Impaired brain GABA in focal dystonia. Ann. Neurol., 51, 93101.
  • Loscher, W. & Horstermann, D. (1992) Abnormalities in amino acid neurotransmitters in discrete brain regions of genetically dystonic hamsters. J. Neurochem., 59, 689694.
  • Luppino, G., Murata, A., Govoni, P. & Matelli, M. (1999) Largely segregated parietofrontal connections linking rostral intraparietal cortex (areas AIP and VIP) and the ventral premotor cortex (areas F5 and F4). Exp. Brain Res., 128, 181187.
  • Matsumura, M., Sawaguchi, T., Oishi, T., Ueki, K. & Kubota, K. (1991) Behavioral deficits induced by local injection of bicuculline and muscimol into the primate motor and premotor cortex. J. Neurophysiol., 65, 15421553.
  • Messer, A. & Gordon, D. (1979) Changes in whole tissue biosynthesis of gamma-amino butyric acid (GABA) in basal ganglia of the dystonia (dtAlb) mouse. Life Sci., 25, 22172221.
  • Nobrega, J.N., Richter, A., Burnham, W.M. & Loscher, W. (1995) Alterations in the brain GABAA/benzodiazepine receptor-chloride ionophore complex in a genetic model of paroxysmal dystonia: a quantitative autoradiographic analysis. Neuroscience, 64, 229239.
  • Pascual-Leone, A., Valls-Sole, J., Wassermann, E.M., Brasil-Neto, J., Cohen, L.G. & Hallett, M. (1992) Effects of focal transcranial magnetic stimulation on simple reaction time to acoustic, visual and somatosensory stimuli. Brain, 115(Pt 4), 10451059.
  • Peller, M., Zeuner, K.E., Munchau, A., Quartarone, A., Weiss, M., Knutzen, A., Hallett, M., Deuschl, G. & Siebner, H.R. (2006) The basal ganglia are hyperactive during the discrimination of tactile stimuli in writer’s cramp. Brain, 129, 26972708.
  • Pollok, B., Krause, V., Butz, M. & Schnitzler, A. (2009) Modality specific functional interaction in sensorimotor synchronization. Hum. Brain Mapp., 30, 17831790.
  • Pratt, G.D., Richter, A., Mohler, H. & Loscher, W. (1995) Regionally selective and age-dependent alterations in benzodiazepine receptor binding in the genetically dystonic hamster. J. Neurochem., 64, 21532158.
  • Rushworth, M.F., Johansen-Berg, H., Gobel, S.M. & Devlin, J.T. (2003) The left parietal and premotor cortices: motor attention and selection. Neuroimage, 20(Suppl. 1), S89S100.
  • Ruspantini, I., Mäki, H., Korhonen, R., D’Ausilio, A. & Ilmoniemi, R.J. (2011) The functional role of the ventral premotor cortex in a visually paced finger tapping task: a TMS study. Behav. Brain Res., 7, 325330.
  • Shimazu, H., Maier, M.A., Cerri, G., Kirkwood, P.A. & Lemon, R.N. (2004) Macaque ventral premotor cortex exerts powerful facilitation of motor cortex outputs to upper limb motoneurons. J. Neurosci., 24, 12001211.
  • Sohn, Y.H. & Hallett, M. (2004a) Disturbed surround inhibition in focal hand dystonia. Ann. Neurol., 56, 595599.
  • Sohn, Y.H. & Hallett, M. (2004b) Surround inhibition in human motor system. Exp. Brain Res., 158, 397404.
  • Starr, A., Caramia, M., Zarola, F. & Rossini, P.M. (1988) Enhancement of motor cortical excitability in humans by non-invasive electrical stimulation appears prior to voluntary movement. Electroencephalogr. Clin. Neurophysiol., 70, 2632.
  • Stinear, C.M. & Byblow, W.D. (2005) Task-dependent modulation of silent period duration in focal hand dystonia. Mov. Disord., 20, 11431151.
  • Toro, C., Deuschl, G. & Hallett, M. (2000) Movement-related electroencephalographic desynchronization in patients with hand cramps: evidence for motor cortical involvement in focal dystonia. Ann. Neurol., 47, 456461.
  • Yazawa, S., Ikeda, A., Kaji, R., Terada, K., Nagamine, T., Toma, K., Kubori, T., Kimura, J. & Shibasaki, H. (1999) Abnormal cortical processing of voluntary muscle relaxation in patients with focal hand dystonia studied by movement-related potentials. Brain, 122, 13571366.