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.