Hemispheric asymmetry and somatotopy of afferent inhibition in healthy humans
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- Helmich, R.C.G., Bäumer, T., Siebner, H.R. et al. Exp Brain Res (2005) 167: 211. doi:10.1007/s00221-005-0014-1
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A conditioning electrical stimulus to a digital nerve can inhibit the motor-evoked potentials (MEPs) in adjacent hand muscles elicited by transcranial magnetic stimulation (TMS) to the contralateral primary motor cortex (M1) when given 25–50 ms before the TMS pulse. This is referred to as short-latency afferent inhibition (SAI). We studied inter-hemispheric differences (Experiment 1) and within-limb somatotopy (Experiment 2) of SAI in healthy right-handers. In Experiment 1, conditioning electrical pulses were applied to the right or left index finger (D2) and MEPs were recorded from relaxed first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles ipsilateral to the conditioning stimulus. We found that SAI was more pronounced in right hand muscles. In Experiment 2, electrical stimulation was applied to the right D2 and MEPs were recorded from ipsilateral FDI, extensor digitorum communis (EDC) and biceps brachii (BB) muscles. The amount of SAI did not differ between FDI, EDC and BB muscles. These data demonstrate inter-hemispheric differences in the processing of cutaneous input from the hand, with stronger SAI in the dominant left hemisphere. We also found that SAI occurred not only in hand muscles adjacent to electrical digital stimulation, but also in distant hand and forearm and also proximal arm muscles. This suggests that SAI induced by electrical D2 stimulation is not focal and somatotopically specific, but a more widespread inhibitory phenomenon.
KeywordsAfferent inhibitionHandednessSomatotopySensorimotor integrationTranscranial magnetic stimulation
There are hemispheric differences in the organisation of the human motor system both intra-individually (Pujol et al. 2002) and between right and left handers (Netz et al. 1995; Dassonville et al. 1997; Volkmann et al. 1998; Triggs et al. 1999; Yahagi and Kasai 1999; Civardi et al. 2000; Ilic et al. 2004). Using transcranial magnetic stimulation (TMS), short-interval intracortical inhibition (SICI) and facilitation (SICF) (Civardi et al. 2000; Hammond et al. 2004; Ilic et al. 2004) and interhemispheric inhibition (Netz et al. 1995) differ between the right and left hemispheres in right handers. In addition, diffusion tensor magnetic resonance imaging (MRI) has revealed structural differences of the white matter underneath the pre-central sulcus related to handedness (Buchel et al. 2004). These data imply an asymmetry of motor organisation, at least in right-handed subjects, which might be related to denser connections between the dominant primary motor cortex (M1) and other parts of the brain. Investigations of the sensory system also showed hemispherical asymmetries of the somatosensory-evoked potentials with higher amplitudes of and more focal N20 peaks in the dominant left hemisphere in right-handers (Buchner et al. 1995).
Motor output is influenced by sensory input (Delwaide and Olivier 1990; Tokimura et al. 2000). The integration of sensory information with motor output is thought to have an important role in motor learning (Asanuma and Pavlides 1997). Such sensorimotor interaction can be tested in a paired pulse paradigm, where conditioning electrical stimuli are given to a digital nerve and TMS test pulses to the contralateral M1 hand area. Typically, motor-evoked potentials (MEPs) are suppressed when preceded by electrical stimuli at interstimulus intervals (ISIs) between 25 and 50 ms, which is referred to as short-latency afferent inhibition (SAI) (Delwaide and Olivier 1990; Maertens de Noordhout et al. 1992; Tokimura et al. 2000). Given its importance for the acquisition of motor skills, we hypothesised that the preferred use of the right hand in right-handers should lead to inter-hemispheric differences of sensorimotor integration as reflected by asymmetric SAI. We investigated this in Experiment 1.
Another question relates to the somatotopic specificity of sensorimotor integration within the dominant left hemisphere. In some parts of the sensory system, a strict spatial somatotopy prevails. For instance, functional MRI studies demonstrated that receptive fields of non-adjacent fingers do not overlap in Brodmann area 3b, where perception is supposed to take place (Kurth et al. 2000; Krause et al. 2001; Ruben et al. 2001; van Westen et al. 2004). In contrast, in Brodmann areas 1 and 2 that are densely connected with M1, receptive fields of the fingers are not segregated (Kurth et al. 2000; Krause et al. 2001). Also, movements rather than muscles seem to be represented in M1 (Rizzolatti et al. 1998; Beisteiner et al. 2001; Schieber 2001; Dechent and Frahm 2003). However, the somatotopy of SAI in the human hand has been reported to be finger-specific (Classen et al. 2000; Tamburin et al. 2001; Tamburin et al. 2003a). Given functional M1 somatotopy this is somewhat surprising, as one might expect SAI to be organised in groups of functionally related muscles rather than single muscles. Therefore, we investigated within-limb somatotopy of SAI in Experiment 2.
Materials and methods
We studied 15 healthy right-handed volunteers (ten men), aged 22–38 years (mean age 28 years ± 4.5 SD) in Experiment 1. Eight healthy right-handed volunteers (4 men / 4 women), aged 23–39 years (mean age 30 years ± 5.8 SD) participated in Experiment 2. Handedness was determined using the Edinburgh Handedness Inventory (Oldfield 1971).
The protocol was approved by the Medical Ethics Committee of the University of Hamburg, and all subjects gave their written informed consent to participate in the study.
EMG activity was recorded with silver surface electrodes from first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles bilaterally in Experiment 1; and from right FDI, ADM, extensor digitorum communis (EDC) and biceps brachii (BB) muscles in Experiment 2. Raw signals were amplified using a D360 eight channel amplifier (Digitimer Limited, Welwyn Garden City, UK) and bandpass-filtered between 5 and 1,000 Hz. EMG signals were sampled at 5,000 Hz, digitised using an analogue–digital converter (Micro1401, Cambridge Electronics Design (CED), Cambridge, UK) and stored on a personal computer for display and later for off-line data analysis. To capture baseline EMG activity during the measurement, EMG signals were continuously monitored acoustically with loudspeakers and visually by means of an oscilloscope.
Transcranial magnetic stimulation (TMS)
Focal TMS was performed using a figure-of-eight shaped magnetic coil with an outer diameter of 70 mm connected to a Magstim stimulator (Magstim 200HP, The Magstim Company, Dyfed, UK). The magnetic stimulus had a nearly monophasic pulse configuration with a rise time of about 100 μs, decaying back to zero over about 0.8 ms. In Experiment 1 the coil was held over the M1 contralateral to the recorded muscles in such a position that stimulation always yielded maximal MEPs in the FDI muscle (referred to as FDI hotspot). In addition to the hotspot of the FDI, we also determined hot spots of the EDC and BB in Experiment 2 and tested SAI in separate blocks for these muscle using individual muscle hot spots.
The coil position was always tangential to the skull with the handle pointing backwards and laterally at an angle of approximately 45° in the sagital plane. Hotspots, including the position and orientation of the coil, were marked on the scalp with a wax pen.
Electrical digital stimulation of the index finger (D2) was performed using a Digitimer Constant Current DS7A Stimulator (Digitimer Limited, UK) and pairs of ring electrodes with the cathode placed at the proximal part of the D2 and the anode 2 cm distally in the middle part of the finger.
Subjects were seated comfortably in an armchair during the experiments. They were instructed not to speak, to relax, to keep their eyes open and to look straight ahead. Resting motor threshold (RMT) was defined as the intensity to elicit MEPs of at least 50 μV in five of ten consecutive trails in relaxed FDI muscle. Active motor threshold (AMT) was defined as the intensity to elicit MEPs of at least 150 μV in five of ten consecutive trails in activated (10% of maximum voluntary contraction) FDI, EDC and BB muscles, respectively. Test pulse intensity was defined as the stimulator intensity that elicited MEPs of approximately 0.4–1.0 mV peak-to-peak amplitude in the target muscle.
The electrical stimulation consisted of a brief pulse (0.1 ms duration, 400 V) at three times the individual’s sensory perception threshold (SPT). Subjects who felt this intensity to be painful were excluded from the study. SPT was defined as the current intensity that was still detected by the subject in two out of four consecutive electrical pulses. We applied two series with increasing and two with decreasing electrical pulse intensities. Thus, starting from a sub-threshold level, electrical pulses with increasing intensities were applied until subjects detected these stimuli in the increasing series, and supra-threshold electrical pulses were given with decreasing intensities until subjects did not notice these pulses any more. In Experiment 2, we additionally determined pain perception threshold in a similar way.
In Experiment 1, we investigated hemispheric asymmetries of SAI in the FDI muscle (target muscle) and ADM muscle (control muscle). SAI was tested at six different intervals (25, 30, 35, 40, 50 and 80 ms). Measurements were performed in two blocks (two conditions; right and left hemispheres) in a randomised order between subjects. Within each block, conditioned MEPs at each ISI were tested 10 times and unconditioned MEPs 20 times. The order of the stimulus conditions was pseudo-randomised within each block.
In Experiment 2, the somatotopy of SAI of the dominant left hemisphere was addressed. We thus examined effects of electrical D2 stimulation of the right hand on MEP amplitudes in an intrinsic hand (FDI), a forearm (EDC) and an upper arm (BB) muscle. As we were interested in the magnitude of SAI, we focussed on those ISIs where inhibition was most pronounced in Experiment 1, i.e. 25, 30, 40 ms (see Results). Conditioned MEPs at each ISI were tested 10 times and unconditioned MEPs 20 times in a randomised order.
MEP amplitudes were measured peak-to-peak in each individual trial, using a custom-made software script (Signal, version 2.10, CED).
RMT, AMT, intensity of TMS pulses to elicit MEPs, test MEP amplitudes in FDI and ADM and SPTs for electrical stimulation were compared between the left and right hemispheres using paired samples t tests. Comparisons between experiments were performed using student’s t tests. Test MEP amplitudes were compared between different muscles using one-way ANOVA.
The amount of SAI was calculated within each muscle by comparing absolute test MEP amplitudes and conditioned MEPs at all ISIs using one-way ANOVAs for repeated measures and post-hoc paired samples t test for pair-wise comparisons. Differences in the amount of SAI between left and right hand muscles and between different muscles of the right arm were calculated by comparing relative amplitudes of conditioned MEPs, i.e. mean conditioned MEP amplitudes at each ISI expressed as percentages of the test MEP. Thus, in Experiment 1, we explored hemispheric asymmetries of SAI in FDI and ADM and differences in SAI between FDI and ADM by performing a three-way repeated measures ANOVA with the factors SIDE (two levels: left and right), MUSCLE (two levels; FDI and ADM) and ISI (six levels; ISIs of 25, 30, 35, 40, 50 and 80 ms).
In Experiment 2, we studied differences in SAI (relative amplitudes) between different muscles of the right arm. We carried out two-way repeated measures ANOVAs with the factors MUSCLE (three levels; FDI, EDC, BB) and ISI (three level; ISIs of 25, 30 and 40 ms). Post-hoc paired samples t tests were used for comparisons of relative MEP amplitudes at a given ISI. Effects were considered significant if P<0.05. The Greenhouse-Geisser correction was used to correct for non-sphericity. Statistical analysis was performed using SPSS 10.0.7.
Stimulation Parameters (Experiment 1 and 2)
Sensory perception threshold
Pain perception threshold
Test MEP amplitudes (mV)
Absolute test MEP amplitudes
In Experiment 1, absolute test MEP amplitudes did not differ between FDI and ADM, or between the right and left sides (Table 1). MEP amplitudes were somewhat higher in FDI as compared to EDC and BB in Experiment 2, but this difference was not significant (one-way ANOVA with the factor MUSCLE). Also, there was no significant amplitude difference between individual muscles (paired samples t tests, Table 1).
Short-latency afferent inhibition
Hemispheric asymmetry of SAI (Experiment 1)
Level of inhibition
Somatotopy of SAI (Experiment 2)
Level of inhibition
In Experiment 1, significant SAI was present at ISIs from 25–50 ms in all muscles apart from right FDI where SAI was significant only at ISIs from 25–40 ms (Table 2; Fig. 1). In Experiment 2, SAI was significant at ISIs of 25, 30 and 40 ms in all muscles (Table 3; Fig. 2).
Experiment 1: Hemispheric asymmetry of SAI
Comparing SAI (normalised values) in FDI and ADM between both sides in a three-way repeated measures ANOVA, there was a significant effect of the factors SIDE (F(1,14)=7.2; P=0.02) and ISI (F(5,70)=5.56; P=0.003) but not of the factor MUSCLE. There was no significant interaction between any of the factors, i.e. the amount but not the time course of SAI was different between sides. In fact, mean SAI at ISIs of 25–50 ms was smaller on the left than on the right side both in FDI (t=−2.42; P=0.03) and ADM (t=−2.26; P=0.04) (Table 2; Fig. 1).
Experiment 2: somatotopy of SAI
SAI was present in each muscle at ISIs of 25, 30 and 40 ms (Table 3; Fig. 2). Comparing SAI (normalised values) between FDI, EDC and BB using two-way repeated measures ANOVA, there was no effect of MUSCLE, ISI or interaction between MUSCLE and ISI, indicating that the amount and time course of SAI did not differ between these muscles (Table 3; Fig. 2).
This study shows that SAI is more pronounced in the dominant left hemisphere of right-handed healthy subjects. In addition, our data do not support the notion that SAI is a focal phenomenon. Instead, electrical stimulation of the right index finger caused widespread inhibition of MEPs in hand (FDI and ADM), forearm (EDC) and upper arm (BB) muscles.
Hemispheric asymmetry of afferent inhibition
Although SAI was present in FDI and ADM bilaterally (at ISIs of 25–50 ms), it was more marked in the dominant left hemisphere in right-handed subjects.
Sailer et al. (2003) found no difference in SAI between the right and left hemispheres in right-handers. This is perhaps not surprising because in their study, there was no significant SAI at ISIs of 23 and 43 ms on either side. Afferent inhibition was present only at an ISI of 200 ms. However, they studied a group of healthy subjects with a mean age of 60 years and D3 instead of D2 was stimulated. Therefore, their results cannot be directly compared with the present experiment.
Previous studies have shown anatomical and functional differences between M1 of both hemispheres. These studies mainly focussed on asymmetries in the motor system, and not on interactions between the sensory and the motor systems. For instance, postmortem studies in humans indicate that the motor cortex in the dominant hemisphere shows a greater volume of neuropil, which could point to denser connectivity with other brain regions (Amunts et al. 1996). The fractional anisotropy in diffusion tensor MRI, a marker of white matter density, was shown to be higher in the dominant hemisphere underneath the pre-central gyrus, both in right and left handers (Buchel et al. 2004). Also, cortical representations of muscles and movements are larger in the dominant left hemisphere in right-handers (Volkmann et al. 1998; Triggs et al. 1999). In addition, using the Kujirai paired pulse paradigm that measures intracortical inhibition (SICI) and facilitation (SICF) (Kujirai et al. 1993), some studies implied that both SICI and SICF are stronger and their thresholds lower in the left than in the right hemisphere in right-handers (Civardi et al. 2000; Hammond et al. 2004). In contrast, Ilic et al. (2004) found SICI to be reduced in left M1 in right-handers. However, they used a modified Kujirai protocol where a range of non-optimal conditioning pulse intensities was tested.
SICI is strongly influenced by GABAA (Ziemann et al. 1996; Di Lazzaro et al. 2000; Ilic et al. 2002; Reis et al. 2002). GABA-related inhibitory tone is important for the fine tuning of movement-related neuronal activity which in turn determines the level of dexterity of complex finger movements (Keller 1993). Thus, it appears likely that hemispheric differences of inhibitory tone in M1 play a role in human handedness. The present study supports and extends this view by directly showing that, apart from structural- and functional-side differences in the motor system, there is also some asymmetry in the strength of interactions between the motor and the sensory systems. This asymmetry has a bias towards stronger connections in the dominant left hemisphere. Whether this is cause or consequence of handedness, i.e. results from more complex hand movements performed with the dominant hand, cannot be decided on the basis of the present experiments.
As we did not include left-handed subjects in this study, no conclusions can be drawn with regard to differences between left- and right-handedness. In previous studies on handedness, less asymmetry was found in left-handed as compared to right-handed subjects (Netz et al. 1995; Amunts et al. 1996; Volkmann et al. 1998; Civardi et al. 2000; Ilic et al. 2004). The reason for this difference could be the fact that left-handers are often forced to develop bimanuality, which would level out hemispheric asymmetries.
Somatotopy of afferent inhibition
Following electrical stimulation of the right index finger, SAI was present in two hand (FDI, ADM) muscles, a forearm (EDC) and also in the BB muscle of the right arm. In fact, the magnitude of SAI did not differ between these muscles.
The observation that SAI is not focal but rather widespread following D2 stimulation is in keeping with current views of motor organisation. There is good evidence that movements rather than muscles are represented in M1 (Beisteiner et al. 2001; Schieber 2001; Dechent and Frahm 2003). Another concept was proposed by Graziano (2002) who found that stimulation at one point in the motor cortex of primates evoked a movement to a specific end posture, regardless of the starting position. Muscle-specific sensorimotor integration would distort rather than support motor programmes and actions that are generated within the cerebral cortex. SAI is probably overlapping, because skilled hand movements require simultaneous integration of multiple sensory inputs onto complex motor patterns involving multiple muscles.
In contrast to our results, previous studies suggested that contiguous but not non-contiguous finger stimulation inhibited MEPs in the recorded muscle(s), implying that there is a rather strict somatotopic organisation of SAI (Manganotti et al. 1997; Classen et al. 2000; Tamburin et al. 2001; Tamburin et al. 2002, 2003a, b).
The apparent contradiction between theses studies and the experiments presented here may be explained by methodological differences, i.e. the site and intensity of electrical stimulation, the number and type of recorded muscles, the number of ISIs tested and the number of investigated subjects.
For instance, Classen et al. (2000) found SAI at some, but not at other ISIs in the abductor pollicis brevis and ADM when stimulating the thumb (D1) or D5, respectively, at two times the SPT. Following non-contiguous finger stimulation, there was no MEP inhibition in the respective muscle. The discrepancies between the work of Classen et al. (2000) and the present study could be explained by the lower intensity of the electrical pulse, the use of smaller, i.e. more focal stimulation electrodes, resulting in a smaller area of skin stimulation, and by the fact that functionally different muscles (thumb muscle vs. muscles acting on digits 2–5 in our experiment) were studied. The functional role of the thumb (e.g. object manipulation) sets this finger somewhat apart from digits 2–5. This in turn could lead to differential SAI induced by thumb stimulation as compared to stimulation of the other fingers, but would not necessarily lead to differential SAI in digits 2–5.
Also, Manganotti et al. (1997) reported that SAI could not be elicited in BB. However, they set the intensity of electrical D2 stimulation at four times the SPT. Given a mean SPT of 8 mA in their paper, intensity of electrical stimulation was in the order of 30 mA, i.e. significantly higher than in the present study, where a mean electrical stimulation of about 12 mA (3 × SPT) was used. In fact, the intensity of electrical stimulation in their study was also significantly higher than the mean pain perception threshold (18.6 mA) in the present study, suggesting that different neuronal pathways were tested in the Manganotti et al. (1997) study (see below).
Tamburin et al. investigated SAI in four different studies in healthy controls and stimulated at three times the SPT, and recorded MEPs from the ADM (2001, 2002, 2003a, b) and FDI muscle (Tamburin et al. 2002). In their first study, where SPTs were 1.8 mA at D5 and 2.1 mA at D2, electrical pulses set at three times the SPT (i.e. absolute intensities between 5.4 and 6.3 mA) induced SAI in contiguous but not in non-contiguous muscles, whereas electrical pulses with an intensity of five times the SPT (i.e. absolute intensities between 9 and 10.5 mA) caused SAI both in contiguous and non-contiguous muscles (Tamburin et al. 2001). However, the strength of SAI was not directly compared between muscles in this study, i.e. no ANOVA with the factor “Muscle” was carried out.
In a later study, where SAI was tested in patients with cerebellar syndromes and compared with healthy controls, SPT were 3.9 in patients and 3.5 in healthy subjects (Tamburin et al. 2003a). Again, intensities of conditioning electrical pulses of three times the SPT were used in this study, i.e. absolute intensities between 10.5 and 11.7, which is identical to the intensities used in the present experiment. Although using higher intensities of the conditioning electrical pulse than in their first study, they confirmed that conditioning digital stimulation applied to D5 produced SAI at ISIs from 20 to 50 ms in ADM of healthy subjects, whereas stimulation of D2 did not (Tamburin et al. 2003a). Again, no direct comparison of SAI between muscles was performed. Finally, in a recent study where SAI was tested in patients with Parkinson’s disease and a control group and stimulation intensities of about 10 mA were used, inhibition was found in ADM in response to D2 stimulation at the ISIs of 20–50 ms in healthy subjects (Tamburin et al. 2003b).
Thus, our finding that painless conditioning digital electrical pulses with intensities at about 10 mA or so produce widespread SAI in neighbouring muscles is in fact supported by two studies by Tamburin and co-workers (2001, 2003b). Additionally, a recent study of Ridding et al. (2005) investigating the somatotopic effect of SAI following D2 and D5 stimulation did not prove a somatotopical effect of electrical conditioning on SICI but not on SICF or unconditioned test pulses in three different hand muscles, supporting the results of our study.
Functional significance and circuitry of SAI
The functional significance of SAI is currently unclear. Interestingly, natural stimulation of muscle, joints and cutaneous receptors in the hand and forearm by passive rotation and muscle stretch increases rather than decreases the excitability of projections to the stretched muscle to some 30 ms after the onset of the movement (Day et al. 1991). In contrast, when these reflexes are elicited electrically, inhibition of the corresponding motor response prevails, as shown in the present work and previous studies (Maertens de Noordhout et al. 1992; Palmer and Ashby 1992; Tokimura et al. 2000; Tamburin et al. 2001). A possible explanation is that electrical stimulation of peripheral afferents has mixed effects on cortical excitation with inhibition of some circuits and excitation of others, whereas more natural input induced by joint movements or muscle stretch probably preferentially cause net excitation. When stimulating at much higher intensities than in our study, withdrawal reflexes can be observed. Floeter et al. (1998) investigated withdrawal reflexes in the upper extremity after applying electrical stimuli at high intensities of four to six times the SPT to D2. They observed an increase in EMG activity in proximal arm muscles 70–100 ms after the electrical stimulus. The typical movement consisted of a flexion of the elbow and an extension of the wrist. Combined with the cutaneous (electrically induced) silent period of ongoing EMG activity in hand muscles (occurring at about the same latency), they posed a protective mechanism of opening and withdrawing the fingers when they are strongly stimulated. However, most studies of SAI did not stimulate at such high intensities. Nevertheless, SAI might reflect part of the reflex mechanism proposed by Floeter et al., i.e. the inhibition of adjacent hand and forearm muscles leading to reflexive loosening of the grip when the fingers are stimulated. This, however, would not explain SAI in the BB muscle where one would expect excitatory rather than inhibitory phenomena following electrical finger stimulation.
There is some controversy concerning the neuronal level at which SAI takes place. Some authors suggested that SAI is mediated via subcortical projections (Classen et al. 2000; Tamburin et al. 2001). However, comparison of TMS with Transcranial Electrical Stimulation (TES) in other studies showed that peripheral electrical pulses reduced the size of MEPs elicited with TMS but not, or much less, those following TES at intervals between 20 and 30 ms indicating that the suppression at these intervals is intracortical in nature (Maertens de Noordhout et al. 1992; Tokimura et al. 2000). Moreover, Tokimura et al. (2000) recorded corticospinal volleys in patients with implanted electrodes in the cervical epidural space and showed that indirect waves (I2 and I3), that are of cortical origin, were smaller when the magnetic stimulus was given at appropriate ISI after the conditioning peripheral electrical pulse. This argues strongly in favour of a transcortical route of SAI.
In view of the broad range of ISIs (25–50 ms) at which MEP suppression occurred in our study, a number of different pathways may be involved in mediating SAI. Our finding of a body-part rather than a muscle-specific somatotopy is consistent with a transcortical route, given the nature of projections from S1 to M1. A subcortical relay involving the thalamus or spinal structures could also be involved, although one would then perhaps expect an even broader somatotopical organisation. Also, spinal inhibition via activation of nociceptive A-delta fibres could play a role. However, electrical stimulation used here was below the pain perception threshold, which renders this possibility unlikely.
In right-handed healthy subjects, there is a side difference in the strength of SAI with a bias towards stronger sensorimotor connections in the dominant left hemisphere. This could represent another aspect of the functional lateralisation underlying handedness in humans. SAI following D2 stimulation is not a focal phenomenon but can be induced in hand, forearm and upper arm muscles.
RCG Helmich was sponsored by De Nederlandse Vereniging voor Dystonie Patiënten, De Hersenstichting Nederland, De Fundatie van de Vrijvrouwe van Renswoude and Stichting Nijmeegs Universiteits Fonds (SNUF). A. Münchau and H.R. Siebner were supported by the Volkswagenstiftung and A. Münchau also by the Forschungsförderungs-Fond of the Hamburg University Hospital. We wish to thank the reviewers of this paper for their thoughtful and constructive criticism. Experiment 2 was redesigned on the basis of their suggestions. We also thank Melanie Jonas for statistical advice.