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Journal of Physiology (2002), 544.2, pp. 631-640
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.22.024091
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ABSTRACT |
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Normal coordinated movement requires that the activity of antagonistic motoneurones may be depressed at appropriate times during the movement. Both glycinergic and GABAergic inhibitory mechanisms participate in this control. Patients with the major form of hyperekplexia (hereditary startle disease) have impaired inhibition of spinal motoneurones from local glycinergic interneurones and represent an ideal opportunity for studying the role of glycinergic inhibition in the control of antagonistic muscles. In the present study we investigated whether impaired glycinergic inhibition affects the corticospinal control of antagonistic spinal motoneurones in 10 patients with hyperekplexia and whether there are mechanisms that may compensate for the lack of glycinergic inhibition. In healthy subjects transcranial magnetic stimulation (TMS) produced a short-latency inhibition of the soleus H-reflex at rest and during tonic dorsiflexion. This inhibition, which has been shown to be mediated by spinal (glycinergic) inhibitory interneurones, was absent in all four patients in whom this experiment was performed. This confirms that glycinergic transmission is impaired in the patients. During voluntary dorsiflexion subthreshold TMS produced a depression of the ongoing EMG activity in the tibialis anterior (TA) muscle in both healthy subjects and all of the six tested patients. This is consistent with the idea that this EMG depression is caused by activation of cortical (GABAergic) inhibitory interneurones. Cross-correlation analysis revealed normal short-term synchronization of TA motor units accompanied by coherence in the 8-12 Hz and 18-35 Hz frequency bands in the 10 patients. As in healthy subjects, 8-12 Hz coherence accompanied by decreased tendency to discharge synchronously (de-synchronization) was found in recordings from the antagonistic TA and soleus muscles in 2 of the 10 patients. This suggests that glycinergic inhibition is not responsible for de-synchronization of antagonistic motor units, but that other GABAergic-inhibitory mechanisms must be involved. We propose that such mechanisms may compensate for the lack of glycinergic reciprocal inhibition in the hyperekplectic patients and explain why voluntary movements are not more severely affected.
(Received 8 May 2002; accepted after revision 1 August 2002; first published online 23 August 2002)
Corresponding author J. B. Nielsen: Division of Neurophysiology, Department of Medical Physiology, The Panum Institute, Copenhagen University, Blegdamsvej 3, 2200 Copenhagen N., Denmark. Email: J.B.Nielsen{at}mfi.ku.dk
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INTRODUCTION |
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Inhibition of antagonistic muscles during activation of agonists is essential for performing coordinated, smooth movements. One important mechanism to achieve this depression is disynaptic reciprocal inhibition, mediated by glycinergic Ia interneurones in the spinal cord (for review see Crone & Nielsen, 1994). An important input to these interneurones comes from Ia afferents and the corticospinal tract (Hultborn, 1972; Jankowska et al. 1976; Nielsen et al. 1993). The Ia inhibitory interneurones ensure an optimal depression of activity in the antagonists (Tanaka, 1974; Day et al. 1984; Crone et al. 1987; Petersen et al. 1999), in so far as Ia inhibitory interneurones projecting to ankle plantarflexors become more active in relation to voluntary dorsiflexion (Tanaka, 1974; Crone et al. 1987; Petersen et al. 1999). This ensures that the activity of the ankle plantarflexors is depressed and that unwanted stretch reflex activity in the plantarflexors, which would oppose the dorsiflexion movement, is prevented. A substantial part of this regulation probably originates in the motor cortex itself (Jankowska et al. 1976; Nielsen et al. 1993).
Hyperekplexia is a neurological disease caused by a point mutation in the 
1 subunit of the glycine receptor (GLRA1 gene; Shiang et al. 1993, 1995; Tijssen et al. 1995; Milani et al. 1996; Elmslie et al. 1996) leaving the glycinergic inhibitory system deficient (Langosch et al. 1994). Stimulation of Ia afferents from ankle muscles failed to produce reciprocal inhibition in antagonistic muscles in patients with the major form of hyperekplexia (Crone et al. 2001).
In view of this well-known inhibitory deficiency of the glycinergic system in the major form of hyperekplexia, the disease provides a unique model to explore which processes are affected by glycinergic inhibition and which mechanisms may compensate for the absence of glycinergic reciprocal inhibition. Patients with hyperekplexia are surprisingly capable of performing voluntary movements and it therefore seems obvious that some other mechanisms must compensate for the lack of reciprocal inhibition. It was the purpose of the present study to use transcranial magnetic stimulation and cross-correlation techniques to investigate whether impaired glycinergic inhibition affects the corticospinal transmission to antagonistic muscles and whether there are mechanisms that may compensate for this impairment.
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METHODS |
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The experiments were carried out on hyperekplectic patients in Leiden and London and on healthy control subjects in Copenhagen. The same experimental equipment and data sampling/analysis hardware and software were used in all three centres.
Subjects
Ten patients with hereditary hyperekplexia were included in the study (age range 18-64 years). Genetic testing revealed a point mutation in the GLRA1 gene in all patients (Rees et al. 1994; Tijssen et al. 1995; Elmslie et al. 1996). Six of the patients belonged to the Dutch pedigree in Leiden (Tijssen et al. 1995), whereas the remaining four patients belonged to two different English pedigrees (Rees et al. 1994; Elmslie et al. 1996). Three patients did not receive medication, while seven patients received oral clonazepam (GABA agonist) treatment. One patient in addition received oral phenobarbital treatment. All patients experienced frequent (daily-weekly) startle reactions evoked by unexpected auditory, tactile and in some cases visual stimuli. All patients had experienced falls following the startle reactions with many instances of subsequent physical damage (concussion, fractures, facial injuries). The six patients from the Dutch pedigree also participated in the study by Crone et al. (2001) and thus had physiologically verified absence of glycinergic reciprocal inhibition between antagonistic ankle muscles.
Control experiments were performed in 25 healthy control subjects (aged 20-37 years) with the same experimental protocol.
All patients and healthy control subjects gave informed consent to the experimental procedures, which were approved by the local ethics committees in Copenhagen, Leiden and London. All procedures conformed with the Declaration of Helsinki.
General experimental arrangement
The subjects were seated in an armchair with the examined leg semiflexed in the hip (120 deg), the knee flexed to 160 deg and the ankle in 110 deg plantarflexion. The foot was attached to a foot plate. Surface electrodes were used for both stimulation and recording EMG (electromyographic) activity. In the beginning of each experiment the maximal voluntary dorsi- or plantarflexion torque that the subject could keep for 5 s was recorded.
Bipolar surface EMG recordings (Ag-AgCl electrodes; 1 cm2 recording area, 2 cm between poles) were made from two sites over the tibialis anterior (TA) muscle at a distance of at least 10 cm from each other, as well as from the soleus muscle. The signals were amplified (
5000-10 000), filtered (25-1000 Hz) and stored as waveforms on a computer for later analysis. Raw analog data with the high-pass filters set to 1 Hz were also stored for analysis of coherence and cross-correlation (see below).
The following three procedures were carried out: (1) recording of EMG activity during dorsiflexion, plantarflexion and co-contraction of plantar- and dorsiflexors for cross-correlation and coherence analysis. All hyperekplectic subjects participated in this part of the study. Control experiments were performed in 23 healthy subjects; (2) recording of the motor evoked potential (MEP) and silent period in the TA EMG following transcranial magnetic stimulation (TMS) during tonic dorsiflexion. This experiment could only be performed in six hyperekplectic patients. Control experiments were performed in 25 healthy subjects; (3) conditioning of the soleus H-reflex by TMS at rest and during tonic dorsiflexion. This experiment was only performed in four of the hyperekplectic patients. Control experiments were performed in 25 healthy subjects.
Coherence analysis and cross-intensity function. The subjects performed three different levels of dorsiflexion and co-contraction corresponding to weak (below 5 % of maximal voluntary effort), medium (10-15 % of maximal voluntary effort) and strong contraction (25-30 % of maximal voluntary effort). It was ensured that the same level of EMG activity was recorded from the TA muscle during co-contraction and dorsiflexion. Each recording lasted 120 s. Coherence and the cross-intensity function of pair-wise recordings (from the two TA electrodes or from the most proximal TA electrode and the soleus electrode) were calculated using the procedures described by Halliday et al. (1995). This analysis was based on the raw analog data signals with high-pass filters set at 1 Hz. The sampling rate was 2000 Hz. The presence of synchronization or de-synchronization effects were determined by setting 95 % confidence intervals in the cross-intensity function. The duration of significant effects was measured as the interval in which the cross-intensity function was above or below the line of significance.
Transcranial magnetic stimulation (TMS). Transcranial magnetic stimulation was applied using a figure-of-eight coil placed over the leg area of the right motor cortex. The stimulator was a MagStim 200 (Magstim Company Ltd, Dyfed, UK). At the beginning of the experiments the stimulating coil was moved in 0.5 cm steps to find the site at which MEPs were elicited in the TA muscle at the lowest intensity of stimulation during weak ankle dorsiflexion. In general the optimal position was 1-2 cm lateral to the vertex.
Series of 30 magnetic stimuli at different intensities were applied while the subject maintained a weak dorsiflexion. The stimuli were varied from well below the threshold of the MEP to around 1.2 MEP threshold. For each intensity of stimulation 30 sweeps of rectified TA EMG were averaged for a period from 50 ms before to 150 ms after the stimulus.
Conditioning of the soleus H-reflex by TMS. The soleus H-reflex was evoked by stimulating the tibial nerve through a monopolar stimulating electrode (1 ms rectangular pulse). The reflex responses were measured as the peak-to-peak amplitude of the non-rectified reflex. The reflexes were recorded with disc electrodes (silver-silver chloride electrodes; 1 cm2 recording area; 2 cm interpole distance) placed over the soleus muscle. The H-reflex was conditioned by TMS of the motor cortex (see above). Time courses of the effect of TMS on the H-reflex were constructed at rest and during tonic dorsiflexion (corresponding to around 5 % of maximal voluntary dorsiflexion effort). Conditioning-test intervals were varied from -5 ms to +15 ms (negative conditioning intervals designate that the test stimulation evoking the reflex was applied before TMS). The intensity of TMS was initially adjusted to be around 0.95 MEP threshold in the soleus muscle during plantarflexion (corresponding to around 10-15 % of maximal voluntary plantarflexion effort). However, if TMS had no effect on the H-reflex either at rest or during dorsiflexion, the intensity was increased until either an inhibition or a short-latency facilitation was observed. The size of the control H-reflex was adjusted to 20-25 % of the maximal motor response (Mmax) both at rest and during dorsiflexion (Crone et al. 1990). Control and conditioned reflexes were randomly alternated at an interval of 4 s. Data were stored on a computer for later statistical analysis.
Data analysis
The mean and standard error of the mean were calculated for all measurements on line. Differences in the size of conditioned and control reflexes were tested using Student's t test. Differences in the population average of the reflexes were tested using an ANOVA test.
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RESULTS |
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Coupling within tibialis anterior (TA)
Figure 1 shows data from a healthy subject (Fig. 1A-C) and a patient with hyperekplexia (Fig. 1D-F). As described previously (Datta & Stephens, 1990; Farmer et al. 1993; Nielsen & Kagamihara, 1994), a central peak of synchrony was observed for the EMG activity recorded from the two TA electrodes during dorsiflexion in the healthy subject (Fig. 1C). As described for several different muscles (Farmer et al. 1993), this correlation peak was accompanied by significant coherence between the two signals in the frequency domain (Fig. 1B). Peaks of coherence were seen around 10 Hz and around 25 Hz, as previously described (Farmer et al. 1993). As seen from Fig. 1D-F, a central peak of synchronization and coherence around 25 Hz was also observed in the hyperekplectic patient. In this particular patient there was no coherence around 10 Hz.
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Figure 1. Synchronization of TA motor unit activity in a healthy subject (A-C) and in a hyperekplectic patient (D-F) Samples of EMG activity recorded by two surface electrodes over the TA muscle are shown in A and D for the healthy subject and the hyperekplectic patient, respectively. The coherence and cross-intensity function calculated for the two signals are shown in B and C for the healthy subject and in E and F for the hyperekplectic patient. Horizontal lines are 95 % confidence intervals. The total sampling time was 120 s for each of the recordings. | ||
In the time domain a central peak was seen in all healthy subjects and hyperekplectic patients (Table 1). The duration and amount of synchronization in both healthy subjects and patients corresponded to that reported previously (Nielsen et al. 1999; Hansen et al. 2002). Coherence was seen in the 18-35 Hz frequency band in all healthy subjects and all patients. Coherence around 10 Hz was seen in about 60 % of both healthy subjects and hyperekplectic patients. The absence of glycinergic inhibition thus does not seem to influence synchronization and coherence within a muscle.
Coupling between TA and soleus
Figure 2 shows data obtained during co-contraction of dorsiflexors and plantarflexors from two different healthy subjects (Fig. 2A-C and D-F respectively) and from a hyperekplectic patient (Fig. 2G-I). In one of the healthy subjects a central synchronization peak was observed between the TA and soleus EMG activity (Fig. 2C), which was accompanied by coherence in the 15-35 Hz frequency band (Fig. 2B). In the other healthy subject a central trough was observed (Fig. 2F). As seen from Fig. 2E, this 'de-synchronization' was accompanied by significant coherence in the 8-12 Hz frequency band. The hyperekplectic patient was similar to the second of these healthy subjects by showing a central trough in the cross-intensity function (Fig. 2I) accompanied by coherence in the 8-12 Hz frequency band.
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Figure 2. Coupling of motor unit activity recorded from the TA and soleus muscles in two healthy subjects (A-C and D-F, respectively) and in a hyperekplectic patient (G-I) A, D and G show samples of TA and soleus EMG activity from the two healthy subjects (A and D) and the hyperekplectic patient (G). B, E and H show the coherence between the two signals, whereas C, F and I show the cross-intensity function. Horizontal lines are 95 % confidence limits. The total sampling time was 120 s for each of the recordings. | ||
It has been reported by Hansen et al. (2002) that troughs in the cross-intensity function accompanied by 8-12 Hz coherence are seen in around 30 % of healthy subjects. Four of the hyperekplectic patients also had coherence in the 8-12 Hz frequency band and in two of them (including the one used for the illustration in Fig. 2G-I) de-synchronization was observed. Since both of these subjects were shown by Crone et al. (2001) not to have any glycinergic reciprocal inhibition between the antagonistic muscles, this suggests that glycinergic inhibition is not responsible for de-synchronization.
Central peaks and coherence in the 15-35 Hz frequency bands were seen in an equal number of healthy subjects and hyperekplectic patients (around 30 %) and were thus, as for motor units within the TA muscle, evidently not affected by deficient glycinergic inhibition.
Effect of TMS on TA EMG activity
Transcranial magnetic stimulation evoked MEPs in the TA muscle in all healthy subjects and in all of the six hyperekplectic patients in whom TMS was applied. Figure 3 shows one example from a hyperekplectic patient. The MEP threshold in this subject was around 39-40 % of the maximal stimulator output (Fig. 3A). It should be noticed that even this small MEP was followed by a period of decreased EMG activity (silent period). On decreasing the intensity of TMS (Fig. 3B) a depression of the EMG was observed with a latency around 5-6 ms longer than the latency of the MEP. This depression had a threshold around 36-37 % of the maximal stimulator output (Fig. 3C). A similar depression was observed in all six hyperekplectic patients and in all healthy subjects. The average duration of the EMG depression was 11 ±3 ms in the healthy subjects and 12 ± 4 ms in the hyperekplectic patients. The EMG was depressed by 35 ± 6 % in the healthy subjects and 39 ± 8 % in the hyperekplectic patients. The existence of this depression in subjects with documented impairment of glycinergic transmission suggests that it is not caused by glycinergic inhibition.
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Figure 3. The effect of TMS on TA EMG activity during voluntary dorsiflexion in a hyperekplectic patient Transcranial magnetic stimulation was applied at different intensities (36, 38 and 40 % of maximal stimulator output), while the subject performed a weak voluntary dorsiflexion (corresponding to approximately 10 % of the maximal voluntary dorsiflexion effort). The EMG activity was filtered, rectified and averaged using the magnetic stimulus as a trigger. A window from 50 ms before until 150 ms after the stimulus was used for the average. Thirty sweeps were averaged for each stimulation intensity. The horizontal dotted line gives the mean EMG level. | ||
Effect of TMS on the soleus H-reflex
In healthy subjects TMS at intensities below the threshold of an MEP in the soleus muscle elicits a short-latency inhibition of the soleus H-reflex at rest and during dorsiflexion (Iles & Pisini, 1992; Nielsen et al. 1993). One example from a healthy subject performing a tonic dorsiflexion is shown in Fig. 4. At an intensity of 35 % of the maximal stimulator output TMS had no effect on the H-reflex (Fig. 4A). However, on increasing the intensity slightly (to 38 % of maximal stimulator output) a clear inhibition was seen at a conditioning-test interval of -2 ms and lasting for 2 ms (Fig. 4B). In this subject the initial inhibition was followed by a second inhibition at an interval of 2 ms and finally a facilitation at conditioning-test intervals longer than 5 ms. When increasing the stimulation intensity still further both the facilitation and the inhibition increased. As shown by Iles & Pisini (1992) and Nielsen et al. (1993), Ia reciprocal interneurones may be involved in the generation of both periods of inhibition. The occurrence of two periods of inhibition is probably explained by multiple descending volleys evoked by TMS (Day et al. 1987), whereas the late facilitation may be caused by transmission in an indirect (polysynaptic) pathway to the soleus motoneurones (Nielsen & Petersen, 1995). The short-latency inhibition was observed in all 25 healthy subjects when the intensity of stimulation was adjusted to be just below the soleus MEP threshold during plantarflexion of medium strength. The amount of inhibition in the 25 subjects ranged between 20 and 50 % (i.e. the conditioned reflex was depressed to between 50 and 80 % of the control H-reflex size).
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Figure 4. Time course of the effect of TMS on the soleus H-reflex in a healthy subject The subject performed a voluntary dorsiflexion corresponding to approximately 10 % of the maximal voluntary dorsflexion effort. Control H-reflexes were randomly alternated with H-reflexes conditioned by TMS at conditioning-test intervals from -5 ms to +5 ms (the negative conditioning-test intervals designate that the test stimulus to the tibial nerve was applied before the conditioning TMS). The size of the control H-reflex was maintained around 15-20 % of the maximal motor response (Mmax) throughout the experiment. In A the intensity of TMS was 35 % of the maximal stimulator output, whereas it was 38 % and 40 % in B and C, respectively. The MEP threshold in the soleus muscle during voluntary plantarflexion was around 45 %. The abscissa in the graphs is the conditioning-test interval in milliseconds, whereas the ordinate is the size of the conditioned H-reflex as a percentage of the control H-reflex size. | ||
In none of the four investigated hyperekplectic patients was it possible to demonstrate any sign of a similar short-latency inhibition. Figure 5 shows one example. At an intensity of 37 % of the maximal stimulator output, TMS had no effect on the soleus H-reflex (Fig. 5A). On increasing the stimulation intensity only a facilitation at a conditioning-test interval of 0 ms without any sign of inhibition was observed (Fig. 5B). Increasing the stimulation intensity further made the facilitation change latency to -3 ms, still without any sign of inhibition (Fig. 5C). In none of the patients was the conditioned reflex depressed to less than 90 % of the control H-reflex at any conditioning-test interval. Three of the patients in whom the effect of TMS on the soleus H-reflex was investigated also participated in the experiment regarding suppression of the TA EMG activity by TMS described above.
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Figure 5. Time course of the effect of TMS on the soleus H-reflex in a patient with hyperekplexia Same legend as in Fig. 4 except that the intensity of TMS was 37, 39 and 41 % of maximal stimulator output in A, B and C, respectively. | ||
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DISCUSSION |
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Synchronization of TA motor units
Renshaw cells, which receive collaterals from motoneurones and project back to the motoneurones, have been shown to release both GABA and glycine (Schneider & Fyffe, 1992). It has been suggested for some time that one function of Renshaw cells may be to influence synchronization in a motoneuronal pool (Windhorst, 1996). Some evidence in support of this has recently been obtained in human subjects (Vedel et al. 2000). We had therefore expected that the central peak of synchrony between TA motor units would be different in the hyperekplectic patients as compared with healthy subjects, but this was not the case. One reason for this may be that release of GABA is sufficient to ensure normal function of the Renshaw cells in the patients. In the study by Floeter et al. (1996), evidence suggesting intact Renshaw-mediated inhibition in hyperekplectic patients was also presented.
De-synchronization of antagonistic motor units
The tendency of some antagonistic motor units not to discharge at the same time (de-synchronization) has been suggested to be caused by reciprocal (glycinergic) inhibition between the antagonistic muscles (Gibbs et al. 1994; Nielsen & Kagamihara, 1994). Therefore, we did not expect to find de-synchronization between antagonistic muscles in the hyperekplectic patients, but evidence for this was found in two patients. This corresponds to the proportion of healthy subjects in whom this is seen (Table 2). Since these patients had a genetically confirmed mutation of the glycinergic receptor and physiologically determined impaired reciprocal inhibition (Crone et al. 2001; Fig. 4, present study), it can be ruled out that de-synchronization is caused by the classical glycinergic reciprocal inhibition between the antagonistic motoneurones. A more likely explanation of the de-synchronization is that it is caused by out-of-phase discharges of inputs to the antagonistic motoneurones. Indeed, Wessberg & Vallbo (1996) have already suggested that slow finger movements are controlled by bursts of agonist activity at 10 Hz, which may sometimes be alternating with activity in the antagonist muscles. It thus seems likely that our finding of 8-12 Hz activity and de-synchronization is caused by similar out-of-phase discharges of inputs to the antagonistic motoneurones. However, the origin of this input is unclear. Coupling between EEG and EMG is only rarely seen in the 8-12 Hz frequency band (Conway et al. 1995; see, however, Raethjen et al. 2002), but it remains a possibility that out-of-phase discharges in antagonistic corticospinal pathways to the antagonistic muscles play a role. One attractive speculation is that cortical (GABAergic) inhibitory mechanisms may be responsible for bringing the activity of the antagonistic pathways out of phase and thus explain the de-synchronization observed in the EMG recordings from the antagonistic muscles.
Reciprocal inhibition mediated by the corticospinal tract
Iles & Pisini (1992) and Nielsen et al. (1993) demonstrated that TMS facilitates the reciprocal Ia inhibition of soleus motoneurones, which is evoked by stimulation of the antagonistic peroneal nerve. This occurred at an interval after TMS corresponding to that of short-latency inhibition and it was therefore suggested that this inhibition can at least partly be explained by corticospinal excitation of the Ia inhibitory interneurones. Nielsen et al. (1993) also provided evidence that the inhibition could be explained by activation of corticospinal cells projecting monosynaptically to tibialis anterior motoneurones and through collaterals to the Ia inhibitory interneurones to soleus motoneurones.
Patients with the major form of hyperekplexia have already been shown to have deficient transmission of reciprocal Ia inhibition, when evoked by stimulation of antagonist Ia afferents (Crone et al. 2001). The observation in the present paper that patients with the major form of hyperekplexia lack short-latency inhibition of the soleus H-reflex evoked by TMS is consistent with these previous findings and suggests that the ability to inhibit antagonist motoneurones via the corticospinal tract is deficient, and that this type of inhibition is mediated via glycinergic mechanisms.
In healthy subjects the parallel control of corresponding spinal motoneurones and Ia inhibitory interneurones exerted by the corticospinal tract and other supraspinal pathways, is thought to be responsible for the depression of antagonist motoneurones during voluntary movement which ensures that the movement can be performed without untoward activity being elicited in the antagonist muscles (Crone et al. 1987). A similar control has also been found in relation to alternating activity in ankle extensors and flexors during walking (Petersen et al. 1999). Without intact glycinergic inhibition the hyperekplectic patients may not be able to fully exert this parallel control and this may explain some of the symptoms that the patients experience, such as muscle stiffness in the legs (Crone et al. 2001) and the clinical sign of lively/hyperactive Achilles reflexes. However, voluntary movements are surprisingly unaffected in these patients and co-contraction of antagonistic muscles is usually not seen (Crone et al. 2001). This suggests that there are mechanisms that can compensate for the lack of reciprocal inhibition
Depression of EMG by TMS
The depression of EMG activity by subthreshold TMS was present in the hyperekplectic patients, which is consistent with the hypothesis that it is caused by cortical GABAergic inhibition (Davey et al. 1994). In cats, there is evidence that reciprocal connections controlling antagonistic muscles are located at a cortical level (Capaday et al. 1998). Data from human subjects also suggest that afferents from one muscle may inhibit the corticospinal pathways to its antagonists (Bertolasi et al. 1998). On the basis of the present findings it seems that this cortical inhibition is intact in the hyperekplectic patients. These cortical influences may explain how the patients are capable of activating agonistic muscles without accompanying co-contraction of antagonists, despite the absence of functional reciprocal inhibition at a spinal level. Perhaps, too, the benzodiazepine clonazepam is effective in hyperekplexia by further increasing compensatory activity in these cortical GABAergic inhibitory mechanisms. Finally, the preserved cortical (reciprocal) inhibition may also explain the presence of de-synchronization between the antagonistic muscles, as already mentioned.
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Acknowledgements
This work was kindly funded by grants from the Danish Health Research Council, the Danish Society of Multiple Sclerosis, the Henry Hansen Foundation and the Desiree and Niels Yde Foundation.
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